Cyclic peptide treatment methods

Abstract

The present disclosure generally relates the cyclic peptide cyclo-((2-Nal)-Leu-Ser-(2- Nal)-Arg) and its use in pharmaceutical compositions, in particular its use in methods of treating or preventing cancer and methods of reducing the level of circulating hGIIA in a subject. The present disclosure also generally relates to methods of treating or preventing hGIIA-dependent diseases, such as cancer, with an agent that inhibits a non-catalytic activity of hGIIA.

Description

[0001] Cyclic peptide treatment methods Cross-reference to related applications The present application claims priority from Australian Provisional Patent Application Nos. 2023902841 and 2023902842 filed on 4 September 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field The present disclosure generally relates the cyclic peptide cyclo-((2-Nal)-Leu-Ser-(2- Nal)-Arg) and its use in pharmaceutical compositions, in particular its use in methods of treating or preventing cancer and methods of reducing the level of circulating hGIIA in a subject. The present disclosure also generally relates to methods of treating or preventing hGIIA-dependent diseases, such as cancer, with an agent that inhibits a non-catalytic activity of hGIIA. Background hGIIA’s primary physiological role is in host defence, with its strong bactericidal action driven by its phospholipase enzyme activity that cleaves phospholipids at the sn-2 position27. However, it is also a known amplifier of cytokine-mediated inflammation in the innate immuneresponse, being upregulated in multiple inflammatory disorders and cancers5. Therefore hGIIAinhibition is an attractive target for the treatment of inflammatory diseases – including cancer. This has led to the development of inhibitors of hGIIA enzymatic activity, such as Varespladib®, which entered clinical trials for the treatment of sepsis, rheumatoid arthritis, asthma and cardiovascular disease4,16. Despite the initial promise of such inhibitors of hGIIA enzymatic activity, there are no clinically approved specific hGIIA inhibitors largely due to safety concerns4,16. Accordingly, there remains a need for alternative hGIIA inhibitors, particularly those that are safe and tolerable. The hallmarks of cancer include six core biological capabilities that tumour cells acquire and enable development of traits such as sustained growth and replicative immortality. In addition to these core capabilities it is increasingly recognised that inflammation is an enabling characteristic, supporting other cancer hallmarks1. Immune and inflammatory cells are frequently present within tumours, and immune cells can affect cancer cells through production of cytokines, growth factors and prostaglandins. The eicosanoid pathway is a key driver of inflammation and cancer2. Phospholipase A2 (PLA2) enzymes cleave membrane phospholipids to release free fatty acids and lysophospholipids, some of which can be metabolised into eicosanoid signalling molecules including prostaglandin E2 (PGE2). These mediators can in turn regulate important cell functions including proliferation, survival, differentiation and motility3. sPLA2-IIA (human Group IIA PLA2), also known as hGIIA is a secreted human PLA2 enzyme that acts both as a catalytic enzyme releasing arachidonic acid, and also amplifies eicosanoid production via an independent (non-catalytic) signalling pathway. The anti-inflammatory cyclic peptide c2 (also known as FLM-c2) (cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg)) (Figure 1A) was developed to inhibit sPLA2- IIA4. Research on synovial inflammation has shown that in rheumatoid fibroblast-like synoviocytes, non-catalytic signalling is associated with rapid internalisation of sPLA2-IIA and co-localisation with vimentin filaments in the cytoplasm5. Inhibitors of sPLA2-IIA were studied and in the presence of c2, exogenous sPLA2-IIA was taken up diffusely in the cytoplasm rather than colocalising with vimentin5. Increased sPLA2-IIA expression in prostate cancer tissue samples from patients has been shown to be inversely related to patient survival, and high serum sPLA2-IIA levels in prostate cancer patients are significantly associated with high Gleason score and advanced disease stage6,7. Given that, globally, cancer causes over 10 million deaths annually, there is a need to develop improved methods of treating cancer. Summary The present disclosure is based, in part, on the recognition that therapies to suppress the growth of sPLA2-IIA expressing cancer cells are required. The present disclosure provides peptides with anti-inflammatory and sPLA2-IIA inhibitory activity that are surprisingly orally available. The inventors have further shown that oral administration of these peptides is safe and tolerable in a range of preclinical animal models and human patients. The present disclosure is also based, in part, on the surprising discovery that therapies targeting the non-catalytic activity of hGIIA (sPLA2-IIa) are safe and effective. The present disclosure provides peptides that surprisingly inhibit the non-catalytic activity of hGIIA across a range of cells, including cancer cells. The inventors have further shown that oral administration of these peptides is safe and tolerable in a range of preclinical animal models and human patients. In particular, these peptides demonstrated no cardiotoxicity in these studies, which is in contrast to prior art hGIIA inhibitors that selectively target the catalytic activity of this enzyme. Accordingly, the present disclosure provides a method of treating or preventing a cancer in a subject, said method including the step of orally administering a therapeutically effective amount of cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof to the subject to thereby treat or prevent the cancer. In any of the methods disclosed herein, c2 or the analogue or derivative thereof may be orally administered at a dose of about 5 mg / day to about 1500 mg / day. In one example, c2 or the analogue or derivative thereof is orally administered at a dose of about 5 mg / day to about 100 mg / day. In any of the methods disclosed herein, c2 or the analogue or derivative thereof may be orally administered daily for a period of at least about 2 weeks. In one example, c2 or the analogue or derivative thereof may be orally administered daily for a period of at least about 6 weeks. The present disclosure also provides the use of cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof in the manufacture of a medicament for of treating or preventing a cancer in a subject, wherein the medicament is formulated for oral administration. The present disclosure also provides cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof for use in treating or preventing a cancer in a subject, wherein the c2 or an analogue or derivative thereof is formulated for oral administration. In any of the methods and uses disclosed herein, the subject may be receiving a further anti-cancer treatment. Any of the methods disclosed herein may include the further step of administering a further anti-cancer treatment to the subject. In any of the uses disclosed herein, the medicament may be formulated for administration with a further anti-cancer treatment. In any of the methods and uses disclosed herein, the further anti-cancer treatment may be selected from the group consisting of a chemotherapeutic agent, a radiation therapy, a molecularly targeted therapeutic agent and an immunotherapeutic agent. In any of the methods and uses disclosed herein, the cancer may be a prostate cancer. Also disclosed herein is a method of reducing a level of circulating hGIIA in a subject, said method including the step of orally administering an effective amount of c2 or an analogue or derivative thereof to the subject to thereby reduce the level of circulating hGIIA. In one example, the method further includes the step of determining the level of circulating hGIIA before and / or after administration of c2 or the analogue or derivative thereof to the subject. In one example, the level of circulating hGIIA in the subject is elevated prior to orally administering the effective amount of c2 or the analogue or derivative thereof. Also disclosed herein is a method of selecting a subject as being suitable for oral administration of c2, or an analogue or derivative thereof, said method including the step of determining a level of circulating hGIIA in the subject, wherein an elevated level of circulating hGIIA is indicative of the subject being suitable for oral administration of c2 or the analogue or derivative thereof. In one example, the method further includes the step of orally administering an effective amount of c2 or the analogue or derivative thereof to the subject if the level of circulating hGIIA in the subject is elevated. Also disclosed herein is a pharmaceutical composition comprising: c2, or an analogue or derivative thereof, in an amount of about 5 mg to about 1500 mg; and a cellulose derivative. In one example, the cellulose derivative may be microcrystalline cellulose. The pharmaceutical composition may be formulated as a capsule. In one example, the pharmaceutical composition may be formulated as a cellulose-based capsule. Also disclosed herein is a unit dosage form comprising c2, or an analogue or derivative thereof, in an amount of about 5 mg to about 1500 mg. In one example, in the pharmaceutical composition or unit dosage form disclosed herein, the c2 or the analogue or derivative thereof may be present in an amount of about 5 mg to about 100 mg. For example, the c2 or the analogue or derivative thereof may be present in an amount of about 5 mg, about 10 mg, about 20 mg, about 40 mg or about 60 mg. The pharmaceutical composition or the unit dosage form disclosed herein may be formulated for oral administration to a subject. In another aspect, the present disclosure provides a method of treating, preventing or ameliorating a hGIIA-dependent disease, disorder or condition in a human subject, said method including the step of administering a therapeutically effective amount of an agent that selectively inhibits a non-catalytic activity of hGIIA to the subject to thereby treat, prevent or ameliorate the hGIIA-dependent disease, disorder or condition. Suitably, the agent induces little or no cardiotoxicity in the subject. In some examples, the agent is orally administered to the subject. Suitably, the agent is administered at a dose of about 5 mg / day to about 1500 mg / day. In certain examples, the agent is administered at a dose of about 5 mg / day to about 100 mg / day. Suitably, the agent is administered daily for a period of at least about 2 weeks or at least about 6 weeks. According to certain examples, the hGIIA-dependent disease, disorder or condition is a cancer, such as a prostate cancer. Suitably, the agent is: (a) cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof; or (b) cFLSYR (cF) or an analogue or derivative thereof. For some examples of the present method, a level of circulating hGIIA in the subject is elevated prior to administering the agent. In a further aspect, the present disclosure provides a method of inhibiting a non-catalytic activity of hGIIA in a cancer cell, said method including the step of contacting the cancer cell with an effective amount of: (a) c2 or an analogue or derivative thereof; or (b) cF or an analogue or derivative thereof. In various examples, the cancer cell is a prostate cancer cell. In a related aspect, the present disclosure provides a method of identifying, designing or producing an hGIIA inhibitor that induces little or no drug-induced toxicity in a human subject, said method including the steps of: (a) contacting hGIIA with a candidate hGIIA inhibitor; and (b) determining whether the candidate hGIIA inhibitor inhibits a non-catalytic activity of hGIIA. Suitably, the method of the present aspect further includes the step of determining whether the candidate hGIIA inhibitor inhibits a catalytic activity of hGIIA. In some examples, the candidate hGIIA inhibitor is a cyclic peptide. More particularly, the candidate hGIIA inhibitor can be a derivative or variant of c2 or cF. For some examples, the present method further includes the step of isolating and / or purifying an agent that inhibits the non-catalytic activity of hGIIA. More particularly, the isolated and / or purified agent suitably does not inhibit or minimally inhibits the catalytic activity of hGIIA. The present method may further include the step of formulating the isolated and / or purified agent into a pharmaceutically acceptable formulation. More particularly, the present method may further include the step of sterilising the formulation. For some examples, the method further includes the step of filling the formulation into a container, such as a vial, an ampoule, a bag, a blister pack, a bottle, a cartridge, an injection needle, an injection syringe, a single dose container, a strip of multiple single dose containers, or a tube. In a final aspect, the present disclosure provides an agent for use in treating, preventing or ameliorating a hGIIA-dependent disease, disorder or condition in a human subject, obtained by the method of the third aspect. Brief description of the drawings The following figures form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these figures in combination with the detailed description of specific embodiments presented herein. Figure 1. Derived from the structure of hGIIA, cF and c2 are orally absorbed, cell permeable and non-toxic. (a) Structure of hGIIA showing disulfide bonds (yellow) and the location of the peptide sequence70FLSYK74(cyan), that was used for the design of pentapeptide cF and further modified to c2. (b) Plasma concentrations of tritiated cF (red) and c2 (blue) following sc (circles) or oral (squares) administration at 5 mg / kg to BALB / c mice (n = 4 per time point). Following sc administration, tissue concentrations of (c) cF and (d) c2 were determined in the liver (green) and kidney (red). Dashed lines indicate estimated background levels of tritium in tissues due to tissue blood content (10% of peak plasma concentration). (e-i) Following oral (po) administration of c2 at 100 mg / kg to male rats (n = 5 per group), levels of c2 were measured in (e) plasma, (f) kidney, (g) faeces, (h) urine and (i) liver at timepoints indicated via LCMS / MS. (j) Serum enzyme levels of PCa xenograft model mice in response to treatment with vehicle, cF (10 mg / kg) or c2 (10 mg / kg) 3 x weekly after 10 weeks (n = 4). (k) PCa cell lines LNCaP, PC-3 and DU145 cells were incubated with 100 µM c2 (green) for 24 hours with DAPI (blue). Figure 2. Oral administration of cF and c2 reduces tumour volume in androgen sensitive xenograft model of PCa. (a-c) Depict results for cF treatment studies, (d-g) depict c2 studies. For both, animals were sc injected with LNCaP-luc tumour cells (1 x 106cells). Mice with established tumours (> 65.5 mm3) were treated with either cF (2 mg / kg, po, daily, n = 13) compared to vehicle (n = 13) or c2 (0.1 mg / kg, po, thrice weekly, n = 7) compared to control vehicle (n = 8) by oral gavage. For cF studies, (a) tumour volume, (b) tumour weights and (c) PSA levels over 10 weeks, data are mean ^ SE. For c2 studies, (d) tumour volume over 8 weeks, (e) PSA levels and (f) luciferase signal of tumours. (g) representative IHC staining of tumours with H&E, Ki67, TUNEL, CD31, vimentin and hGIIA (scale bars 250 µm, inset 100 µm2). Figure 3. Oral administration of cF and c2 increases animal survival and tumour apoptosis in androgen-insensitive model of PCa. (a) Castrate model of PCa; median relative tumour volume of vehicle (n = 10) and cF (2 mg / kg, po, daily, n = 9) over 10 weeks. Androgen insensitive model of PCa; Animals injected sc with PC-3M-luc (1 x 106cells). Mice with established tumours (> 65.5 mm3) were treated with c2 (1 mg / kg, po, thrice weekly, n = 15) cF (2 mg / kg, po, daily, n = 15) or vehicle (n = 15) by oral gavage. (b) Median relative tumour volume, (c) survival graph of c2 and cF and (d) tumour volume of animals that survived over 8 weeks (c2 n = 4, cF n = 2). (e) representative IHC staining of tumours with H&E, TUNEL, vimentin and hGIIA (scale bar 250 µm, inset 100 µm2). (f) TUNEL staining of cells showing an increase in apoptotic cells with c2 treatment (n = 6) than control (n = 7). Figure 4. hGIIA follows both autocrine and paracrine pathways, promotes eicosanoid production via a catalysis-independent mechanism and is inhibited by c2 which blocks hGIIA binding to EGFR. (a) Prostate cancer cell lines LNCaP, PC-3 and DU145 and fibroblast-like synoviocyte cells RA57 were incubated with 200 ng / mL hGIIA / AF647 and imaged over 16 hours. (n = 3, 5 cells per replicate). (b) ) PC-3, LNCaP and DU145 cell lines incubated with hGIIA / AF647 (red) at 2 µg / mL with and without c2 (green) at 100 µM for 24 hours. (c) PGE2 production of PCa cell lines PC-3, LNCaP and DU145 in response to treatment with TNF at 10 ng / mL, hGIIA at 2 µg / mL, catalytically inactive hGIIA mutant H48Q at 2 µg / mL, or c2 at 50 µM for 16 hours (n = 3). (d) PC-3 lysate with p-cPLA2-α and cPLA2-α (e) Intracellular hGIIA / AF647 and Ca2+of LNCaP cells incubated with hGIIA / AF647 at 200 ng / mL for 24 hours (n = 3, 20 cells per replicate). (f) PC-3 cells were treated with and without c2 (100 µM) for two hours, then washed and incubated with hGIIA at 2 µg / mL for two hours. Lysate was incubated with hGIIA antibody and EGFR levels in lysate and Co-IP detected. Figure 5. hGIIA binds to and is trafficked by vimentin in prostate cancer cells. (a) Immunofluorescence images PCa cell lines LNCaP, PC-3 and DU145 cells with vimentin (green) hGIIA (red) and colocalization of vimentin and hGIIA (pink) (n < 30 cells per cell line). Projections of example cells generated in Imaris from Z-stack of PC-3 and LNCaP cells, with colocalization calculated using Costes et al. Biophys J. 86 (6):3993-4003 (2004) method shown in yellow. (b) Lifetime images (left) and phasor plot of fluorescence lifetime (middle) of LNCaP cells immunostained with primary conjugated antibody 4A1 / AF568 for hGIIA, and RV202 / AF488 for vimentin showing areas of FRET (right) (n = 3). (c) LNCaP cell lysate incubated with α-hGIIA overnight, with bands for hGIIA (14 kDa) and vimentin (57 kDa) detected. (d) Enzyme immuno-assay of hGIIA binding to coil 1 (red), coil 2 (green) and full length (blue) vimentin fragments. (e) Live cell imaging of PC-3 cell following transfection with EGFP-vimentin and incubation with hGIIA / AF568 (200 ng / mL) for 24 hours (left panel), followed by identification of hGIIA-positive vesicles as either vimentin positive (red, n = 405 vesicles) or vimentin negative (yellow, n = 123 vesicles) (middle panel). Dynamics were tracked over two minutes and mean speed calculated (right panel) with mean track speed and vesicle (spot) area calculated using Imaris. Figure 6. c2 blocks hGIIA interaction with vimentin in vitro, and hGIIA interaction with EGFR in vivo, modulating hGIIA trafficking and vesicle size. (a) in vitro enzyme immmuno- assay of hGIIA binding to coil 2 of vimentin in the presence of c2 (blue), hGIIA inhibitor LY31127 (red) and vimentin inhibitor Withaferin A (green). (b) Molecular docking studies identifying binding confirmation of c2 to coil 2 of vimentin. (c) PC-3 cells treated with DMSO at 1 hr or c2 (10 μM) for 1 hr or 24 hours. with hGIIA mean fluorescence intensity, hGIIA % area, vimentin mean fluorescence intensity vimentin % area and total cell area calculated (n = 3, > 15 cells per replicate, scale bars 50 μm, error bars min to max). (d) Live imaging with 63 xobjective of LNCaP, PC-3, DU145 and DU145 vimentin knockout cells incubated with 200ng / mL hGIIA / AF568 with either DMSO or c2 at 100 μM for 24 hours. Cells were live imaged for 3 minutes, with hGIIA dynamics tracked and analysed using Imaris 8.2. Spot tracks colour coded from 0 μm / s (blue) to 1.5 μm / s (red). Graphs show (e) track displacement, (f) track speed and (g) vesicle area (n = 3, 20 cells per replicate, scale bar is 10 μm). (h) Comparison of wtDU145 and DU145 vimentin knockout speed and (i) vesicle area in response to c2 treatment. (j) FACS analysis of PC-3, (k) LNCaP, (l) DU145 WT vs DU145 vimKO treated with either control (nothing), DMSO (0.5%), c2 100 μM for 72 hours stained with Annexin V-FITC and propidium iodide (PI), before FACS analysis. The Annexin V / PI data was measured on FL1-H versus FL2-H scatter plot using FlowJo™ v10.9 software (n = 3, 2-way ANOVA). Figure 7. Putative model of c2’s multimodal mechanism of action – inhibition of the hGIIA / EGFR interaction, reducing cPLA2-α activation, eicosanoid production and hGIIA trafficking, as well as binding the coil of vimentin, resulting in aggresome formation and apoptosis. Figure 8. Pharmacokinetics of cF and c2 after intravenous and oral administration. (a) Identity and validation of cF and c2 radioactively-labelled with tritium. Mice (BALB / c, n = 4 per timepoint) were administered with 5 mg / kg of tritiated cF or c2, by the routes and times indicated. Peptide content of tissues were determined by liquid scintillation counting. Stability of peptides following administration to animals was evaluated by thin layer chromatography of tissue-extracted peptide (red and blue lines) relative to peptide prior to injection (purple and green lines). (b) Plasma concentrations in BALB / c mice 0-4 hours after intravenous administration of either cF or c2 (5 mg / kg; cF n = 4, c2 n = 6). (c) Plasma concentrations in BALB / c mice 1.35-18 hours after oral administration of either cF or c2 (5 mg / kg; both n = 4) with (d) whole blood also measured at 8 hours. (e-f) Concentration of cF (e) or c2 (f) in liver, kidney, muscle, heart and lung from 1-24 hours after oral administration of cF or c2 (5 mg / kg; both n = 4), respectively. Figure 9. Characterisation of c2 autofluorescence. (a) Fluorescent lifetime images (left) and phasor plot of fluorescence lifetime (right) of LNCaP cells immunostained with primary conjugated anti-hGIIA antibody 4A1 / AF568 and vimentin antibody RV202 / AF488 identified a distinct lifetime at 1.3 ns in cells incubated with c2 (100 μM) shown in yellow cursor. (b) Emission spectrum of c2 in response to 405 nm excitation. Figure 10. Validation of hGIIA tagged with Alexa Fluor 647 (hGIIA / AF647). (a) Iso- electric focusing (IEF) of hGIIA and hGIIA / AF647 yields pI (both at ~10.5). (b) Representative images of immunofluorescence of exogenous untagged hGIIA, detected with primary conjugated anti-hGIIA antibody 4A1 / AF568 (red) entry compared to live cell imaging of hGIIA / AF647 (green) entry over 24 hours in RA57 and LNCaP cell lines. hGIIA or hGIIA / AF647 protein (200 ng / mL) was added and fluorescence intensity was measured at 0, 2 min on ice, or 1 h, 16 h and 24 h at 37 degrees. Scale bar 50 μm. Graphs show quantitation of fluorescence, n =1, 20 cells per replicate, error bars SE. Figure 11. hGIIA and c2 entry and localisation. (a) Immunofluorescent staining of PC-3, LNCaP and DU145 cell lines with hGIIA (red), caveolin-1 (green) and DAPI (blue) shown in overlay. Colocalisation (pink) between hGIIA and cav-1 staining as calculated by Costes et al. Biophys J. 86 (6):3993-4003 (2004) method. Cells with 63 x objective, n = 3, 5 cells per replicate, scale bar is 10 μm. (b) PC-3 cells incubated without (control) or with 200 μg / mL of protamine sulfate for 60 min prior to washing with PBS and incubation with 200 ng / mL of hGIIA / 647 for 24 hours. Scale bar 50 μm, n = 3, >15 cells per replicate, error bars SEM. ***, p<0.0001; statistical significance determined by Student’s unpaired two-tailed t test. Figure 12. Vimentin knockout in DU145 cells. (a) Nuclease mismatch assay of wtDU145 and DU145 vimentin knockout. Single bands in wtDU145 indicate homoduplexes (no editing), while multiple bands (indicated by arrows) in the DU145 vimentin knockout lane confirm the formation of heteroduplexes and correct editing at the desired site. (b) Immunofluorescence staining of vimentin (green) and DAPI in wtDU145 and (c) vimentin knockout. (d) Western blot of SDS-size-fractionated cell lysates from wtDU145 (WT) and vimentin knockout mutant clonal colonies detected for vimentin and GAPDH. Arrow indicates clone chosen for further studies. Figure 13. Chemical structure of c2 free base (A), and simplified structure of c2 (B). Abbreviations: Ala, alanine; Leu, leucine; Ser, serine; Arg, arginine; NP, 2-naphthyl. Figure 14. Waterfall plot of percentage change in serum PSA level from start of continuous c2 dosing to end of trial for all participants. Figure 15. Pharmacokinetic analysis of blood samples from selected patients (subjects 1, 4 and 7) treated with an initial single dose of c2 (5 mg, 10 mg and 40 mg c2 respectively) in part 1 of study. c2 concentration expressed as a ratio with a spiked standard peptide (cF). Figure 16. In Part 1 of the trial, plasma sPLA2-IIA concentrations were measured in patient blood samples including on Day 1 (pre-dose) and 24 hours later on Day 2. Sample analyses were repeated in triplicate and error bars represent SEM. Figure 17. In Part 2 of the trial, plasma sPLA2-IIA concentrations were measured in blood samples including on Day 1 and at the end of the 6-week doing period on Day 43. Sample analyses were repeated in triplicate and error bars represent SEM. ^PSA = change in PSA from start to end of Part 2, as per PSA response criteria. *PSA decreased in patients 3, 8 and 12 but did not meet criteria for a PSA response. Figure 18. Trend to a positive correlation between plasma sPLA2 levels at the end of the trial, and increasing PSA levels over the course of the trial. Figure 19. sPLA2 was detectable in urine of three participants at baseline. Urine samples collected from these patients at the planned timepoints in Part 1 (A) and Part 2 (B) were analysed. Samples were analysed in triplicate and error bars represent SEM. Figure 20. Forest plots for all lipids (vertically segregated into classes) for 5 mg, 10 mg, 40 mg and 60 mg dose groups in Part 1. Grey confidence intervals are non-significant; dark blue are nominally significant; cyan are significant even after Benjamini-Hochberg multiple testing correction. Abbreviations: AC, acylcarnitine; CE, cholesteryl ester; Cer, ceramide; Cer1P, ceramide-1-phosphate; COH, free cholesterol; DE, dehydrocholesterol; DG, diacylglycerol; FA, fatty acyl; GM1, monosialotetrahexosylganglioside; GM3, monosialodihexosylganglioside; HexCer, monohexosylceramide; Hex2Cer, dihexosylceramide; Hex3Cer, trihexosylceramide; LPC, lysophosphatidylcholine; LPC-O, lysoalkylphosphatidylcholine; LPC-P, lysoalkenylphosphatidylcholine; LPE, lysophosphatidylethanolamine; LPE-P, lysoalkenylphosphatidylethanolamine; LPI, lysophosphatidylinositol; NL, neutral loss; OH, hydroxyl; PA, phosphatidic acid; PC, phosphatidylcholine; PC-O, alkylphosphatidylcholine; PC- P, alkenylphosphatidylcholine; PE, phosphatidylethanolamine; PE-O, alkylphosphatidylethanolamine; PE-P, alkenylphosphatidylethanolamine; PG, phosphatidylglycerol; PI, phosphatidylinositol; PIP1, phosphatidylinositol monophosphate; PS, phosphatidylserine; SIM, selected ion monitoring; SM, sphingomyelin; Sph, sphingosine; S1P, sphingosine-1-phosphate; TG, triacylglycerol; TG-O, alkyl-diacylglycerol. Figure 21. Forest plots for all lipids (vertically segregated into classes) for 5 mg and 10 mg continuous dosing groups in Part 2. Grey confidence intervals are non-significant; dark blue are nominally significant; cyan are significant even after Benjamini-Hochberg multiple testing correction. Figure 22: hGIIA binds to EGFR, initiating signalling via a catalytically independent mechanism with binding inhibited by c2. (a) PC-3 cells incubated with hGIIA (2 μg / mL) for two hours, washed before immunoprecipitation of lysates with anti-hGIIA, anti-EGFR or negative control (beads only) overnight, then detection of hGIIA and EGFR levels in lysate and Co-IP samples (n = 3 biological replicates). (b) PC-3 cells were treated with or without c2 (100 μM) for two hours, washed, then incubated with hGIIA (2 μg / mL) for two hours, before immunoprecipitating the lysates with anti-hGIIA antibody and detecting EGFR levels in lysate and Co-IP samples. (c) % of EGFR signal from hGIIA IP treated with hGIIA and with hGIIA + c2 (n = 4). (d) The c2 peptide analogue cFLSFR was docked on to the crystal structure of EGFR (PDB 1nq1) at the ligand binding site using quCBit software. EGFR is depicted as a surface model (red, basic surfaces; blue, acidic surfaces, yellow; cysteine residues; green, hydrophobic surfaces; white neutral surfaces), while cFLSFR is depicted as sticks. (e) Representative live cell image of a PC-3 cell treated with 200 ng / mL of hGIIA / AF647 (purple) for 24 hours and transfected to express EGFR-EGFP (green) and Rab5-mCherry (red), with colocalization between all three proteins appearing in overlay as white (scale bar 20 μm, inset 20 μm2). (f) PC- 3 cells treated with combinations of DMSO, hGIIA (2 μg / mL), H48Q (2 μg / mL), TNF (10 ng / mL) and c2 (100 μM) for 10 min before fixing and staining with antibodies for either (g) p- EGFR, (h) p-ERK or (i)p-cPLA2-α (scale bar 50 μm, n > 20 cells, one-way ANOVA). Figure 23: c2 initiates apoptosis via a vimentin-mediated mechanism. PC-3, LNCaP, DU145 WT and DU145 vimKO were treated with either control (nothing), DMSO (0.5%), c2100 μM for 72 hours or positive control of all cell lines incubated at 42 °C for 5 min. Cells were then stained with Annexin V-FITC and propidium iodide (PI), before FACS analysis). The Annexin V / PI data was measured on FL1-H versus FL2-H scatter plot using FlowJoTM v10.9 software (n=3 biological replicates). Figure 24: Pharmacokinetic plot of the patients’ blood plasma average c2 concentrations obtained from LC-MS / MS at 0 (Predose), 0.5, 1, 2, 3, 4, 6 and 24 hours, rerun 15 days after initial triplicate run and stored at 4℃. Key to the Sequence Listing SEQ ID NO: 1 Amino acid sequence for a reference human hGIIA protein (including signal peptide) SEQ ID NO: 2 Amino acid sequence for a reference human hGIIA protein (mature protein) SEQ ID NO: 3 Amino acid sequence for a reference human EGFR protein (including signal peptide) SEQ ID NO: 4 Amino acid sequence for a reference human EGFR protein (mature version without signal peptide) Detailed Description General Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, feature, composition of matter, group of steps or group of features or compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, features, compositions of matter, groups of steps or groups of features or compositions of matter. Those skilled in the art will appreciate that the present disclosure is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The present disclosure is not to be limited in scope by the specific examples described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the present disclosure. Any example of the present disclosure herein shall be taken to apply mutatis mutandis to any other example of the disclosure unless specifically stated otherwise. Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (for example, in cell culture, molecular genetics, immunology, immunohistochemistry, protein chemistry, and biochemistry). Unless otherwise indicated, the recombinant DNA, recombinant protein, cell culture, and immunological techniques utilized in the present disclosure are standard procedures, well known to those skilled in the art. Such techniques are described and explained throughout the literature in sources such as, J. Perbal, A Practical Guide to Molecular Cloning, John Wiley and Sons (1984), J. Sambrook et al. Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989), T.A. Brown (editor), Essential Molecular Biology: A Practical Approach, Volumes 1 and 2, IRL Press (1991), D.M. Glover and B.D. Hames (editors), DNA Cloning: A Practical Approach, Volumes 1-4, IRL Press (1995 and 1996), and F.M. Ausubel et al. (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley- Interscience (1988, including all updates until present), Ed Harlow and David Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, (1988), and J.E. Coligan et al. (editors) Current Protocols in Immunology, John Wiley & Sons (including all updates until present). Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", is understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers but not the exclusion of any other step or element or integer or group of elements or integers. The term “and / or”, e.g., “X and / or Y” shall be understood to mean either “X and Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning. Throughout the present specification, various aspects and components of the disclosure can be presented in a range format. The range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the present disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub- ranges as well as individual numerical values within that range, unless specifically indicated. For example, description of a range such as from 1 to 5 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 5, from 3 to 5 etc., as well as individual and partial numbers within the recited range, for example, 1, 2, 3, 4, 5, 5.5 and 6, unless where integers are required or implicit from context. This applies regardless of the breadth of the disclosed range. Where specific values are required, these will be indicated in the specification. The term “about” in relation to a numerical value x is optional and means, for example, any number within 1, 5 or 10% of the referenced number. In certain examples, the term “about” encompasses the exact number recited. The term “substantially” does not exclude “completely” (e.g., a composition which is “substantially free” from Y may be completely free from Y). All computer programs, algorithms, patent and scientific literature referred to herein is incorporated herein by reference. Methods of treating The inventors have surprisingly demonstrated that the hGIIA inhibitor c2 is safe and well tolerated in preclinical animal models when administered chronically at high doses and in human patients. This finding was unexpected owing to prior art hGIIA inhibitors that target the catalytic activity of hGIIA (e.g., Varespladib) being previously found to induce high rates of cardiotoxicity in patients. Without being bound by any theory, it is believed that the lack of toxicity, and more particularly cardiotoxicity, demonstrated by c2 in patients relates to the cyclic peptide’s selective inhibition of the non-catalytic activity of hGIIA. Accordingly, in one form, the present disclosure provides a method of treating, preventing or ameliorating a hGIIA-dependent disease, disorder or condition in a subject, said method including the step of administering a therapeutically effective amount of an agent that inhibits a non-catalytic activity of hGIIA to the subject to thereby treat, prevent or ameliorate the hGIIA- dependent disease, disorder or condition. In a related form, the present disclosure provides for the use of an agent that inhibits a non-catalytic activity of hGIIA in the manufacture of a medicament for the treatment, prevention or amelioration of a hGIIA-dependent disease, disorder or condition in a subject. In a further form, the present disclosure relates to an agent that inhibits a non-catalytic activity of hGIIA for use in a method of treating, preventing or ameliorating a hGIIA-dependent disease, disorder or condition in a subject. The inventors have further surprisingly demonstrated that the hGIIA inhibitor c2 is safe and effective when administered orally in preclinical animal models and human patients with cancer. As such, in another form, the present disclosure provides a method of treating or preventing a cancer in a subject, said method including the step of orally administering a therapeutically effective amount of cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof to the subject to thereby treat or prevent the cancer. In a related form, the present disclosure also provides for the use of cyclo-((2-Nal)-Leu- Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof in the manufacture of a medicament for of treating or preventing a cancer in a subject, wherein the medicament is formulated for oral administration. In a further related form, the present disclosure relates to cyclo-((2-Nal)-Leu-Ser-(2-Nal)- Arg) (c2) for use in a method of treating or preventing a cancer in a subject, said method including the step of orally administering a therapeutically effective amount of c2 or the analogue or derivative thereof to the subject to thereby treat or prevent the cancer. As used herein, the terms “treating”, “treat” or “treatment” and variations thereof, refer to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. As used herein, the terms “prevent”, “prevented”, or “preventing”, refer to a prophylactic treatment which increases the resistance of a subject to developing the disease or condition or, in other words, decreases the likelihood that the subject will develop the disease or condition as well as a treatment after the disease or condition has begun in order to reduce or eliminate it altogether or prevent it from becoming worse. These terms also include within their scope preventing the disease or condition from occurring in a subject which may be predisposed to the disease or condition but has not yet been diagnosed as having it. The term “ameliorate” as used herein, unless otherwise specified, means to eliminate, delay, or reduce the prevalence or severity of symptoms associated with a disease, disorder or condition. The terms “oral administration”, “orally administering” and the like represent any method of administration in which an active agent, such as c2, cF or an analogue or derivative thereof or an agent that inhibits a non-catalytic activity of hGIIA described herein, can be administered by swallowing, chewing, sucking or drinking an oral dosage form of said active agent. Such solid or liquid oral dosage forms are traditionally intended to substantially release and or deliver the active agent in the gastrointestinal tract beyond the mouth and / or buccal cavity. Examples of solid dosage forms include conventional tablets, multi-layer tablets capsules, caplets, etc., which do not substantially release the drug in the mouth or in the oral cavity. The term “therapeutically effective amount” describes a quantity of a specified agent, such as c2, cF or a derivative or analogue thereof or an agent that inhibits a non-catalytic activity of hGIIA described herein, sufficient to achieve a desired effect in a subject being treated with that agent or composition. For example, this can be the amount of the agent and optionally one or more further therapeutic agents (e.g., one or more further anti-cancer agents), necessary to reduce, alleviate and / or prevent an hGIIA-related disease, disorder or condition, such as a cancer, and more particularly an hGIIA-dependent cancer. Suitably, a “therapeutically effective amount” is sufficient to reduce or eliminate a symptom of an hGIIA-related disease, disorder or condition, such as a cancer, and more particularly an hGIIA-related cancer. More particularly, a “therapeutically effective amount” may be an amount sufficient to achieve a desired biological effect, for example an amount that is effective to decrease or prevent disease progression, such as cancer metastasis or recurrence, or overcome resistance to and / or enhance the anti-cancer activity of a further anti-cancer agent. Ideally, a therapeutically effective amount of an agent is an amount sufficient to induce the desired result without causing a substantial cytotoxic effect, such as cardiotoxicity, in the subject. The therapeutically effective amount of an agent useful for reducing, alleviating and / or preventing the diseases, disorders and conditions described herein will be dependent on the subject being treated, the type and severity of any associated disease, disorder and / or condition (e.g., disease progression), and the manner of administration of the therapeutic composition. Suitably, a therapeutically effective amount of the agent is administered orally to the subject. As used herein, the term “subject” refers to any animal, for example, a mammalian animal, including, but not limited to humans, non-human primates, livestock (e.g., sheep, horses, cattle, pigs, donkeys), companion animals (e.g., pets such as dogs and cats), laboratory test animals (e.g., mice, rabbits, rats, guinea pigs), performance animals (e.g., racehorses, camels, greyhounds) or captive wild animals. In various examples, the “subject” is a human, such as a male human or a female human. Typically, the terms “subject” and “patient” are used interchangeably herein, particularly in reference to a human subject. In any of the methods disclosed herein, the subject has a cancer, such as an hGIIA-related cancer. In one example, the cancer is a prostate cancer. As generally used herein, the terms “cancer”, “tumour”, “malignant” and “malignancy” refer to diseases or conditions, or to cells or tissues associated with the diseases or conditions, characterized by aberrant or abnormal cell proliferation, differentiation and / or migration often accompanied by an aberrant or abnormal molecular phenotype that includes one or more genetic mutations or other genetic changes associated with oncogenesis, expression of tumour markers, loss of tumour suppressor expression or activity and / or aberrant or abnormal cell surface marker expression. Cancers may include any aggressive or potentially aggressive cancers, tumours or other malignancies such as listed in the NCI Cancer Index at http: / / www.cancer.gov / cancertopics / alphalist, including all major cancer forms such as sarcomas, carcinomas, lymphomas, leukaemias and blastomas, although without limitation thereto. These may include breast cancer, lung cancer inclusive of lung adenocarcinoma, cancers of the reproductive system inclusive of ovarian cancer, cervical cancer, uterine cancer and prostate cancer, cancers of the brain and nervous system, head and neck cancers, gastrointestinal cancers inclusive of colon cancer, colorectal cancer and gastric cancer, liver cancer, kidney cancer, skin cancers such as melanoma and skin carcinomas, blood cell cancers inclusive of lymphoid cancers and myelomonocytic cancers, cancers of the endocrine system such as pancreatic cancer and pituitary cancers, musculoskeletal cancers inclusive of bone and soft tissue cancers, although without limitation thereto. According to certain examples, the cancer is associated with an elevated level or activity of hGIIA. In this regard, the cancer may be considered to be a hGIIA-related, hGIIA-associated or hGIIA-dependent cancer. The terms “hGIIA-dependent cancer”, “hGIIA-related cancer”, “hGIIA-associated cancer” and the like are used interchangeably herein and refer to cancers associated with a disease state, where increased levels of hGIIA expression and / or activity and / or increased activation of cellular cascades or downstream signalling pathways involving hGIIA are found (e.g., those mediated by prostaglandins and / or leukotrienes). Accordingly, such cancers may be associated with increased or elevated levels of non-catalytic activity and / or catalytic activity of hGIIA. In particular examples, however, these terms are intended to encompass cancers associated with an increased or elevated level of non-catalytic activity of hGIIA. In general, these terms refer to any cancer, the onset, progression or the persistence of the symptoms of which requires the participation of hGIIA. Exemplary hGIIA-related cancers include those of the brain, head and neck, prostate, ovary, breast, cervix, lung and oesophagus, as well as melanoma, rhabdomyosarcoma, mesothelioma and squamous carcinomas of the skin. In particular examples, the hGIIA-related cancer is prostate cancer. Suitably, the present methods further including the earlier or initial step of identifying whether the subject’s cancer, such as from a sample (e.g., a biopsy sample or a biological sample, such as a blood, plasma, serum, urine etc.) obtained from the subject (e.g., from the subject’s cancer), is an hGIIA-related cancer (e.g., an hGIIA-dependent cancer). In such instances, the present method may include the step of determining a level of hGIIA expression and / or activity, such as a level of circulating hGIIA, of the subject’s cancer. Well known assays, such as those described herein, can be used for determining the hGIIA expression, activity and / or signalling status of the subject to be treated if such prior determination is desired. In any of the methods disclosed herein, the subject may be receiving a further anti-cancer treatment. As such, the methods described herein may further include the step of administering a further therapeutic agent, such as those described herein. The further anti-cancer treatment may be selected from the group consisting of a chemotherapeutic agent, a radiation therapy, a molecularly targeted therapeutic agent and an immunotherapeutic agent. The further anti-cancer treatment may be administered sequentially in any order, at the same time or at different times. For example, the subject may have received a further anti-cancer treatment prior to receiving cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof. In another example, the subject may receive a further anti-cancer treatment after receiving cyclo-((2-Nal)- Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof. In yet another example, the subject may receive a further anti-cancer treatment at the same time as cyclo-((2-Nal)-Leu-Ser- (2-Nal)-Arg) (c2) or an analogue or derivative thereof. Suitable examples of chemotherapeutic agents include, but are not limited to, a platinum- based chemotherapeutic agent, such as oxaliplatin or cisplatin, an anthracycline, a taxane, and / or a camptothecin. The chemotherapeutic agents may be an EGFR inhibitor or an immune checkpoint inhibitor. The immunotherapeutic agent may be one or more of: Atezolizumab, Avelumab Ipilimumab, Bevacizumab, Cemiplimab, Durvalumab, Pembrolizumab, Nivolumab and / or Pidilizumab). The chemotherapeutic agent may be selected from: temozolomide, dacarbazine, carmustine (BCNU), lomustine (CCNU), paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine etoposide, teniposide, topotecan, irinotecan, doxorubicin, daunomycin, epirubicin, idarubicin, methotrexate, cytarabine, gemcitibine, capecitabine, cisplatin, carboplatin, cyclophosphamide, oxaliplatin, or a mixture thereof. In further examples, the further anti-cancer treatment may be surgery. In alternative examples, the further anti-cancer treatment is or comprises hormone therapy. Suitable hormone therapies are known in the art and include, but are not limited to, anti-androgens such as abiraterone, enzalutamide, flutamide, nilutamide, apalutamide and darolutamide. The methods disclosed herein may be a method of treating or preventing a cancer in a subject having or susceptible to the disease, disorder or condition. Accordingly, in a particular form, the present disclosure provides a method of treating or preventing a cancer in a subject, said method including the step of orally administering a therapeutically effective amount of cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof to the subject to thereby treat or prevent the cancer. In any of the methods disclosed herein, the cancer may be a prostate cancer. In any of the methods disclosed herein, the method may include the further step of administering a further anti-cancer treatment to the subject. The further treatment may be administered in combination (e.g., simultaneously, before or after) with the therapeutic agent which aims to treat, ameliorate of prevent an hGIIA-related cancer or a disease, disorder or condition associated therewith. The further treatment may be administered simultaneously with or before or after treatment with the cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof. In one example, the further treatment is administered to the subject simultaneously with cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof. In another example, the further treatment is administered to the subject before the cyclo- ((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof. In another example, the further treatment is administered to the subject after the cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof. According to certain examples, the agent described herein may be co-administered with or formulated to be co-administered with (separately, simultaneously or sequentially) a further therapeutic agent (e.g., a further anti-cancer agent, a further anti-inflammatory agent) for the treatment of the hGIIA-related disease, disorder or condition. In certain examples, the agent described herein may be co-administered with or formulated to be co-administered with (separately, simultaneously or sequentially) a further anti- cancer agent for the treatment of the hGIIA-related cancer. Additional cancer treatments (i.e., cancer treatments in addition to the agent provided herein) for use in the methods described herein may include drug therapy, chemotherapy, antibody, nucleic acid and other biomolecular therapies, radiation therapy, surgery, nutritional therapy, relaxation or meditational therapy and other natural or holistic therapies, although without limitation thereto. Generally, drugs, biomolecules (e.g., antibodies, inhibitory nucleic acids such as siRNA) or chemotherapeutic agents are referred to herein as “anti-cancer therapeutic agents” or “anti-cancer agents”. Also disclosed herein is the use of a therapeutically effective amount of cyclo-((2-Nal)- Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof, wherein the medicament is formulated for oral administration. In some examples, the medicament is formulated for administration with a further anti- cancer treatment. Also disclosed herein is a therapeutically effective amount of cyclo-((2-Nal)-Leu-Ser-(2- Nal)-Arg) (c2) or an analogue or derivative thereof for use in a method of treating or preventing a cancer in a subject, wherein the c2 or an analogue or derivative thereof is formulated for oral administration. In one example, the further treatment is or comprises a further treatment for a cancer. Suitable further treatments for a cancer are known in the art and examples are described above. In one example, the anti-cancer treatment or further anti-cancer treatment is selected from the group consisting of a chemotherapeutic agent, a radiation therapy, a molecularly targeted therapeutic agent and an immunotherapeutic agent. Drug-induced toxicity Suitably, the agent described herein demonstrates little or no toxicity, and more particularly little or no drug-induced toxicity in the subject, such as when administered at a dosage described herein (e.g., about 5 mg / day to about 1500 mg / day or more particularly about 5 mg / day to about 100 mg / day). Such drug-induced toxicity may include, but is not limited to, cardiotoxicity, hepatotoxicity, neurotoxicity, nephrotoxicity or myotoxicity. In particular examples, the agent induces little or no cardiotoxicity in the subject, such as when administered at a therapeutically effective dose like those provided herein. The term “cardiotoxicity” refers to a broad range of adverse effects on heart function induced by therapeutic molecules. It may emerge early in pre-clinical studies or become apparent later in the clinical setting. Cardiovascular toxicity described herein includes, but is not limited to, any one or more of increased QT duration, arrhythmias, myocardial ischemia, hypertension and thromboembolic complications, myocardial dysfunction, cardiomyopathy, heart failure, atrial fibrillation, cardiomyopathy and heart failure, heart failure and LV dysfunction, atrial flutter and fibrillation, and, heart valve damage and heart failure. Drug-induced toxicity, and more particularly cardiotoxicity, may be assessed in vitro or in vivo by any means known in the art, such as cell-, tissue- or organoid-based assays, in vivo imaging techniques (e.g., echocardiography, cardiac magnetic resonance imaging), electrophysiological techniques and biomarkers. Exemplary biomarkers of cardiotoxicity include QTc prolongation, electrophysiological arrhythmias, circulating troponin c, heart rate, blood pressure, circulating lipids, C-reactive protein (CRP), brain or B-type natriuretic peptide (BNP), ex vivo platelet aggregation and imaging biomarkers. As used herein, the terms “little or no toxicity” and “little or no cardiotoxicity” refer to a level or incidence of toxicity and cardiotoxicity respectively for an agent of the present disclosure administered at a therapeutically effective dose (e.g., about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 200 mg / day, about 500 mg / day or about 1000 mg / day of the agent) that typically is essentially equivalent to (e.g., no more than about 1%, 5% or 10% above) that level or incidence of toxicity or cardiotoxicity observed in patients when using a control or placebo only (e.g., a vehicle, such as PBS) that does not contain the agent. cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2) Suitably, the agent of the present disclosure is a cyclic peptide. In one example, the agent is selected from the group consisting of cFLSYK, cFLSYR (cF, also known as FLM-cF) and c(2NapA)LS(2NapA)R (c2, also referred to as FLM-c2). When used herein, the term “cFLSYK” means “cyclic FLSYK”, “cFLSYR” means “cyclic FLSYR” and “c(2NapA)LS(2NapA)R” means “cyclic (2NapA)LS (2NapA)R”. The terms “2NapA” and “2-Nal” are abbreviations for 2-naphthylalanine. For some examples, the agent is cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2) or cFLSYR (cF). In one example, the agent is cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) (c2). In other examples, the agent is cFLSYR (cF). In other examples, the agent is a derivative or analogue of c2 or cF. Such a derivative or analogue for use according to the present disclosure is suitably a functional peptide. By “functional peptide” is meant a peptide able to bind to a hGIIA binding domain on an interacting protein, such as EGFR and / or vimentin, and thereby selectively prevent or inhibit a non-catalytic activity of hGIIA. Determining whether a cyclic peptide derivative or analogue is functional may be assessed by any method or means known in the art. Cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg), also known as c2, has been shown to exert anti- inflammatory effects by targeting sPLA2-IIa, also known as hGIIA. Any of the methods herein may include the step of orally administering a therapeutically effective amount of cyclo-((2- Nal)-Leu-Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof to the subject. The term “analogue” as used herein refers to a modified or variant peptide, wherein one or more amino acid residues of the peptide have been substituted by other amino acid residues and / or wherein one or more amino acid residues have been deleted from the peptide. As used herein, “derivatives” refers to proteins or peptides, inclusive of fragments or variants thereof, that have been altered, for example by conjugation or complexing with other chemical moieties, such as by post-translational modification (e.g., phosphorylation, acetylation and the like), modification of glycosylation (e.g., adding, removing or altering glycosylation), lipidation and / or inclusion of additional amino acid sequences as would be understood in the art. Derivatives contemplated by the disclosure include, but are not limited to, modification to side chains, incorporation of unnatural amino acids and / or their derivatives during peptide, or protein synthesis and the use of crosslinkers and other methods which impose conformational constraints on the cyclic peptides of the disclosure. In this regard, the skilled person is referred to Chapter 15 of CURRENT PROTOCOLS IN PROTEIN SCIENCE, Eds. Coligan et al. (John Wiley & Sons NY 1995-2008) for more extensive methodology relating to chemical modification of proteins. Further derivatives may include conjugates of the cyclic peptide (e.g., c2 or cF). The term “conjugated” can be used in the context of the present disclosure to describe the cyclic peptide (e.g., c2 or cF) conjugated to another compound or structure, such as a label or carrier molecule or protein. Accordingly, in one example, the cyclic peptide (e.g., c2 or cF) is “conjugated”. The cyclic peptide (e.g., c2 or cF) may be modified via conjugation or complexing with other chemical moieties, by post-translational modification (e.g., phosphorylation, ubiquitination, glycosylation), chemical modification (e.g., cross-linking, acetylation, biotinylation, oxidation or reduction) and / or conjugation with labels (e.g., fluorophores, enzymes, radioactive isotopes) and / or other functional elements (e.g., a half-life extender, a therapeutic agent), as are known in the art. In one example, the cyclic peptide (e.g., c2 or cF) derivative may be a pharmaceutically acceptable salt, solvate or prodrug thereof. The cyclic peptide (e.g., c2 or cF) may be utilized per se or in the form of a pharmaceutically acceptable salt, ester, amide, solvate, prodrug, or isomer, as appropriate. For example, it may be provided as a pharmaceutically acceptable salt. If used, a salt of the cyclic peptide (e.g., c2 or cF) should be both pharmacologically and pharmaceutically acceptable, but non- pharmaceutically acceptable salts may conveniently be used to prepare the free active compound or pharmaceutically acceptable salts thereof and are not excluded from the scope of this disclosure. Such pharmacologically and pharmaceutically acceptable salts can be prepared by reaction of the cyclic peptide (e.g., c2 or cF) with an organic or inorganic acid, using standard methods detailed in the literature. The cyclic peptide (e.g., c2 or cF) may be in the form of any pharmaceutically acceptable salt. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of salts derived from inorganic bases can include aluminium, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Exemplary salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the cyclic peptide (e.g., c2 or cF) disclosed herein is basic, acid addition salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, carboxylic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, TFA, and the like. Acid addition salts of c2, are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, TFA, citric, tartaric, maleic, succinic or methanesulfonic acid. In particular examples, the cyclic peptide (e.g., c2 or cF) is in the form of an acetate salt. The cyclic peptide (e.g., c2 or cF) can also exist in solvated forms, including solvates of the free peptide or solvates of a salt of the compound, as well as unsolvated forms. The term “solvate” is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term “hydrate” is employed when said solvent is water. It is to be understood that all polymorphs, including mixtures of different polymorphs, are included within the scope of the cyclic peptide (e.g., c2, cF or analogues or derivatives thereof) described herein. Esters of the cyclic peptide (e.g., c2 or cF) may be prepared through functionalization of hydroxyl and / or carboxyl groups that may be present within the compound. Amides and prodrugs may also be prepared using techniques known to those skilled in the art. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine. Moreover, esters and amides of compounds of the invention can be made by reaction with a carbonylating agent (e.g., ethyl formate, acetic anhydride, methoxyacetyl chloride, benzoyl chloride, methyl isocyanate, ethyl chloroformate, methanesulfonyl chloride) and a suitable base (e.g., 4- dimethylaminopyridine, pyridine, triethylamine, potassium carbonate) in a suitable organic solvent (e.g., tetrahydrofuran, acetone, methanol, pyridine, Ν,Ν-dimethylformamide) at a temperature of 0 °C to 60 °C. As used herein, the term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a cyclic peptide described herein. Prodrugs may become active upon such reaction under biological conditions, or they may have activity in their unreacted forms. Examples of prodrugs contemplated for the present disclosure include, but are not limited to, analogues or derivatives of c2 that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of compounds described herein that comprise —NO, —NO2, —ONO, or —ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed). Accordingly to alternative examples, the agent provided herein is not cFLSYR, cFLSYK or c2. In certain examples, the agent provided herein is not cFLSYK. For other examples, the agent provided herein is not cFLSYR (cF). In various examples, the agent provided herein is not c2. Given that aberrant hGIIA function and signalling is implicated in a range of disorders, the hGIIA-dependent disease, disorder or condition can be characterised by aberrant hGIIA enzyme-independent activity and optionally aberrant hGIIA enzyme activity. Examples of such disorders can include malignant conditions, such as cancer, and also chronic and acute inflammatory conditions, such as rheumatoid arthritis, sepsis, atherosclerosis, cardiovascular disease, asthma, coronavirus, psoriasis, inflammatory bowel disease and Crohn's disease. They also may be useful in the treatment of certain neurological conditions with an inflammatory component, such as Alzheimer’s disease and schizophrenia. In view of the above, and according to certain examples, the hGIIA-dependent disease, disorder or condition is an inflammatory disease, disorder or condition, such as those described above. As used herein, the term “inflammatory disease, disorder or condition” refers to a large group of diseases, disorders or conditions characterized by abnormal or excessive inflammation, such as that at least partly mediated by a non-catalytic activity of hGIIA. The immune system is frequently involved in inflammatory diseases, disorders or conditions, with many immune system disorders resulting in inflammation. In certain examples, however, the hGIIA-dependent disease, disorder or condition is not an inflammatory joint disease, disorder or condition, and more particularly arthritis, such as rheumatoid arthritis, osteoarthritis, infectious arthritis, psoriatic arthritis, gouty arthritis and lupus-related arthritis. In particular examples, the hGIIA-dependent disease, disorder or condition is a cancer. Suitably, the cancer described herein is at least partly mediated by or associated with hGIIA and more particularly a non-catalytic activity thereof. As such, in a particular form, the present disclosure provides a method of treating, preventing or ameliorating an hGIIA-related cancer in a subject, said method including the step of administering a therapeutically effective amount of the agent described herein to the subject to thereby treat, prevent or ameliorate the hGIIA-related cancer. Without wishing to be bound by any theory, the inventors have found previously that c2 binds to amino acid residues within the amino acid residues numbered 347 to 357, and 342 to 350 which are located on vimentin coil 2. hgIIA Without wishing to be bound by any theory, the inventors have found that the level of circulating human group IIA-secreted phospholipase A2 (hGIIA), also known as sPLA2-IIa, may be decreased by c2. Human group IIA secreted phospholipase A2 (hGIIA), also known as human Group IIA secretory phospholipase A2 (human sPLA2-IIA), is an enzyme that catalyses the hydrolysis of phosphatidylcholine to lysophosphatidylcholine and arachidonic acid. hGIIA contributes towards the release and / or formation of at least three important lipid mediators from the cell membrane, which are arachidonic acid, platelet activating factor and lysophospholipids such as lysophosphatidic acid (LPA). The release of arachidonic acid from membrane phospholipids by hGIIA is believed to be a key step in the control of eicosanoid production within the cell. To this end, arachidonic acid can be metabolized further by cyclooxygenase, lipoxygenase and cytochrome P450 enzymes to produce a range of eicosanoid autocrine and paracrine signalling molecules. LPA and eicosanoids have various physiological roles acting through G-protein coupled receptors (GPCRs). The protein sequence of hGIIA is publicly available (e.g., P14555) and exemplary amino acid sequences are set forth in SEQ ID NO: 1 and SEQ ID NO: 2 below. Thus, the hGIIA amino acid sequence may be a protein which is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2 or a fragment or derivative thereof. The sequence in SEQ ID NO: 1 includes a signal peptide at the beginning of the protein (i.e., amino acid residues 1 to 20 of SEQ ID NO: 1), with the sequence for the mature hGIIA protein beginning at Asn 21 of SEQ ID NO: 1, which is absent in the mature protein of SEQ ID NO: 2. hGIIA protein sequence with signal sequence (SEQ ID NO: 1) MKTLLLLAVIMIFGLLQAHGNLVNFHRMIKLTTGKEAALSYGFYGCHCGVGGRGSPKDAT DRCCVTHDCCYKRLEKRGCGTKFLSYKFSNSGSRITCAKQDSCRSQLCECDKAAATCFAR NKTTYNKKYQYYSNKHCRGSTPRC hGIIA protein sequence without signal sequence (SEQ ID NO: 2) NLVNFHRMIKLTTGKEAALSYGFYGCHCGVGGRGSPKDATDRCCVTHDCCYKRLEKRGCG TKFLSYKFSNSGSRITCAKQDSCRSQLCECDKAAATCFARNKTTYNKKYQYYSNKHCRGS TPRC Terms used generally herein to describe sequence relationships between respective nucleotides or polypeptides include “sequence identity”, “percentage of sequence identity” and “substantial identity”. Because respective nucleotides or polypeptides may each comprise (i) only one or more portions of a complete nucleotide or polypeptide sequence that are shared by the nucleotides or amino acids, and (ii) one or more portions which are divergent between the nucleotides or amino acids, sequence comparisons are typically performed by comparing sequences over a “comparison window” to identify and compare local regions of sequence similarity. A “comparison window” refers to a conceptual segment of typically 6, 9 or 12 contiguous residues that is compared to a reference sequence. The comparison window may comprise additions or deletions (i.e., gaps) of about 20% or less as compared to the reference sequence for optimal alignment of the respective sequences. Optimal alignment of sequences for aligning a comparison window may be conducted by computerised implementations of algorithms (Geneworks program by Intelligenetics; GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Drive Madison, WI, USA, incorporated herein by reference) or by inspection and the best alignment (i.e. resulting in the highest percentage homology over the comparison window) generated by any of the various methods selected. Reference also may be made to the BLAST family of programs as for example disclosed by Altschul et al., 1997, Nucl. Acids Res.253389, which is incorporated herein by reference. A detailed discussion of sequence analysis can be found in Unit 19.3 of CURRENT PROTOCOLS IN MOLECULAR BIOLOGY Eds. Ausubel et al. (John Wiley & Sons Inc NY, 1995-1999). The term “sequence identity” is used herein in its broadest sense to include the number of exact nucleotide or amino acid matches having regard to an appropriate alignment using a standard algorithm, having regard to the extent that sequences are identical over a window of comparison. Thus, a “percentage of sequence identity” is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U) or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. For example, “sequence identity” may be understood to mean the “match percentage” calculated by the DNASIS computer program (Version 2.5 for windows; available from Hitachi Software engineering Co., Ltd., South San Francisco, California, USA). The terms “hGIIA-dependent disease, disorder or condition”, “hGIIA-related disease, disorder or condition”, “hGIIA-associated disease, disorder or condition” and the like are used interchangeably herein and refer to disease states and / or symptoms associated with a disease state, where increased levels of hGIIA expression and / or activity and / or increased activation of cellular cascades or downstream signalling pathways involving hGIIA are found (e.g., those mediated by prostaglandins and / or leukotrienes). Accordingly, such diseases, disorders and conditions may be associated with increased or elevated levels of non-catalytic activity and / or catalytic activity of hGIIA. In particular examples, however, these terms are intended to encompass disease states and / or symptoms associated with an increased or elevated level of non- catalytic activity of hGIIA. In general, these terms refer to any disease, disorder or condition, the onset, progression and / or the persistence of the symptoms of which requires the participation of hGIIA. Exemplary hGIIA-dependent diseases, disorders or conditions include, but are not limited to, for example, inflammatory diseases, disorders or conditions and cancer. Suitably, the present methods further including the earlier or initial step of identifying whether the subject’s disease, disorder or condition (e.g., a cancer), such as from a sample (e.g., a biopsy sample or a biological sample, such as a blood, plasma, serum, urine etc.) obtained from the subject (e.g., from the subject’s cancer), is an hGIIA-related disease, disorder or condition (e.g., an hGIIA-dependent cancer), such as by those methods described herein. In such instances, the present method may include the step of determining a level of hGIIA expression and / or activity, such as a level of circulating hGIIA, of the subject’s disease, disorder or condition, and more particularly, cancer. Well known assays, such as those described herein, can be used for determining the hGIIA signalling status of the subject to be treated if such prior determination is desired. According to alternative examples, the determination or confirmation of the level of hGIIA expression and / or activity of the subject’s disease, disorder or condition prior to initiating treatment with the agent or composition of the present disclosure is not necessary. To this end, there are hGIIA-related diseases, disorders or conditions that are commonly known to be mediated by hGIIA, such as inflammatory diseases, disorders or conditions (e.g., sepsis, arthritis, acute coronary syndrome) and particular cancers (e.g., prostate cancer). For such diseases which usually are hGIIA-dependent, the level of hGIIA expression and / or activity of the subject is suitably not determined prior to treatment with the agent. As used herein, the term “a catalytic activity of hGIIA” refers to an activity of hGIIA which involves catalysing the hydrolysis of the sn-2 ester bond of glycerphospholipids, thereby releasing equimolar amounts of free fatty acids and lysophospholipids, as described in more detail above (see also review by Scott et al., Molecules 2021, 26(23), 7267). The phrases “reduces a catalytic activity” and “inhibits a catalytic activity” are intended to encompass partial or complete inhibition of hGIIA enzymatic activity. The catalytic activity of hGIIA may be measured by any means known in the art, such as through assays which measure the level of one or more inflammatory markers, such as LPA, arachidonic acid, eicosanoids, inflammatory cytokines, inflammatory prostaglandins and inflammatory leukotrienes that may be produced by the enzymatic activity of hGIIA. As used herein, the term “a non-catalytic activity of hGIIA” means an enzyme activity- independent function of hGIIA. An example of a non-catalytic activity, or an enzyme activity- independent function of hGIIA is hGIIA-dependent signalling or signal transduction. In this regard, hGIIA may contribute to the eicosanoid pathway by a means other than directly providing arachidonic acid through catalysis, such as promoting activation / phosphorylation of cPLA2-α, prostaglandin (e.g., PGE2) production, COX-2 expression, EGFR activation and activation of MAPK signalling (e.g., activation of ERK signalling). Such non-catalytic activities of hGIIA may be attributed to direct interaction or binding of this enzyme with another molecule or molecules (e.g., a partner protein, such as vimentin, EGFR or an integrin), such as those reviewed in Kim et al. (Molecules 2020, 25, 4459). Such binding can be either by covalent or non-covalent interactions, or both. Examples of non-covalent interactions include electrostatic interactions, van der Waals interactions, hydrophobic interactions and hydrophilic interactions. In view of the foregoing, the agent of the present disclosure may be considered to be an hGIIA inhibitor. The term “inhibitor” as used herein refers to a molecule having the ability to inhibit a biological function and / or expression of a target polypeptide, such as hGIIA. The term “selective inhibition” or “selectively inhibit” refers to the agent’s ability to preferentially reduce the target polypeptide’s expression and / or signalling activity, such as an enzymatic activity or binding activity, as compared to off-target signalling activity, via direct or indirect interaction with the target polypeptide. Suitably, the agent is a selective inhibitor of a non-catalytic activity of hGIIA. For such examples, the agent suitably also demonstrates a reduced or limited ability to inhibit a catalytic or enzymatic activity of hGIIA versus a non-catalytic activity of hGIIA. In particular examples, the agent demonstrates a Ki (inhibition constant) for inhibiting a non-catalytic activity of hGIIA that is at least one order of magnitude, more particularly at least two orders of magnitude or even more particularly at least three orders of magnitude less than a Ki for inhibiting a catalytic activity of hGIIA. For some examples, the agent exhibits little or no inhibition of a catalytic or enzymatic activity of hGIIA (e.g., a Ki for a catalytic or enzymatic activity of hGIIA of at least about 10 μM, more particularly at least about 50 μM, or even more particularly at least about 100 μM), such as at a concentration of less than about 1 μM (e.g., no more than about 1, 5, 10, 20, 30, 40, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 μM or any range therein), more particularly less than about 5 μM, even more particularly less than about 10 μM, yet even more particularly less than about 50 μM or still even more particularly less than about 100 μM. Methods for obtaining Ki data are well known in the art and have been described, for example, in Brown et al. (J Amer Chem Soc 2000, 122(28), 6799-6800) and the references cited therein. Other useful analyses and techniques are described in U.S. Patent Publication No.2009 / 0209615, which is hereby incorporated by reference in its entirety. Any suitable inhibitor of a non-catalytic activity of hGIIA, such as those known in the art, may be utilized in the methods described herein. Examples include, but are not limited to, cyclic peptides, antibodies, nucleic acids, aptamers and small molecules, such as those described herein. According to certain examples, the subject has an elevated level of circulating hGIIA, such as prior to administration of the agent. Accordingly, the present method may include the initial or earlier step of determining the level of circulating hGIIA before and / or after administration of the agent to the subject. In one example, the level of circulating hGIIA may be determined before administration of the agent to the subject. In another example, the level of circulating hGIIA may be determined after administration of the agent to the subject. In a particular example, the level of circulating hGIIA may be determined before and after administration of the agent to the subject. Suitable methods to determine the level of circulating hGIIA are known in the art. For example, western blot, spectrophotometry, mass spectrometry and / or ELISA methods may be utilised in this regard. In one example, the level of circulating hGIIA may be measured in a blood sample obtained from the subject. In another example, the level of circulating hGIIA may be measured in a plasma sample obtained from the subject. In still a further example, the level of circulating hGIIA is measured in a serum sample obtained from the subject. In yet another example, the level of circulating hGIIA is measured, such as indirectly measured, in a urine sample obtained from the subject. In one example, the level of circulating hGIIA in the subject may be elevated prior to administering the therapeutically effective amount of the agent. As used herein, the level of circulating hGIIA is considered “elevated” when it is higher than a predetermined reference or threshold level. The level of circulating hGIIA may also be compared to a reference or threshold level of circulating hGIIA. Thus, any of the methods disclosed herein may comprise a step of establishing a reference or threshold level of hGIIA. Suitable threshold levels can then be determined according to the particular methodology used to measure the levels of hGIIA, which threshold levels can establish a significant difference in the levels of hGIIA and a healthy control, such a difference then being indicative of an increase in the level of circulating hGIIA in the subject. It will be appreciated that the precise threshold levels will vary depending on the samples used to establish those threshold levels of circulating hGIIA and according to the particular analytical methodology used in each instance. In broad terms, a threshold level for hGIIA in a biological sample, such as blood, plasma, serum or urine, may be at least about 1 ng / mL (e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 ng / mL or any range therein). In particular examples, a threshold level for hGIIA in a biological sample, such as blood, plasma or serum, is at least about 1 ng / mL, more particularly at least about 2.5 ng / mL, even more particularly at least about 5 ng / mL or still even more particularly at least about 10 ng / mL. By way of example, a hGIIA level in a biological sample, such as blood, plasma or serum, from the subject that is less than about 10 ng / mL, more particularly less than about 5 ng / mL, still more particularly less than about 2.5 ng / mL or even more particularly less than about 1 ng / mL, in the subject is considered within the normal range. Similarly, a hGIIA level in a biological sample, such as blood, plasma or serum, from the subject that is greater than about 5 ng / mL, more particularly greater than about 10 ng / mL, still even more particularly greater than about 20 ng / mL or even more particularly greater than about 30 ng / mL, may be considered an elevated level of hGIIA and by extension could be indicative of a poor prognosis for a subject with cancer. Additionally, a hGIIA level in a biological sample, such as blood, plasma, serum or urine, from the subject that is at least about 20 ng / mL, more particularly at least about 25 ng / mL, or even more particularly at least about 30 ng / mL, may be indicative of the subject, such as the subject’s cancer, being at least partly responsive to the agent. As such, an “elevated” or “increased” level of the circulating hGIIA is a level that is greater (e.g., at least about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 75%, 100%, 200% or any range therein greater) than the reference level of circulating hGIIA. The reference level of circulating hGIIA may be considered a normal or standard level thereof. The “normal” level of circulating hGIIA may be determined by selecting any suitable biological sample from which to derive the circulating level of hGIIA in a non-disease state (e.g., from a population of non-diseased individuals, such as those known not to have cancer). The “elevated” or “increased” level of circulating hGIIA may be determined by selecting any suitable biological sample from which to derive the level hGIIA in a disease state (e.g., from a population of diseased individuals, such as those known to have cancer). The level of hGIIA may be measured in any one or more cells, tissues, organs or biological samples. The biological sample may be or may comprise a bodily fluid. The bodily fluid may blood, serum, plasma or urine. For example, the circulating level of hGIIA may be measured in plasma. In another example, the circulating level of hGIIA may be measured in serum. In another example, the circulating level of hGIIA may be measured in urine. The biological sample may be subject to any suitable pre-treatment steps before the measurement is performed, in order to improve the accuracy and / or efficiency of the measurement. Thus, any of the methods disclosed herein may comprise a step of taking a biological sample from a subject and determining the circulating level of hGIIA in the sample. Alternatively, any of the methods disclosed herein may not comprise a step of taking a biological sample from a subject and determining the circulating level of hGIIA in the sample. Instead, the circulating level of hGIIA in the sample may have been determined previously. Any of the methods disclosed herein may comprise a step of establishing a reference level of circulating hGIIA. Alternatively, any of the methods disclosed herein may comprise a step of comparing the level of circulating hGIIA to a predetermined reference level. For example, the predetermined reference level may be stored in a database including such information. Suitable threshold levels can then be determined according to the particular methodology used to identify and / or measure the level of circulating hGIIA. It will be appreciated that the precise thresholds will vary depending on the samples used to establish those threshold levels and according to the particular analytical methodology used in each instance. Thus, a “low” or “normal” level of circulating hGIIA is a level of circulating hGIIA that is decreased relative to a reference or threshold level of circulating hGIIA. Conversely, a “high”, “elevated” or “increased” level of circulating hGIIA is a level that is greater than a reference or threshold level of circulating hGIIA. A “reference” level can be determined by selecting any suitable sample from which to derive the level of circulating hGIIA. That sample may be from any biological sample obtained from one or more subjects, such as control subjects who do not have a hGIIA-dependent disease, disorder or condition, such as cancer. It is envisaged that the current methods can also improve the prognosis of the subject being treated. For example, administration of an agent and / or composition described herein to the subject with a hGIIA-dependent disease, disorder or condition may reduce the probability of a clinical worsening event (e.g., metastasis, cancer progression, cancer recurrence or a combination thereof) during the treatment period, and / or a modulation (i.e., an increase or decrease) from baseline in one or more biomarkers of disease progression. In some examples, the methods described herein provide a reduction of at least about 25%, at least about 50%, at least about 75% or at least about 80%, in probability of a clinical worsening event during the treatment period. In other examples, the current methods prevent a change of at least about 25%, at least about 50%, at least about 75% or at least about 80% of the concentration of one or more biomarkers of hGIIA-dependent disease, disorder or condition progression. Again, without wishing to be bound by theory, it is believed that in certain cancers, the elevation of circulating hGIIA in the subject is correlated with a poorer outcome. Accordingly, disclosed herein is a method reducing a level of circulating hGIIA in a subject, said method including the step of orally administering an effective amount of c2 or an analogue or derivative thereof to the subject to thereby reduce the level of circulating hGIIA. The method may further include including the step of determining the level of circulating hGIIA before and / or after administration of c2 or the analogue or derivative thereof to the subject. In one example, the level of circulating hGIIA may be determined before administration of c2 or the analogue or derivative thereof to the subject. In another example, the level of circulating hGIIA may be determined after administration of c2 or the analogue or derivative thereof to the subject. In a particular example, the level of circulating hGIIA may be determined before and after administration of c2 or the analogue or derivative thereof to the subject. Suitable methods to determine the level of circulating hGIIA are known in the art. For example, western blot, spectrophotometry, mass spectrometry and / or ELISA methods may be utilised in this regard. In one example, the level of circulating hGIIA may be measured in a blood sample obtained from the subject. In another example, the level of circulating hGIIA may be measured in a plasma sample obtained from the subject. In still a further example, the level of circulating hGIIA is measured in a serum sample obtained from the subject. In yet another example, the level of circulating hGIIA is measured, such as indirectly measured, in a urine sample obtained from the subject. In one example, the level of circulating hGIIA in the subject may be elevated prior to orally administering the effective amount of c2 or the analogue or derivative thereof. As used herein, the level of circulating hGIIA is considered “elevated” when it is higher than a predetermined reference or threshold level. The level of circulating hGIIA may also be compared to a reference or threshold level of circulating hGIIA. Thus, any of the methods disclosed herein may comprise a step of establishing a reference or threshold level of hGIIA. Suitable threshold levels can then be determined according to the particular methodology used to measure the levels of hGIIA, which threshold levels can establish a significant difference in the levels of hGIIA and a healthy control, such a difference then being indicative of an increase in the level of circulating hGIIA in the subject. It will be appreciated that the precise threshold levels will vary depending on the samples used to establish those threshold levels of circulating hGIIA and according to the particular analytical methodology used in each instance. In broad terms, a threshold level for hGIIA in a biological sample, such as blood, plasma or serum, may be about 1 ng / mL, about 2 ng / mL, about 3 ng / mL, about 4 ng / mL, about 5 ng / mL, about 6 ng / mL, about 7 ng / mL, about 8 ng / mL, about 9 ng / mL, about 10 ng / mL, about 11 ng / mL, about 12 ng / mL, about 13 ng / mL, about 14 ng / mL, about 15 ng / mL, about 16 ng / mL, about 17 ng / mL, about 18 ng / mL, about 19 ng / mL, about 20 ng / mL, about 21 ng / mL, about 22 ng / mL, about 23 ng / mL, about 24 ng / mL, about 25 ng / mL, about 26 ng / mL, about 27 ng / mL, about 28 ng / mL, about 29 ng / mL, about 30 ng / mL or any range therein. In particular examples, a threshold level for hGIIA in a biological sample, such as blood, plasma or serum, is at least about 1 ng / mL, more particularly at least about 2.5 ng / mL, even more particularly at least about 5 ng / mL or still even more particularly at least about 10 ng / mL. By way of example, a hGIIA level in a biological sample, such as blood, plasma or serum, from the subject that is less than about 10 ng / mL, more particularly less than about 5 ng / mL, still more particularly less than about 2.5 ng / mL or even more particularly less than about 1 ng / mL, in the subject is considered within the normal range. Similarly, a hGIIA level in a biological sample, such as blood, plasma or serum, from the subject that is greater than about 5 ng / mL, more particularly greater than about 10 ng / mL, still even more particularly greater than about 20 ng / mL or even more particularly greater than about 30 ng / mL, may be considered an elevated level of hGIIA and by extension could be indicative of a poor prognosis for a subject with cancer. Additionally, a hGIIA level in a biological sample, such as blood, plasma, serum or urine, from the subject that is at least about 20 ng / mL, more particularly at least about 25 ng / mL, or even more particularly at least about 30 ng / mL, may be indicative of a treatment for cancer not being efficacious or only partly efficacious in the subject. An “elevated” or “increased” level of the circulating hGIIA is suitably a level that is greater than the reference, control or normal level of circulating hGIIA. The “normal” level of circulating hGIIA may be determined by selecting any suitable biological sample or samples from which to derive the circulating level of hGIIA in a non-disease state (e.g., a mean or median level). The “elevated” or “increased” level of circulating hGIIA may be determined by selecting any suitable biological sample from which to derive the level hGIIA in a disease state. The level of hGIIA may be measured in any one or more cells, tissues, organs or biological samples. The biological sample may be or may comprise a bodily fluid. The bodily fluid may blood, serum, plasma or urine. For example, the level of hGIIA may be measured in plasma. In another example, the level of hGIIA may be measured in serum. In another example, the level of hGIIA may be measured in urine. The biological sample may be subject to any suitable pre- treatment steps before the measurement is performed, in order to improve the accuracy and / or efficiency of the measurement. Thus, any of the methods disclosed herein may comprise a step of taking a biological sample from a subject and determining the level hGIIA in the sample. Alternatively, any of the methods disclosed herein may not comprise a step of taking a biological sample from a subject and determining the level hGIIA in the sample. Instead, the level of hGIIA in the sample may have been determined previously. Any of the methods disclosed herein may comprise a step of establishing a reference level of hGIIA. Alternatively, any of the methods disclosed herein may comprise a step of comparing the level of hGIIA to a predetermined reference level. For example, the predetermined reference level may be stored in a database including such information. Suitable threshold levels can then be determined according to the particular methodology used to identify and / or measure the level of hGIIA. It will be appreciated that the precise thresholds will vary depending on the samples used to establish those threshold levels and according to the particular analytical methodology used in each instance. Thus, a “low” level of hGIIA is a level of hGIIA that is decreased relative to a reference level of hGIIA. Conversely, a “high or “elevated” or “increased” level of hGIIA is a level that is greater than a reference level of hGIIA. A “reference” level can be determined by selecting any suitable sample from which to derive the level of hGIIA. That sample may be from any biological sample obtained from one or more subjects, such as control subjects who do not have cancer. Also disclosed herein is a method of selecting a subject as being suitable for oral administration of c2, or an analogue or derivative thereof, said method including the step of determining a level of circulating hGIIA in the subject, wherein an elevated level of circulating hGIIA is indicative of the subject being suitable for oral administration of c2 or the analogue or derivative thereof. Any of the methods disclosed herein may further include the step of orally administering an effective amount of c2 or the analogue or derivative thereof to the subject if the level of circulating hGIIA in the subject is elevated. Dosage Suitably, the agent disclosed herein can be administered to a subject already suffering from a hGIIA-dependent disease, disorder or condition, in an amount sufficient to cure, or at least partially arrest said disease, disorder or condition and its complications. In some examples, c2 or the compositions disclosed herein can be administered to a patient already suffering from cancer, in an amount sufficient to cure, or at least partially arrest the cancer and its complications. In other examples, the methods, compositions and uses disclosed herein also include or relate to prophylactic or preventative application of a suitable effective dose of the agent, c2 or the compositions described herein. In some examples, the agent, c2 or the compositions provided herein, in an appropriate effective dose, is used as a maintenance therapy. The therapeutically effective dose level for any particular patient or subject, will depend upon a variety of factors familiar to one skilled in the art, including, for example: the disease, disorder or condition, or more particularly the cancer, being treated and / or the severity of the disease, disorder or condition, or more particularly the cancer, the age, body weight, general health, sex and diet of the patient, the time of administration, the route of administration, the duration of the treatment, drugs used in combination or coincidental with the treatment, together with other related factors well known in medicine. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, gender, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, a patient's body surface area, whether the patient is undergoing therapy, and any specific contraindications. In one example, the agent, such as c2, cF or the analogue or derivative thereof, is administered, such as orally administered, at a dose of about 5 mg / day to about 1500 mg / day, or about 5 mg / day to about 1200 mg / day, or about 5 mg / day to about 1000 mg / day, or about 5 mg / day to about 900 mg / day, or about 5 mg / day to about 800 mg / day, or about 5 mg / day to about 700 mg / day, or about 5 mg / day to about 600 mg / day, or about 5 mg / day to about 500 mg / day, or about 5 mg / day to about 400 mg / day, or about 5 mg / day to about 300 mg / day, or about 5 mg / day to about 200 mg / day, or about 5 mg / day to about 100 mg / day. According to various examples, the agent, such as c2, cF or the analogue or derivative thereof is orally administered at a dose, such as a daily dose, of about 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 mg or any range therein. For some examples, the agent, such as c2, cF or the analogue or derivative thereof, is orally administered at a dose of about 5 mg / day to about 1500 mg / day. In other examples, the agent described herein (e.g., c2, cF or the analogue or derivative thereof) is orally administered at a dose of about 5 mg / day to about 100 mg / day. In one example, the medicament comprises the agent described herein (e.g., c2, cF or the analogue or derivative thereof) at a dose of about 5 mg / day to about 1500 mg / day, or about 5 mg / day to about 1200 mg / day, or about 5 mg / day to about 1000 mg / day, or about 5 mg / day to about 900 mg / day, or about 5 mg / day to about 800 mg / day, or about 5 mg / day to about 700 mg / day, or about 5 mg / day to about 600 mg / day, or about 5 mg / day to about 500 mg / day, or about 5 mg / day to about 400 mg / day, or about 5 mg / day to about 300 mg / day, or about 5 mg / day to about 200 mg / day, or about 5 mg / day to about 100 mg / day. In one example, the medicament is formulated for administration, and more particularly oral administration, of the agent described herein (e.g., c2, cF or the analogue or derivative thereof) at a dose of about 5 mg / day to about 1500 mg / day. In another example, the medicament is formulated for administration, and more particularly oral administration, of the agent described herein (e.g., c2, cF or the analogue or derivative thereof) at a dose of about 5 mg / day to about 100 mg / day. Further, it will be apparent to one of ordinary skill in the art that the optimal quantity and spacing of the treatment for the disease, disorder or condition, and more particularly the cancer, being treated, the form, route and site of administration, and the nature of individual dosages will be determined by the nature and extent the particular individual being treated. Also, such optimum conditions can be determined by conventional techniques. It is further contemplated that the agent described herein (e.g., c2, cF or the analogue orderivative thereof) may be orally administered daily or alternatively every 2nd, 3rd, 4th, 5th, 6th or7thday, such as with those dosages hereinbefore provided. In particular examples, the agent described herein (e.g., c2, cF or the analogue or derivative thereof) are orally administered once, twice, three times, four times or five times per week over the course of the treatment regime. For some examples, the agent described herein (e.g., c2, cF or the analogue or derivative thereof) are orally administered at a dosage of about 5 mg to about 1500 mg, about 5 mg to about 1200 mg, about 5 mg to about 1000 mg, about 5 mg to about 900 mg, about 5 mg to about 800 mg, about 5 mg to about 700 mg, about 5 mg to about 600 mg, about 5 mg to about 500 mg, about 5 mg to about 400 mg, about 5 mg to about 300 mg, about 5 mg to about 200 mg, about 5 mg to about 100 mg, or about 0.5 mg to about 50 mg, two, three, four or five times per week. In any of the methods disclosed herein, the agent described herein (e.g., c2, cF or the analogue or derivative thereof) may be administered, and more particularly orally administered, daily for a period of at least about 2 weeks (e.g., at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 weeks or any range therein), or at least about 3 weeks, or at least about 4 weeks, or at least about 5 weeks, or at least about 6 weeks. In one example, the agent (e.g., c2, cF or the analogue or derivative thereof)is administered, and more particularly orally administered, daily for a period of at least about 2 weeks. In another example, the agent (e.g., c2, cF or the analogue or derivative thereof) is administered, and more particularly orally administered, daily for a period of at least about 6 weeks. In any of the uses disclosed herein, the medicament may be formulated for administration or oral administration of the agent (e.g., c2, cF or the analogue or derivative thereof)for a period of at least about 2 weeks, or at least about 3 weeks, or at least about 4 weeks, or at least about 5 weeks, or at least about 6 weeks. In one example, the medicament may be formulated for administration or oral administration of the agent (e.g., c2, cF or the analogue or derivative thereof)daily for a period of at least about 2 weeks. In another example, the medicament may be formulated for administration or oral administration of the agent (e.g., c2, cF or the analogue or derivative thereof) daily for a period of at least about 6 weeks. Those skilled in the art will appreciate that in accordance with the presently disclosed methods and uses, the agent (e.g., c2, cF or the analogue or derivative thereof) or the pharmaceutical composition may be administered alone or in conjunction with one or more additional agents as part of a combination chemotherapy. For example, the agent (e.g., c2, cF or the analogue or derivative thereof) or the composition may be administered together with one or more additional compounds capable of decreasing cell proliferation and invasion and increasing apoptosis in cancer. In some examples, methods of treatment and / or prevention according to the present disclosure may be applied in combination with a standard chemotherapeutic agent. The chemotherapeutic agent may be selected from, for example: an oxaliplatin, a cisplatin an anthracycline, a taxane, and / or a camptothecin. In some examples, chemotherapeutic agents may be an EGFR inhibitor. In some examples, chemotherapeutic agents may be immune checkpoint inhibitors. In some examples, chemotherapeutic agents may be an immunomodulatory agent (for example, one or more of: Atezolizumab, A velumab Ipilimumab, Bevacizumab, Cemiplimab, Durvalumab, Pembrolizumab, Nivolumab and / or Pidilizumab). In some examples, the chemotherapeutic agent is selected from: temozolomide, dacarbazine, carmustine (BCNU), lomustine (CCNU), paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, etoposide, teniposide, topotecan, irinotecan, doxorubicin, daunomycin, epirubicin, idarubicin, methotrexate, cytarabine, gemcitibine, capecitabine, cisplatin, carboplatin, cyclophosphamide, oxaliplatin, or a mixture thereof. In further examples, the further anti-cancer treatment may be surgery or hormone therapy. Suitable hormone therapies are known in the art and include but are not limited to, anti- androgens such as abiraterone, enzalutamide, flutamide, nilutamide, apalutamide and darolutamide. For such combination therapies, each component of the combination therapy may be administered sequentially in any order, at the same time or at different times, so as to provide the desired effect. Alternatively, the chemotherapeutic agent may be formulated to be administered in the same formulation as the agent (e.g., c2, cF or the analogue or derivative thereof) or the composition. Therapeutic advantages of the presently disclosed methods and uses may also be realised through combination regimens in conjunction with conventional therapy, such as radiotherapy, chemotherapy, surgery, or other forms of medical intervention. In some examples, the conventional therapy is radiotherapy, which may be administered with or without temozolomide or any other chemotherapeutic agent, such as those described above. The temozolomide or any other chemotherapeutic agent may be administered sequentially in any order, at the same time or at different times as the composition, so as to provide the desired effect. Alternatively, the temozolomide or any other chemotherapeutic agent may be formulated to be administered in the same formulation as the agent (e.g., c2, cF or the analogue or derivative thereof) or the compositions. Inhibiting hGIIA in a cell The present disclosure also provides methods of inhibiting a non-catalytic activity of hGIIA in a cancer cell. In this regard, the present inventors have surprisingly shown that c2 and cF can selectively inhibit the non-enzymatic functions of hGIIA, such as hGIIA-dependent cell signalling, in cancer cells. As a result, selective inhibitors of hGIIA non-enzymatic activity, such as c2 and cF, can be selectively toxic to hGIIA-dependent cancer cells and thereby inhibit their viability and / or growth. Accordingly, in one form, the present disclosure provides a method of inhibiting a non- catalytic activity of hGIIA in a cancer cell, said method including the step of contacting the cancer cell with an effective amount of: (a) c2 or an analogue or derivative thereof; or (b) cF or an analogue or derivative thereof. More particularly, the present disclosure provides a method of inhibiting a non-catalytic activity of hGIIA in a cancer cell, said method including the step of contacting the cancer cell with an effective amount of c2 or an analogue or derivative thereof. Suitably, a level of a non-catalytic activity of hGIIA in the cell in the presence of c2, cF or an analogue or derivative thereof is less than about 99%, 98%, 97%, 96%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10%, or even less than about 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.01%, 0.001% or 0.0001% of the level of such hGIIA activity of a control or reference cell in the absence of c2, cF or the analogue or derivative thereof. Such levels of the non- catalytic activity of hGIIA may be determined by any means known in the art, such as those described herein. Such inhibition may lead to reductions in the viability and / or growth of a cancer cell. Accordingly, inhibition of the non-catalytic activity of hGIIA in cancer cells may also be assessed indirectly by assessing their viability and / or growth, such as through those assays described herein. Similarly, such inhibition may lead to increases in the levels of apoptosis and / or cell death in a cancer cell or population of cancer cells. The term “reducing the viability and / or growth” is used to mean reducing the ability of a cancer cell, such as an hGIIA-dependent cancer cell, to survive and / or proliferate. Cell viability and / or growth may be inhibited in any measurable amount. Inhibition of cell viability and / or growth may be complete or may be partial. Thus, the methods disclosed herein may comprise at least partial inhibition of cancer cell viability and / or growth. Suitably, the viability and / or growth of the cancer cell in the presence of the c2, cF or an analogue or derivative thereof is less than about 99%, 98%, 97%, 96%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10%, or even less than about 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.01%, 0.001% or 0.0001% of the viability and / or growth of a control or reference cancer cell in the absence of c2, cF or the analogue or derivative thereof. Suitably, the level of apoptosis and / or cell death of a population of cancer cells in the presence of c2, cF or an analogue or derivative thereof is greater than about 101%, 102%, 103%, 104%, 105%, 110%, 115%, 120%, 125%, 130%, 140%, 150%, 160% or 170%, or even greater than about 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600% or 700%% of the level of apoptosis and / or cell death of a control or reference cancer cell population in the absence of c2, cF or the analogue or derivative thereof. Viability, apoptosis and / or cell death of the cancer cells may be assessed by any suitable means or method known in the art. Typically, cell viability is quantified as the percentage of living cells present (i.e., the number of live cells divided by the total number of cells). As cells are either live or dead, cell viability may be determined by quantifying either dead cells or live cells. One suitable method is trypan blue exclusion. Other assays for determining cell viability may include, without limitation, propidium iodide staining, TUNEL, Resazurin, methyl violet, lactate dehydrogenase, fluorescein diacetate hydrolysis, MTT, caspase, Annexin V and ATP assays. Growth or proliferation of the cancer cells may also be measured by methods known in the art. Suitable methods include measuring the size of the cell population (e.g., by counting cells using a marker specific for the cell population, i.e. a tumour specific marker) or by performing cell cycle analysis using 5-bromo-2'-deoxyuridine (BrdU) which becomes incorporated into newly made DNA and propidium iodide (PI) and analysing by flow cytometry in combination with a cell population specific marker. Other suitable methods for measuring proliferation include proliferations assays, such as MTT assays, MTS assays, intracellular ATP assays, measuring cellular LDH activity, 3H-thymidine incorporation and the Cell Titer Glo Assay. In relation to the aforementioned methods, the cell is suitably a cancer cell and more particularly an hGIIA-related cancer cell. The hGIIA-related cancer cell may be derived from any vertebrate, such as a mammal, and in particular, a human. Additionally, the hGIIA-related cancer cell may be derived from any cancer, such as those described herein. In some examples, the cancer cell is a prostate cancer cell, a brain cancer cell, a head and neck cancer cell, an ovarian cancer cell, a breast cancer cell, a cervical cancer cell, a lung cancer cell, a pancreatic cancer cell, a colon cancer cell, an oesophageal cancer cell, a melanoma cell, a rhabdomyosarcoma cell, a mesothelioma cell, a squamous carcinoma cell or a glioblastoma cell. According to particular examples, the cancer cell is a prostate cancer cell. As used herein, the term “effective amount” and the like refers to an amount of c2, cF or an analogue or derivative thereof that is sufficient to induce a desired physiological outcome (e.g., at least partly inhibiting a non-catalytic activity of hGIIA in the cell). An effective amount can be administered in one or more administrations, applications or dosages. It is envisaged that the method of the present methods may be performed in relation to cells in vitro, in vivo and / or ex vivo. In some examples, the method is performed in vitro, such as with hGIIA-dependent cancer cells isolated from a subject or a patient-derived xenograft model. Accordingly, in some examples, the present method includes the earlier step of isolating the cells expressing hGIIA, such as hGIIA-dependent cancer cells, from the subject. In other examples, the present method is performed in vivo in a subject. For the purposes of the present disclosure, by “isolated” is meant material that has been removed from its natural state or otherwise been subjected to human manipulation. Isolated material (e.g., hGIIA-dependent cancer cells) may be substantially or essentially free from components that normally accompany it in its natural state, or may be manipulated so as to be in an artificial state together with components that normally accompany it in its natural state. The present method may include the initial or earlier step of determining a level of a non- catalytic activity of hGIIA of a cell, such as a level of hGIIA-dependent cell signalling of a cancer cell to identify an hGIIA-dependent cancer cell. Such determining, assessing, evaluating or assaying an hGIIA status of a cancer cell, may be performed by any technique known in the art, such as those methods described herein. According to certain examples, the present methods further include the step of contacting the hGIIA-related cancer cell with an effective amount of a further anti-cancer agent, such as those described herein. Compositions Further aspects of the present disclosure provide a composition comprising an agent described herein, and one or more pharmaceutically acceptable carriers, diluents or excipients. By “pharmaceutically-acceptable carrier, diluent or excipient” is meant a solid or liquid filler, diluent or encapsulating substance that may be safely used in systemic administration. Depending upon the particular route of administration, a variety of carriers well known in the art may be used. These carriers may be selected from a group including sugars, starches, cellulose and its derivatives, malt, gelatine, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline and salts such as mineral acid salts including hydrochlorides, bromides and sulfates, organic acids such as acetates, propionates and malonates and pyrogen-free water. A useful reference describing pharmaceutically acceptable carriers, diluents and excipients is Remington's Pharmaceutical Sciences (Mack Publishing Co. NJ. USA, 1991), which is incorporated herein by reference. According to some examples, the present composition is in the form of a therapeutic composition. A therapeutically effective amount of a composition comprising a cyclic peptide may be administered in a single dose, or in several doses, for example daily, during a course of treatment. However, the frequency of administration is dependent on the preparation applied, the subject being treated, the severity of the disease, disorder or condition (e.g., cancer), and the manner of administration of the therapy or composition. Any safe route of administration may be employed for administering an agent and pharmaceutical composition described herein. For example, oral, rectal, parenteral, sublingual, buccal, intravenous, intra- articular, intra-muscular, intra-dermal, subcutaneous, inhalational, intraocular, intraperitoneal, intracerebroventricular, transdermal and the like may be employed. Dosage forms include tablets, dispersions, suspensions, injections, solutions, syrups, troches, capsules, suppositories, aerosols, transdermal patches and the like. These dosage forms may also include injecting or implanting controlled releasing devices designed specifically for this purpose or other forms of implants modified to act additionally in this fashion. Controlled release of the therapeutic agent may be achieved by coating the same, for example, with hydrophobic polymers including acrylic resins, waxes, higher aliphatic alcohols, polylactic and polyglycolic acids arid certain cellulose derivatives such as hydroxypropylmethyl cellulose, in addition, the controlled release may be achieved by using other polymer matrices, liposomes and / or microspheres. In particular examples, the agent or composition is capable of being or configured or adapted to be administered orally to a subject in need thereof. For such examples, the composition is suitably enterically coated. Compositions of the present disclosure suitable for oral or parenteral administration may be presented as discrete units such as capsules, sachets or tablets each containing a pre- determined amount of one or more therapeutic agents of the disclosure, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an οil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association one or more therapeutic agents as described above with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the therapeutic agents of the disclosure with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. The above compositions may be administered in a manner compatible with the dosage formulation, and in such an amount as is effective to prophylactically and / or therapeutically treat hGIIA-associated or hGIIA-dependent diseases, disorders or conditions and / or alleviate symptoms associated therewith. The dose administered to a patient, in the context of the present disclosure, should be sufficient to achieve a beneficial response in a patient over time such as a complete or partial response or stable disease (e.g., little or no disease progression). The quantity of the therapeutic agent(s) to be administered may depend on the subject to be treated inclusive of the age, sex, weight and general health condition thereof. In this regard, precise amounts of the therapeutic agent(s) required to be administered will depend on the judgement of the clinician. The total dose required for each treatment may be administered by multiple doses or in a single dose. In any event, suitable dosages of the therapeutic agents described herein may be readily determined by those skilled in the art. Such dosages may be in the order of nanograms to milligrams of the therapeutic agents of the disclosure. In particular examples, the composition comprises the agent in an amount of about 5 mg to about 1500 mg (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 mg or any range therein), or about 5 mg to about 1400 mg, or about 5 mg to about 1300 mg, or about 5 mg to about 1200 mg, or about 5 mg to about 1100 mg, or about 5 mg to about 1000 mg, or about 5 mg to about 900 mg, or about 5 mg to about 800 mg, or about 5 mg to about 700 mg, or about 5 mg to about 600 mg, or about 5 mg to about 500 mg, or about 5 mg to about 400 mg, or about 5 mg to about 300 mg, or about 5 mg to about 200 mg, or about 5 mg to about 100 mg, or about 5 mg to about 10 mg, or about 5 mg to about 20 mg, or about 5 mg to about 40 mg, or about 5 mg to about 60 mg. Suitably, the composition further comprises one or more further or additional therapeutic agents, such as an anti-cancer agent or an anti-inflammatory agent, inclusive of those described herein. According to various examples, the composition described herein is for use in therapy. More particularly, the composition described herein is suitably for use in treating, preventing or ameliorating a hGIIA-dependent disease, disorder or condition, such as a cancer. Also disclosed herein is a pharmaceutical composition comprising c2, cF or the analogue or derivative thereof, in an amount of about 5 mg to about 1500 mg (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 mg or any range therein), or about 5 mg to about 1400 mg, or about 5 mg to about 1300 mg, or about 5 mg to about 1200 mg, or about 5 mg to about 1100 mg, or about 5 mg to about 1000 mg, or about 5 mg to about 900 mg, or about 5 mg to about 800 mg, or about 5 mg to about 700 mg, or about 5 mg to about 600 mg, or about 5 mg to about 500 mg, or about 5 mg to about 400 mg, or about 5 mg to about 300 mg, or about 5 mg to about 200 mg, or about 5 mg to about 100 mg, or about 5 mg to about 10 mg, or about 5 mg to about 20 mg, or about 5 mg to about 40 mg, or about 5 mg to about 60 mg. In one example, c2, cF or the analogue or derivative thereof is orally administered at a dose of about 5 mg to about 1500 mg; and a cellulose derivative. In one example, c2, cF or the analogue or derivative thereof is orally administered at a dose of about 10 mg per day. In one example, c2, cF or the analogue or derivative thereof is orally administered at a dose of about 30 mg per day. In one example, c2, cF or the analogue or derivative thereof is orally administered at a dose of about 50 mg per day. In one example, c2, cF or the analogue or derivative thereof is orally administered at a dose of about 100 mg per day. In one example, the pharmaceutical composition comprises c2, cF or an analogue or derivative thereof, in an amount of about 5 mg to about 1500 mg; and a cellulose derivative. In another example, the pharmaceutical composition comprises c2, cF or an analogue or derivative thereof, in an amount of about 5 mg to about 100 mg; and a cellulose derivative. In another example, the pharmaceutical composition comprises c2, cF or an analogue or derivative thereof, in an amount of about 5 mg. In another example, the pharmaceutical composition comprises c2, or an analogue or derivative thereof, in an amount of about 10 mg. In another example, the pharmaceutical composition comprises c2, cF or an analogue or derivative thereof, in an amount of about 20 mg. In another example, the pharmaceutical composition comprises c2, cF or an analogue or derivative thereof, in an amount of about 30 mg. In another example, the pharmaceutical composition comprises c2, or an analogue or derivative thereof, in an amount of about 40 mg. In another example, the pharmaceutical composition comprises c2, cF or an analogue or derivative thereof, in an amount of about 50 mg. In another example, the pharmaceutical composition comprises c2, cF or an analogue or derivative thereof, in an amount of about 60 mg. In another example, the pharmaceutical composition comprises c2, cF or an analogue or derivative thereof, in an amount of about 100 mg. Suitable cellulose derivatives are known in the art. In one example, the cellulose derivative is microcrystalline cellulose. The pharmaceutical composition may be formulated as capsule or a pill. In one example, the pharmaceutical composition may be formulated as capsule. In another example, the pharmaceutical composition may be formulated as a pill. In one specific example, the capsule is a cellulose-based capsule. Also disclosed herein is a unit dosage form comprising c2, cF or an analogue or derivative thereof, in an amount of about 5 mg to about 1500 mg (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 mg or any range therein), or about 5 mg to about 1500 mg, or about 5 mg to about 1400 mg, or about 5 mg to about 1300 mg, or about 5 mg to about 1200 mg, or about 5 mg to about 1100 mg, or about 5 mg to about 1000 mg, or about 5 mg to about 900 mg, or about 5 mg to about 800 mg, or about 5 mg to about 700 mg, or about 5 mg to about 600 mg, or about 5 mg to about 500 mg, or about 5 mg to about 400 mg, or about 5 mg to about 300 mg, or about 5 mg to about 200 mg, or about 5 mg to about 100 mg, or about 5 mg to about 10 mg, or about 5 mg to about 20 mg, or about 5 mg to about 40 mg, or about 5 mg to about 60 mg. In another example, the unit dosage form comprises c2, cF or an analogue or derivative thereof, in an amount of about 5 mg to about 100 mg. In another example, the unit dosage form comprises c2, cF or an analogue or derivative thereof, in an amount of about 5 mg. In another example, the unit dosage form comprises c2, cF or an analogue or derivative thereof, in an amount of about 10 mg. In another example, the unit dosage form comprises c2, cF or an analogue or derivative thereof, in an amount of about 20 mg. In another example, the unit dosage form comprises c2, cF or an analogue or derivative thereof, in an amount of about 40 mg. In another example, the unit dosage form comprises c2, cF or an analogue or derivative thereof, in an amount of about 60 mg. The pharmaceutical composition or the unit dosage form may be formulated for oral administration to a subject. Single or multiple administrations of the compositions are administered depending on the dosage and frequency as required and tolerated by the subject. The dosage and frequency will typically vary according to factors specific for each patient depending on the specific therapeutic or prophylactic agents administered, the severity and type of disease or condition, the route of administration, as well as age, body weight, response, and the past medical history of the patient. Suitable regimens can be selected by one skilled in the art by considering such factors and by following, for example, dosages reported in the literature and recommended in the Physician's Desk Reference (56th ed., 2002). Generally, the dose is sufficient to treat or ameliorate symptoms or signs of disease without producing unacceptable toxicity to the patient. Screening methods In light of the present disclosure, the person skilled in the art may conduct screening assays to identify, design or produce an agent, such as a cyclic peptide, a peptidomimetic or a small molecule, capable of inhibiting, and more particularly selectively inhibiting, a non- catalytic activity of hGIIA and that induce little or no drug-induced toxicity, such as cardiotoxicity. In a particular form, the present disclosure relates to a method of identifying, designing or producing an hGIIA inhibitor that induces little or no drug-induced toxicity in a subject, said method including the steps of: (a) contacting hGIIA with a candidate hGIIA inhibitor; and (b) determining whether the candidate hGIIA inhibitor inhibits a non-catalytic activity of hGIIA. In a related form, the present disclosure provides an agent for use in treating, preventing or ameliorating a hGIIA-dependent disease, disorder or condition in a subject, obtained by the above method. Accordingly to particular examples, the hGIIA inhibitor induces little or no drug-induced cardiotoxicity. Such drug-induced toxicity may be assessed by any means or method known in the art, including those described herein. Suitably, the hGIIA inhibitor induces little or no drug- induced toxicity, inclusive of cardiotoxicity, at a therapeutically effective dose, such as those described herein (e.g., about 5 mg / day to about 1500 mg / day or more particularly about 5 mg / day to about 100 mg / day) and when administered to a subject for a suitable or appropriate dosing or treatment period (e.g., a period of at least about 2 weeks or more particularly a period of at least about 6 weeks), such as those provided herein. Suitably, the present method is performed in vitro, such as in relation to isolated, synthetic and / or recombinant hGIIA. Suitably, the present method comprises contacting a cell expressing hGIIA with the candidate hGIIA inhibitor and / or determining whether the candidate hGIIA inhibitor inhibits a non-catalytic activity of hGIIA of the cell. In this regard, hGIIA may be present inside the cell and / or at or associated with the cell surface thereof. According to various examples, the cell expressing hGIIA is a cancer cell, such as those described herein. In certain examples, the cell expressing hGIIA is an hGIIA-related cancer cell. For some examples, the cell expressing hGIIA is a prostate cancer cell, such as those described herein. It is envisaged that any method known in the art to assess a non-catalytic activity of hGIIA, or a level thereof, may be utilised for the present method. In particular examples, the ability of a candidate compound to reduce a non-catalytic activity of hGIIA (e.g., signal transduction via hGIIA) can be assessed by any one of the cell-based assays described herein (e.g., an ability of the candidate hGIIA inhibitor to inhibit cPLA2-α activation (e.g., reduces cPLA2-α phosphorylation), PGE2 production, EGFR activation or MAPK or ERK signalling in prostate cancer cell lines, such as LNCaP, PC-3 and DU145 cell lines, in the presence of TNF and hGIIA, an ability of the candidate hGIIA inhibitor to inhibit hGIIA binding to EGFR, or an ability to induce or promote apoptosis in prostate cancer cell lines, as described in Example 1). In some examples, the present method further includes the step of determining whether the candidate hGIIA inhibitor inhibits cPLA2-α activation, PGE2 production, EGFR activation and / or ERK signalling in the cell in the presence of TNF and hGIIA. Suitably, the present method further includes the step of determining whether the candidate hGIIA inhibitor inhibits hGIIA binding to epidermal growth factor receptor (EGFR) in the cell. In this regard, the candidate hGIIA inhibitor is suitably capable of interacting with or binding to an hGIIA binding domain of EGFR. Without being bound by any theory, it is hypothesized that the non-catalytic activity of hGIIA is at least partly mediated by its binding or interaction with EGFR. The terms “epidermal growth factor receptor” or “EGFR” as used herein generally refer to the Epidermal Growth Factor Receptor, also known as ErbB1 or HER1 (Ullrich et al., Nature 309:418-425, 1984), which is a 170kDa transmembrane glycoprotein encoded by the c-ErbB1 protooncogene. EGFR is a member of the human epidermal growth factor receptor (HER) family of Receptor Tyrosine Kinases (RTKs) which also includes HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB 4). EGFR signalling is initiated by ligand binding, followed by initiation of a signalling cascade by inducing conformational changes, homo- or hetero-dimerization of the receptor with other ErbB family members, and trans-autophosphorylation of the receptor, among others (see Ferguson et al., Annu Rev Biophysis, 37: 353-73, 2008), ultimately affecting a variety of cellular functions (e.g., cell proliferation and survival). Increased expression of EGFR, or its kinase activity, is associated with a range of human cancers, such as glioma, lung cancer, colorectal cancer, head and neck cancer, breast cancer, ovarian cancer, prostate cancer, cervical cancer, and the like. Protein sequences of EGFR are publicly available (e.g., P00533). An exemplary amino acid sequence of human EGFR is set forth in SEQ ID NO: 3. The present disclosure also envisages naturally-occurring variants of EGFR. Such variants include the well known EGFRvIII and other alternatively spliced variants (e.g., as identified by UniProt Accession numbers P00533-1, P00533-2, P00533-3, P00533-4), or other variants (e.g., GLN-98, ARG-266, LYS-521, ILE-674, GLY-962, and PRO-988), inclusive of disease- (e.g., cancer) and drug resistance-based EGFR variants, known in the art. The present disclosure also encompasses the mature version of the EGFR protein (i.e., minus the signal peptide – residues 1-24 of SEQ ID NO: 3), such as that provided in SEQ ID NO: 4. Thus, the EGFR amino acid sequence may be a protein which is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% or 100% identical to SEQ ID NO:3 or SEQ ID NO:4 or a fragment or derivative thereof. EGFR protein (SEQ ID NO: 3) MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEV VLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALA VLSNYDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDF QNHLGSCQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGC TGPRESDCLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYV VTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFK NCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAF ENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKL FGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCN LLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVM GENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVV ALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGS GAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGI CLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAA RNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSY GVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPK FRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQ QGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTED SIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLN TVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRV APQSSEFIGA Mature EGFR protein (SEQ ID NO: 4) LEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVVLGNLEITYVQRNYDLSFLKTIQE VAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSNYDANKTGLKELPMRNLQEIL HGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGSCQKCDPSCPNGSCWGAGE ENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESDCLVCRKFRDEATCKDTC PPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSCVRACGADSYEMEEDGVR KCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHT PPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLN ITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQ VCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLP QAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNC TYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRRRHIVRKRTLRRLLQ ERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAI KELREATSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQLITQLMPFGCLLDYVRE HKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKLLGA EEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEIS SILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARDPQRYLVIQGD ERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNN STVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGS VQNPVYHNQPLNPAPSRDPHYQDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQ ISLDNPDYQQDFFPKEAKPNGIFKGSTAENAEYLRVAPQSSEFIGA Suitably, the hGIIA binding domain of EGFR comprises or is defined by one or more residues selected from amino acids Q8, G9, T10, S11, N12, K13, L14, T15, Q16, L17, H23, F24, L25, S26, L27, Q28, R29, M30, L41, E42, T43 and T44 of SEQ ID NO: 4. More particularly, the ligand binding domain of EGFR suitably comprises or is defined by one or more residues selected from amino acids L17, H23, F24, L25, S26, L27, Q28, R29, M30, L41, E42, T43 and T44 of SEQ ID NO: 4. It is envisaged that any method known in the art to assess hGIIA binding to EGFR and / or EGFR activity in the presence of a candidate hGIIA inhibitor may be utilised for the present method. In particular examples, a level of EGFR expression and / or activity, such as by way of a kinase assay, downstream signalling, such as ERK signalling (e.g., phosphorylated ERK levels), or a cell viability assay employing an EGFR-dependent cell line (e.g., an EGFR-dependent cancer cell line, such as PC-3) is assessed. In other examples, a level of hGIIA binding to EGFR, such as by way of an immunoassay or an in vitro competition assay (e.g., ELISA, AlphaLISA), is assessed. The candidate hGIIA inhibitor may block or reduce hGIIA binding to EGFR in the cell by at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% when compared to binding of hGIIA to EGFR in the absence of the candidate hGIIA inhibitor described herein using the same assay conditions. According to certain examples, the present method further includes the step of determining whether the candidate hGIIA inhibitor inhibits a catalytic activity of hGIIA, such as that expressed by a cell. The catalytic activity of hGIIA may be assessed by any means known in the art, such as those described herein. Suitably, the candidate hGIIA inhibitor is a selective inhibitor of a non-catalytic activity of hGIIA and so by extension exhibits little or no inhibitory activity in respect of a catalytic activity of hGIIA. To this end, the candidate hGIIA inhibitor may block or reduce a catalytic activity of hGIIA, such as that expressed by the cell, by no more than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%, when compared to the catalytic activity of hGIIA in the absence of the candidate hGIIA inhibitor described herein using the same assay conditions. Suitably, the candidate hGIIA inhibitor is a cyclic peptide. In particular examples, the candidate hGIIA inhibitor is a derivative or variant of c2. For other examples, the candidate hGIIA inhibitor is a derivative or variant of cF. It is also envisaged, however, that the candidate agent may comprise, for example, a linear peptide, a peptidomimetic or a small molecule that utilise the binding structures or moieties of the cyclic peptides of the present disclosure in an attempt to mimic their inhibitory activity in relation to the non-catalytic activity of hGIIA. The cyclic peptides described herein may also be utilised to search existing compound libraries, numbering hundreds of thousands to millions of candidate inhibitors (chemical compounds including synthetic, small organic molecules or natural products, such as inhibitory peptides or proteins), which may be screened or tested for biological activity at any one of hundreds of molecular targets in order to find potential new drugs, or lead compounds. Screening methods may include, but are not limited to, computer-based (“in silico”) screening and high throughput screening based on in vitro assays. Thus, the present disclosure provides methods to identify, design or produce an agent capable of inhibiting, or more particularly selectively inhibiting, a non-catalytic activity of hGIIA when administered to a cell, tissue, or subject. Such methods may be carried out in vivo, for example in animal subjects; or using in vitro and / or ex vivo assays, such as described herein. Typically, the active compounds, or "hits", from this initial screening process are then tested sequentially through a series of other in vitro and / or in vivo tests to further characterize the active compounds. A progressively smaller number of the "successful" compounds at each stage are selected for subsequent testing, eventually leading to one or more drug candidates being selected to proceed to being tested in human clinical trials. At the clinical level, screening a candidate agent may include obtaining samples from test subjects before and after the subjects have been exposed to a test compound. The levels in the samples of a non-catalytic activity of hGIIA or hGIIA signalling (and optionally a level of catalytic activity of hGIIA) may then be measured and analysed to determine whether the levels and / or activity thereof changes after exposure to a candidate agent. By way of example, protein product levels in the samples may be determined by mass spectrometry, western blot, ELISA, electrochemistry and / or by any other appropriate means known to one of skill in the art. In this regard, candidate agents that are identified of being capable of reducing, eliminating, suppressing or inhibiting the non-catalytic activity of hGIIA (and optionally demonstrates little or no inhibition of the catalytic activity of hGIIA) may then be administered to patients who are suffering from an hGIIA-dependent disease, disorder or condition. For example, the administration of a candidate agent which inhibits or decreases the non-catalytic activity of hGIIA may treat the hGIIA-dependent disease, disorder or condition and / or decrease the risk or progression of the hGIIA-dependent disease, disorder or condition, if increased non- catalytic activity of hGIIA is responsible, at least in part, for the persistence, progression and / or onset of said hGIIA-dependent disease, disorder or condition. In various examples, the methods disclosed herein may further include the step of isolating and / or purifying an agent that inhibits the non-catalytic activity of hGIIA, such as that expressed by the cell. Suitably, the isolated and / or purified agent does not inhibit or minimally inhibits the catalytic activity of hGIIA, such as that expressed by the cell. In particular examples, the method further includes the step of formulating the isolated and / or purified agent into a pharmaceutically acceptable formulation. Other steps in the method may include sterilising the formulation and / or filling the formulation into a container, such as a vial, an ampoule, a bag, a blister pack, a bottle, a cartridge, an injection needle, an injection syringe, a single dose container, a strip of multiple single dose containers, or a tube. It is also contemplated that the candidate agent or inhibitor may be rationally designed or engineered de novo based on desired or predicted structural characteristics or features that indicate the candidate agent could block or inhibit the non-catalytic activity of hGIIA. In other examples, the candidate agent may be identified by screening a library of molecules without initial selection based on desired or predicted structural characteristics or features that indicate the candidate modulator could block or inhibit the non-catalytic activity of hGIIA. Such libraries may comprise randomly generated or directed libraries of proteins or peptides, and more particularly cyclic peptides, libraries of naturally-occurring molecules and / or combinatorial libraries of synthetic organic molecules. Non-limiting examples of techniques applicable to the design and / or screening of candidate agents may employ X-ray crystallography, NMR spectroscopy, computer assisted screening of structural databases, computer-assisted modelling or biochemical or biophysical techniques which detect molecular binding interactions, as are well known in the art. Biophysical and biochemical techniques which identify molecular interactions include competitive radioligand binding assays, co-immunoprecipitation, fluorescence-based assays including fluorescence resonance energy transfer (FRET) binding assays, electrophysiology, analytical ultracentrifugation, label transfer, chemical cross-linking, mass spectroscopy, microcalorimetry, surface plasmon resonance and optical biosensor-based methods, such as provided in Chapter 20 of CURRENT PROTOCOLS IN PROTEIN SCIENCE Eds. Coligan et al., (John Wiley & Sons, 1997) Biochemical techniques such as two-hybrid and phage display screening methods are provided in Chapter 1 of CURRENT PROTOCOLS IN PROTEIN SCIENCE Eds. Coligan et al, (John Wiley & Sons, 1997). Accordingly, an earlier step of the method may include identifying a plurality of candidate agents that are selected according to broad structural and / or functional attributes, such as an ability to bind a hGIIA binding domain of EGFR. Additionally, the present method may further include one or more of the steps of: selecting a candidate agent that inhibits or blocks the non-catalytic activity of hGIIA, such as that expressed by the cell; optionally selecting a candidate agent that does not inhibit or minimally inhibits the catalytic activity of hGIIA, such as that expressed by the cell; optionally selecting a candidate agent that reduces the growth and / or viability of the cell; optionally selecting a candidate agent that is capable of binding or interacting with a hGIIA binding domain of EGFR; isolating or purifying the candidate agent; formulating the candidate agent into a pharmaceutical formulation; and adding the candidate agent or the pharmaceutical formulation to packaging and / or a container, such as a vial, ampoule, bag, blister pack, bottle, cartridge, injection needle, injection syringe, single dose container, strip of multiple single dose containers, or tube. EXAMPLES Example 1. Secreted phospholipase A2 interactions with EGFR and vimentin link innate immunity to prostate cancer The present Example investigated the catalysis-independent mechanism of hGIIA and the effect of its pharmacological inhibition in the context of prostate cancer. Recent studies have shown that while hGIIA catalytic activity is crucial for its physiological roles, such as microbial defence, hGIIA also drives eicosanoid overproduction and inflammation in human rheumatoid arthritis through a catalysis-independent mechanism, acting as an activator of cytosolic PLA2-α (cPLA2-α)3,5,8. Further, hGIIA has been identified as an activator of epidermal growth factor receptor (EGFR)9,10, which leads to extracellular receptor kinase (ERK) phosphorylation and potentially cPLA2-α activation. In rheumatoid synoviocytes, hGIIA-induced activation of cells was accompanied by its rapid internalization and colocalization with the intermediate filament protein vimentin5. In these cells, the present inventors have shown that, unlike other inhibitors, cF and c2 selectively inhibit the previously untargeted catalysis-independent mechanism of hGIIA8, resulting in inhibition of eicosanoid production coinciding with a loss of hGIIA colocalization with vimentin5. Materials & methods Peptides. Peptides were obtained following custom synthesis from either Auspep Pty Ltd, (Melbourne VIC, Australia) or Bachem Ltd, (Bubendorf, Switzerland). Peptides were supplied at >95% purity. Pharmacokinetics. All animal studies were performed according to the guidelines for the ethical use of animals published by the National Health and Medical Research Council of Australia. For mouse pharmacokinetic studies were conducted with approval from the Garvan Institute Animal Ethics committee (approval #02 / 21). cF and c2 were radioactively labelled with tritium by catalytic saturation of peptide analogues containing dehydroleucine (Sibtech Inc.Newington, CT), yielding high specific activity (50-60 Ci / mmol) peptides. Their identity was confirmed by three separate analytical methods prior to delivery. Mice (BALB / c, n=4 per timepoint) were administered a single dose of peptide, by the routes and times indicated. Animals were then exsanguinated by cardiac puncture under halothane anaesthesia followed by cervical dislocation. Tissues and plasma were stored at -80°C prior to analysis. For plasma, a known volume of plasma was added to liquid scintillant (Ultima Gold, Perkin Elmer, Melbourne, VIC, Australia). For tissues, a known amount of tissue (50-100 mg) was incubated in NaOH (1 ml, 1 M) overnight at room temperature. The solutions were then bleached with disodium EDTA (100 µl, 0.1%) and hydrogen peroxide (300 µl, 30%) and incubated at 50 °C for one hour. Peptide content of plasma and tissues were determined by liquid scintillation counting. The stability of the peptides following administration to animals was evaluated by thin layer chromatography of tissue extracted peptide relative to peptide prior to injection (Fig.8A). Rat studies were performed under contract to the accredited animal research establishment ICP Firefly Pty Ltd, (Alexandria, NSW, Australia)(Ref. No AW96 / 042, NSW Dep’t Primary Industries) with ethics approval from the ICP Firefly animal ethics committee. Briefly, male rats (Sprague Dawley, n=5 / group) were treated with c2 (single dose 100mg / kg suspended in 0.1% carboxymethylcellulose, po) and housed in metabolic cages. Animals were sacrificed at 1, 2, 8 or 24 hrs, blood and tissue samples taken for further analysis, with urine and faeces collected for 1, 6 and 16 hours respectively. Following extraction, c2 concentration in plasma was measured using a validated LC MS / MS assay (limit of detection 7.5 ng / mL and lower limit of quantitation 15 ng / mL in plasma, accuracy 98 % and imprecision 12.7% at 10 ng / mL). Xenograft models Xenograft model studies were conducted with the approval of the University of New South Wales Animal Ethics Committee (approval 17 / 92A). Androgen sensitive xenograft model BALB / c nu / nu mice (n=13 per group) were injected subcutaneously with 1 x 106luciferase-tagged LNCaP cells (LNCaP-luc) in RPMI 5% FBS / Matrigel (1:1). Subcutaneous tumours (> 65.5 mm3), in mice randomised to two groups, were treated by gavage with either vehicle (saline, 1% dimethylformamide (DMF), po, daily) cF (2 mg / kg po, daily) or c2 (0.1 mg / kg, thrice weekly). Mouse weight and tumour diameter, ((d1) and at 90 degrees to d1 (d2) measured with calipers) were recorded twice weekly. Diameter measurements were used to calculate tumour volume; Vol. = p / 6(d1.d2)3 / 2, with treatments blinded to experimentalists. Animals were treated for 8-10 weeks unless culled due to tumour volume reaching 15 x 15 mm (1768 mm3). End of study plasma PSA levels were measured by ELISA. Bioluminescence images were obtained weekly using the IVIS® Lumina (Perkin-Elmer, Waltham MA USA). D- Luciferin, Firefly, potassium salt (150mg / kg), (Gold Biotechnology Inc.,St Louis, MO, USA) substrate was administered intraperitoneally prior to imaging. Images were acquired after 10 mins with an image time of 60 s, medium binning, F / Stop=1. Images were quantified using the Living Image software (Perkin-Elmer). Castrate -resistant xenograft model Mice (BALB / c nu / nu) carrying LNCaP-luc xenograft tumours (>65.5 mm3) were surgically castrated 2.0-6.6 weeks post-tumour establishment (Tumour vol. median 164.6 mm3, range 74.6 mm3– 378.4 mm3). Treatment was commenced five weeks post-castration (Tumour vol. on treatment commencement (T=0); vehicle (saline 1% DMF, po, daily, n = 10), median 106.5 mm3, range 67.5 mm3– 623.9 mm3; cF (2 mg / kg, po, daily, n=9), median 165.3 mm3, range , 60.7 mm3– 526.3 mm3, and the study terminated 10 weeks post-treatment commencement. Data are expressed relative to time of treatment commencement (T=0). Androgen-resistant xenograft model Mice (BALB / c nu / nu) carrying luciferase-tagged PC-3M cells (PC-3M-luc) were each injected sc with 1 x 106cells suspended in RPMI culture medium. Once tumours were established (> 65.5 mm3), animals were treated with ether cF (2 mg / kg, po, daily), c2 (1 mg / kg, po, thrice weekly) or vehicle (saline, 2.5% DMF, po, thrice weekly) administered over a period of 8-24 weeks. Tumour volume and animal weights were measured twice weekly. Immunohistochemistry Tumours were fixed with 10% neutral buffered formalin and stored in 70% ethanol, then paraffin embedded and cut into 5 µm consecutive sections. Samples were deparaffinised with xylene and dehydrated with ethanol using standard protocols, with antigens retrieved by incubating samples in Citrate buffer (pH 6) at 95oC for 20 min. Samples were then incubated with 3% H2O2 in methanol for 30 min to remove endogenous peroxidases, then blocked with 10% goat serum in PBS for 30 min. Samples were then incubated overnight at 4oC with a range of antibodies; Ki67 (1:100), Vimentin (1:333), CD31 (1:50) (abcam) and hGIIA (1:100) (Caman Chemical, Ann Arbor, MI). TUNEL assay (abcam) was also used to identify apoptosis. Samples were then washed, stained with Rabbit IHC secondary antibody (1:100) (Dako, Glostrup, Denmark) and counterstained with Gills heamotoxylin (1:5) (Dako). Samples were imaged using M8 digital microscope (PreciPoint GmbH, Freising, Germany) and DAB staining scored in a blind manner using ImageJ as described previously11. Preclinical safety studies Potential toxicity of c2 was evaluated with a 28-day repeated dose oral toxicity study (OECD 407)37. in male Sprague Dawley rats, with a recovery period. Animals (n=10 per group) were treated with vehicle (1% carboxymethylcellulose in distilled water), c2 at 1 mg / kg or at 20 mg / kg every three days for 28 days. Animals were sacrificed on day 29 and blood and tissues taken for further analysis. Two recovery groups treated concomitantly with the main study (n=5, vehicle of 20 mg / kg c2) were monitored for a further 14 day treatment free period, sacrificed on Day 43 and blood and tissues taken for analysis. Cell lines Prostate cancer cell lines PC-3, LNCaP, DU145 were a gift from Professor P. Russell (Queensland University of Technology, Brisbane, Australia). Patient derived fibroblast-like synoviocyte cell line RA57 (Bidgood et al. 2000) and astrocytoma cell line 1321N1 (a gift from Chris Jones, Western Sydney University, Hawkesbury, Australia) were used as control cell lines. PC-3 was grown in RPMI (Lonza, Basel, Switzerland), LNCaP and 1321N1 in DMEM (Lonza), DU145 in MEM (Sigma-Aldrich, St. Louis, MO), and RA57 in DMEM-F12 (Lonza) in complete growth medium, all with 10% FCS, 4 mM L-glutamine (Sigma-Aldrich) and 1% penicillin andstreptomycin (Sigma-Aldrich). Cells were incubated at 37 °C and 5% CO2, and sub-culturedwhen culture neared confluency. Identity of cancer cell lines was confirmed by short tandem repeat (STR) analysis from the Australian genomic research facility (AGRF). Cells were used between passage 2-30. All cell lines were mycoplasma negative following regular routine testing using the mycoplasma detection kit (Lonza) as per the manufacturer’s instructions. Vimentin knockout gRNA oligos designed for the insertion into exon 1 of VIM gene using the selection tool CRISPOR. ‘CACCGGAGGACGAGGACACGGACC’ and ‘AAACGGTCCGTGTCCTCGTCCTCC’ were annealed, phosphorylated and then ligated to pSpCas9(BB)-2A-GFP (PX458) (Addgene, Watertown, MA) for the creation of sgRNA. DU145 cells were grown to 80% confluency in a 6-well plate, then transfected with 0.2% Lipofectamine 3000 reagent. After 72 hours, cells were trypsinised, resuspended in PBS and GFP positive cells were sorted using the FACS Melody (BD Biosciences), with single cells isolated and added to a 96 well plate with conditioned MEM media. Remaining positive cells were analysed against wild type DU145 cells in a nuclease mismatch assay (Fig. 12a). Single cells were grown to confluency before transfer to a 6 well plate, where cell colonies were analysed and confirmed as vimentin knockout via western blot and immunofluorescence (Fig.12b and 12c). hGIIA tagging hGIIA was purified from conditioned media obtained from 25 litre culture grown on alginate beads of hGIIA-expressing CHO cell line 2B15using AKTA Smart FPLC (GE Healthcare). Aliquots of hGIIA (100 µL, 1 mg / mL) in PBS were added to 15 µL of 1M NaHCO3 and conjugated to 20 µg of Alexa Fluor 568 or 647 NHS ester. The solution was then put into 5000-8000 MWCO Spectra / Por dialysis tubing (Spectrum) and dialysed overnight in 3 × 1000 mL PBS on a magnetic stirrer to remove unconjugated dye. The degree of labelling (DOL) was < 1 for live cell imaging and was validated via isoelectric focusing and immunofluorescence comparison with untagged hGIIA Immunofluorescence Samples were fixed with 4% paraformaldehyde for 10 min and permeabilized with 0.4% Triton X-100 in PBS for 10 min. Samples were then blocked with 10% goat serum for 20 min before incubation with primary conjugated antibodies for vimentin / Alexa Fluor 488 (BD Biosciences, 1:100) and hGIIA / Alexa Fluor 568 (in-house, 1:50) for 1 hour at room temperature. Samples were imaged with the Zeiss LSM 800 confocal microscope (Zeiss, Oberkochen, Germany). Z-stacks were acquired with a 0.2 µm step-size. Weighted colocalization coefficients were calculated using the Zen Blue colocalization module, with thresholds set for each cell line using a single antibody control group. Analysis of fluorescence mean and % positive area was quantified using ImageJ. Live cell imaging For all live cell imaging, cells were seeded on a 24-well glass bottom Senso plates (Greiner Bio-one, Kremsmünster, Austria) and imaged at 37 °C and 5% CO2 with the LSM 800 (Zeiss). For c2 imaging, cells were incubated with c2100 µM for 24 hours before excitation with 488 nm and emission 500-700 nm detected. For hGIIA entry, PC-3, LNCaP, DU145 and RA57 hGIIA / AF647 at cells were stained with 30 nM DAPI for 10 mins, cells were washed with PBS and then stained with 1 μg / mL of propidium iodide for 10 mins to confirm cell viability. Cells were washed three times with PBS and then cells were incubated with 200 ng / mL hGIIA / AF647, with entry imaged over 16 hours. For vimentin-hGIIA interactions, PC-3 cells were transfected with a plasmid encoding fusion protein EGFP-Vim7 (Addgene plasmid #56439, a gift from Michael Davidson) using Lipofectamine 3000 (Invitrogen) as per the manufacturer’s instructions. Three days after transfection, cells were incubated with 200 ng / mL hGIIA / AF568. For hGIIA dynamics, PC-3, LNCaP, DU145 or DU145 vimentin knockout cells were incubated with 200 ng / mL hGIIA / AF568 and with and without inhibitor c2 at 100 μM for 24 hours. Cells were then live imaged at a frame rate of 633 ms for 3 min and analysed using Imaris 8.2.0 (Bitplane) using the spot creation wizard. Briefly, average hGIIA punctate diameter was measured at 0.8 μm, which was used along with fluorescent intensity to calibrate spot creation for each hGIIA punctate and vesicle speed, total displacement and vesicle size were measured. For calcium imaging, PC-3 LNCaP, DU145 and 1321N1 cell lines were seeded overnight. Media was removed and cells were washed with 500 μL of calcium recording buffer (125 mM NaCl, 2 mM MgCl2, 4.5 mM KCl, 10 mM Glucose, 2 mM CaCl2, 20 mM HEPES, pH 7.4) then incubated with calcium buffer including 5 µM Fura Red AM (Thermo Fisher Scientific) dye for 30 mins. Cells were excited using the 405 nm laser at 20%, and the 488 nm laser at 2.5%, and emission captured from 495-700 nm. All settings remained constant for all measurements. Baseline intracellular calcium levels were measured for 60 sec before cells were incubated with either hGIIA (200 ng / mL) and TNF (10 ng / mL), LPA (2 µM) or hGIIA / AF647 (200 ng / mL) with calcium measured for another 300 sec. Ratiometric images were created using the Ratio Plus plugin for ImageJ. Fluorescence Lifetime Imaging LNCaP cells were fixed, permeabilized, blocked and stained as described above with α- vimentin / AF488 and α-hGIIA / AF568. Samples were imaged with the Zeiss LSM 880, excited with 2- photon excitation tuned to 960 nm at 80 MhZ and fluorescence lifetime of the donor only was captured and collected with the 520-535 nm filter. Fluorescence lifetime was processed using the PicoQuant system and captured until fluorescence lifetime had decayed to background levels (~1 min). For calibration, the lifetime of cells stained with only donor fluorescence (α- vimentin / AF488) was captured (0% FRET point), as well as unstained cells (100% FRET point). All captured fluorescence lifetime analysed, and FRET calculated analysed using SimFCS (Globals, Irvine, CA) for FLIM as described by previously12. PGE2 ELISA PC-3, LNCaP and DU145 cells were seeded in a 6-well plate at 300000 cells / well and incubated overnight. Complete media was removed and replaced with serum-free medium was supplemented with L-glutamine and 0.1% fatty-acid free BSA (Sigma-Aldrich) for 1 hours. Cells were then incubated with combinations of TNF (10 ng / mL), hGIIA (2 μg / mL) H48Q (2 μg / mL) and c2 (50 µM) for 24 hours at 37 °C and 5% CO2. Each treatment was conducted in triplicate. Media was harvested then acidified to pH 2 with 150 μL of formic acid prior to solid phase extraction (SPE) using Oasis HLB 30 mg SPE cartridges (Waters, Eschborn, Germany). Cartridges were conditioned with 1 mL of methanol and equilibrated with 1 mL of water. Cell media was loaded onto columns and passed through using a 20-position cartridge manifold (Waters). Columns were washed with 1 mL aqueous 0.1% formic acid, then 1 mL 5% MeOH + 0.1% formic acid, then eluted with 1 mL 100% methanol. Loaded samples were then dried down for 4 hours in a Savant SPD131DDA Speedivac (Thermo Fisher Scientific). Samples were resuspended in 100 μL ELISA buffer and PGE2 concentration quantified using a commercial EIA kit (Cayman Chemical) according to the manufacturer’s instructions. Western Blot PC-3, LNCaP and DU145 cells were treated for the time and with hGIIA, TNF and c2 as indicated in the figure legends. After treatment, cells were lysed in lysis buffer (150 mM NaCl, Triton X-100 0.5%, EDTA 2 mM, EGTA 2mM, NaF 25 mM, b-glycerophosphate 25 mM, glycerol 10%, 50 mM Tris-HCl, pH 7.5) and incubated at 4 °C for 30 min. Lysates were then processed for western blot analysis. Phospho-cPLA2-α (Ser505; 2831), cPLA2-α (2832) and EGFR (2232) were purchased from Cell signalling. Vimentin (V9) antibody was purchased from Abcam. hGIIA (9C1) antiserum was prepared in-house as previously described. All antibodies were used at 1:1000, except for hGIIA antiserum at 1:500. Co-immunoprecipitation After cell lysis, lysate was incubated with monoclonal α-hGIIA SCACC353 (Cayman Chemical) for two hours, then with 20 μL protein G agarose beads (Abcam) were added to lysate and incubated overnight. Beads were centrifuged, washed three times with lysis buffer, then run on a gel and detected via western blot with either EGFR or vimentin antibodies as described above. Enzyme Immunoassay Prior to assay, hGIIA antibody 4A1 conjugated to alkaline phosphatase (4A1-AP), produced using the lightning-link conjugation kit (ab102850, Abcam) as per the manufacturer’s instructions. Purified vimentin fragments (full length or coil 2) were seeded to a 96 well microplate at 15 μg / mL with a 100 μL / well volume. After an overnight incubation at 4 °C, the plate was emptied. Each well was then blocked overnight at 4 °C with 200 μL of 1% BSA in PBS. The plate was emptied and washed with PBST (PBS + 0.05% Tween20). hGIIA solution of 100 ng / mL in PBS with 0.1% BSA was prepared with and without inhibitors c2, Withaferin A and LY311727 in DMSO with concentrations 0.1-100 µM. hGIIA working solution with 0.4% DMSO served as a positive control and PBS with 0.1% BSA serving as negative control. A 100 μL volume of each prepared hGIIA-inhibitor mixture was added to wells in triplicate and incubated at 37 °C for two hours. The plate was washed twice with PBST then incubated with The 4A1-AP conjugate at 1 μg / mL 0.1% BSA in PBS and incubated for one hour at 37 °C. Plates were then emptied and washed three times with PBST, followed by washing twice with carbonate buffer (8 mM Na2CO3, 36 mM NaHCO3, 2 mM MgCl2, pH 9.8), before incubation with AP substrate p-nitro-phenyl phosphate (PNPP) powder at 1 mg / mL concentration in carbonate buffer. The plate was incubated at 37 °C for 60 mins then absorbance was read at 405 nm by a Spectramax M2 plate reader. All washes were a 200 µL / well volume. Molecular docking studies Docking of the c2 ligand on the second domain of vimentin was conducted with Glide XP flexible docking as part of the Maestro software suite 10.2 (Schrödinger, LLC). The X-ray crystal structure 3TRT was imported. The docking on vimentin was performed on five grids to allow for the inclusion of the entire surface area. The dimensions of the grid was 36 Å × 36 Å × 36 Å. The c2 ligand structure was processed by the LigPrep module as per default settings under the OPLS 2005 force field and were ionized by generating possible states at pH 7.4 using the Epik module of Maestro. In addition, specific docking of C2 to the vimentin coil 2 dimer was also performed using quCBit software (www.medchemsoft.com). The best docked conformation is displayed in Figure 6b. Statistical analysis All graphs and statistical analysis including student’s t-tests, one-way and two-way analysis of variance (ANOVA), and regression of linear and non-linear functions were performed with GraphPad Prism 8. Results cF and c2 are non-toxic and orally active. Through structure-based drug design approaches, cyclic peptides cF and c2 were derived from the primary sequence of hGIIA, (70FLSYK74, Fig. 1a)13,14. Both c2 and cF selectively suppress the synthesis of exogenous hGIIA-mediated prostaglandin (PG) production in fibroblast-like synoviocytes derived from patients with rheumatoid arthritis confirming their anti-inflammatory effect5,8. A key failing of previous enzymatic inhibitors of hGIIA was toxicity, resulting in increased incidence of myocardial infarction in a phase III clinical trial15. Pharmacokinetic studies following both subcutaneous (sc) and oral (po) administration of tritiated cF and c2 to BALB / c mice found both compounds were detected in plasma, resulting in 10 % and 20 % bioavailability of c2 and cF relative to sc delivery, respectively (Fig. 1b). Sc administration of cF and c2 found systemic uptake of both compounds in the liver and kidney, with cF at ~10-fold higher concentrations than c2 (Fig. 1c and 1d, respectively; integrity of peptides in blood validated by thin-layer chromatography; Fig. 8). Subsequent pharmacokinetic investigation of c2 oral bioavailability in Sprague Dawley rats identified its presence in the plasma, kidney and liver, peaking in the urine after 2 hrs with the majority excreted in faeces as expected (Fig.1e-i). Pharmacokinetics of cF and c2 are further described in Fig.8. No gross toxicity of c2 and cF was identified at max dosages of 10 mg / kg thrice weekly in mice, with no observable damage to organs and no significant changes in creatine, aspartate aminotransferase, alanine aminotransferase or creatine kinase enzyme levels (Fig. 1j). A comprehensive 28-day repeat dose oral toxicity study in Sprague Dawley rats treated with vehicle, or c2 at either 1 mg / kg or 20 mg / kg every three days and analysed according to the OECD 407 protocol16, established no observable toxicity by any measure (mortality, daily clinical observations, weekly body weights, weekly food consumption, weekly detailed clinical examinations, functional observations, haematology, biochemistry, urinalysis, organ weights, gross necropsy on day of sacrifice) (see Examples 3 and 4 below). Extensive histopathology was performed on all animals in control and high dose groups sacrificed on day 29. These data further support the safety of oral administration of c2. c2 is fluorescent and cell permeable. The naphthyl groups in c2’s structure gives the compound a unique autofluorescence emission spectral signature, which was characterised (Fig. 9), allowing the direct imaging of c2 internalisation and localisation. To test cell permeability, c2 (100 µM) was added to PCa cell lines LNCaP, PC-3 and DU145 for 24 hours and live cells were confocally imaged using 488 nm excitation and emission captured at 490-620 nm. c2 was detected in all cell lines with a punctate localisation pattern while DU145 also showed increased c2 localisation on the cell surface (Fig. 1k). cF and c2 reduce tumour volume and increases animal survival in xenograft models. The efficacy of cF was first evaluated in a luciferase tagged androgen-dependent xenograft model of PCa, LNCaP-luc. Once tumours were established (65.5 mm3), animals were treated with either vehicle dimethylformamide (DMF) (n = 13), or cF (2 mg / kg, thrice-weekly, po n = 13). cF administration resulted in significant suppression of tumour volume (Fig.2a, P = 0.0229; two-way ANOVA) and tumour weight (Fig. 2b, P = 0.0235, unpaired t-test) relative to vehicle-treated animals over eight-weeks. PSA levels were significantly reduced with cF treatment (P = 0.0158, unpaired t-test) (Fig.2c). c2’s efficacy was also investigated in the same androgen-sensitive model with animals treated with DMF control (n = 8) or c2 (0.1 mg / kg, po thrice weekly, n = 7). c2 was found to significantly reduce tumour volume, measured over eight weeks (Fig. 2d, P = 0.0479, two-way ANOVA) which was also observed with luciferase signal (Fig. 2f); it also caused a non- significant reduction in PSA (Fig.2e, P = 0.1151, two tailed t test). Immunohistochemical tissue staining showed no significant change in tissues for Ki67, CD31, vimentin and hGIIA (Fig.2g) The therapeutic value of cF was also tested in a castrate model of PCa, where animals were again injected with androgen-sensitive LNCaP-luc cells, castrated, and then treated with vehicle (DMF, n = 10) or cF (2 mg / kg, n = 8) over 10 weeks. At the end of the 10-week period, there was a significant reduction in relative tumour volume size from time 0 (P = 0.0419, Fig. 3a). c2 and cF efficacy was also investigated in a castrate independent model of PCa. Mice bearing an established tumour (65.5 mm3) derived from androgen insensitive cell line PC-3M-luc were orally administered either vehicle control (n = 15), c2 (1 mg / kg, thrice weekly, n = 15) or cF (5 mg / kg, daily, n = 15) for 8-24 weeks. Both c2 (P < 0.001, one-way ANOVA, Bonferroni’s multiple comparison test) and cF (P < 0.05), treatment significantly slowed and in the case of c2, completely stopped the growth of tumours relative to vehicle controls, improving animal survival (Fig. 3b and 3c). Several animals (c2, n = 4 cF, n = 2, 27% and 13% of animals, respectively), survived until study termination at 6 months (Fig. 3c), while all vehicle-treated animals were euthanized due to excessive tumour size (1757 mm3) by nine weeks (Fig. 3c). Of six survivors, three showed complete tumour regression by three months, with the remaining three survivors showing a decline from peak tumour volume over six months of treatment (Fig. 3d). Furthermore, while vimentin and hGIIA expression showed no significant change (Fig. 3e), c2 treated mice had significantly increased TUNEL signal (P = 0.026, unpaired t-test), indicating an increase in tumour cell apoptosis (Fig.3f). hGIIA follows autocrine and paracrine pathways, inhibited by c2. To determine whether c2 functions as an hGIIA inhibitor, hGIIA was first investigated in PCa cells. hGIIA is known to be initially expressed by innate immune cells such as macrophages and can induce its own expression via positive feedback loops17-20. To determine whether exogenous hGIIA can interact with and enter PCa cell lines, hGIIA tagged with Alexa Fluor 647 (hGIIA / AF647), was incubated onto PCa cell lines LNCaP, PC-3 and androgen insensitive DU145 as well as patient derived rheumatoid arthritis cell line RA57, as a positive control, and imaged over 16 hours. hGIIA / AF647 functionality was validated relative to untagged hGIIA via i) isoelectric focusing and ii) comparative fluorescence imaging of hGIIA localisation with immunostained LNCaP and FLS cells RA57, confirming no changes in charge or localisation, respectively (Fig. 10). hGIIA / AF647 was detectable on the surface of cells as aggregates in LNCaP and PC-3 cell lines after 1 hour, with a more diffuse surface localisation observed on DU145 cells, (Fig. 4a). After 24-hour incubation, hGIIA / AF647 signal was detected in both the hGIIA positive cell lines LNCaP and PC-3, as well as the hGIIA negative cell line DU14521, confirming hGIIA can be internalised by both autocrine and paracrine pathways. Patient derived rheumatoid arthritis cell line RA57 previously observed to sequester hGIIA5was used as a positive control. Quantification of the fluorescent signal over time demonstrated continual accumulation of hGIIA / AF647 over a 16-hour period with sequestration rates as follows RA57 (4.7 A.U.) > LNCaP (2.96 A.U.) > PC-3 (1.96 A.U.) > DU145 (1.03 A.U.) (Fig.4a). Incubation of PC-3, LNCaP and DU145 cells with both hGIIA / AF647 and c2 (100 µM) demonstrated that both protein and inhibitor colocalise, reducing hGIIA sequestration in all cell lines (Fig. 4b). This is the first evidence that c2 acts as a competitive inhibitor of hGIIA internalisation, entering the cell via the same pathway. Furthermore, hGIIA colocalises with cav- 1 protein (a marker of caveolae) and enters the cell via a charge-dependent interaction suppressed by protamine sulfate (Fig. 11), indicating both hGIIA and c2 interact with heparan sulfate proteoglycans (HSPGs) before internalisation in to the caveolae. hGIIA contributes to eicosanoid production via a catalytically independent mechanism. hGIIA’s primary contribution to inflammation-driven pathologies is through its increase of cytokine dependent eicosanoid production, such as PGE24. To investigate hGIIA’s contribution to PGE2 production in PCa, cell lines LNCaP, PC-3 and DU145 were grown in serum free media with hGIIA (2 µg / mL) and inflammatory cytokine tumour necrosis factor (TNF) (10 ng / mL) for 16 hours, before media was harvested and PGE2 concentration detected via ELISA. TNF or hGIIA alone did not yield a significant increase in any cell line (Fig. 4c). However in comparison to TNF, co-incubation of hGIIA with TNF resulted in a significant increase in PGE2 in LNCaP (P = 0.0198, one-way ANOVA), and a non-significant increase in PC-3 cells (P = 0.2582). Furthermore, in comparison to TNF treatment, cells co-incubated with the catalytically inactive mutant of hGIIA known as H48Q (2 µg / mL) and TNF resulted in significant increases in PGE2 in both LNCaP (P = 0.0120) and PC-3 (P = 0.0131), indicating that hGIIA upregulates eicosanoid production via a catalytically independent mechanism (Fig. 4c). The co-incubation of c2 (50 µM) with hGIIA and TNF significantly reduced PGE2 levels in PC- 3 (P = 0.0065) and non-significantly in LNCaP (P = 0.0940). DU145 did not respond to any treatments (Fig. 4c). DU145’s lack of response may be a result of decreased hGIIA and c2 internalisation seen in Fig.4a and 4b. It has previously been shown in rheumatoid arthritis cells that increased PGE2 production induced by hGIIA is abrogated by cytosolic PLA2-α (cPLA2-α) inhibitors8. Similarly, western blot of PC-3 lysate showed that c2 greatly reduces cPLA2-α phosphorylation (Fig.4d), inhibiting the catalytically independent activation of cPLA2-α by hGIIA. As hGIIA requires millimolar calcium concentration for catalytic activity4, the caveloaeCa2+concentration was determined using the ratiometric dye FURA Red AM, to evaluate whether hGIIA has intracellular catalytic activity in PCa cells. It was found that in all three PCa cell lines, hGIIA / AF647 signal in the caveolae coincided with negligible Ca2+concentration (Fig.4e). This again confirmed that the observable effects of hGIIA are a result of a catalytically independent mechanism, however, the precise interactions of hGIIA in PCa cells still require further examination. hGIIA binds to epidermal growth factor receptor (EGFR), inhibited by c2. hGIIA has been recently identified as a ligand for the epidermal growth factor receptor (EGFR)7,10, providing a potential mechanism for hGIIA to initiate ERK phosphorylation, activation of cPLA2-α and subsequent eicosanoid production. As c2 is derived from the structure of hGIIA, its ability to potentially inhibit the hGIIA / EGFR interaction was investigated. PC-3 cells were incubated with c2 (100 µM) for two hours before c2 was removed, cells washed and incubated with hGIIA (2 µg / mL) for two hours. Cell lysate was incubated with hGIIA antibody and co-immunoprecipitated EGFR was detected using western blot. c2 reduced EGFR signal (Fig. 6c). This indicates that c2 competitively inhibits hGIIA’s catalytically independent mechanism through blocking its binding to EGFR, inhibiting downstream signalling resulting in decreased PGE2 production. hGIIA binds to vimentin in prostate cancer cells. A previous study suggested a protein-protein interaction between hGIIA and vimentin in rheumatoid arthritis cells that may contribute to its catalytically independent amplification of inflammation12. To investigate this interaction in PCa cells, preliminary immunofluorescence analysis confirmed expression and colocalization of endogenous hGIIA and vimentin in LNCaP and PC-3 cells, with no expression of hGIIA detected in DU145 cells (Fig 5a). Direct binding between these proteins was demonstrated using fluorescence lifetime imaging microscopy (FLIM) of Förster resonance energy transfer (FRET) between donor vimentin and acceptor hGIIA (Fig. 5b). LNCaP cells show a shift in the lifetime of donor, indicating FRET with acceptor, thus establishing localisation of hGIIA and vimentin within 10 nm. This novel interaction between hGIIA and vimentin in PCa cells was confirmed by the co- immunoprecipitation (Co-IP) of vimentin with hGIIA in LNCaP cells (Fig.5c). To further characterise this interaction, hGIIA binding to full length vimentin and specifically, to vimentin’s coil 2, was demonstrated using an in vitro binding assay, with hGIIA showing no affinity for coil 1 (Fig.5d). hGIIA-vimentin dynamics were next examined through live cell imaging of PC-3 cells transiently transfected with vimentin-EGFP (Addgene plasmid #56439) and incubated with hGIIA / AF568 for 24 hours. Cells were imaged over a two-minute period with an example cell shown in Fig. 5e. Analysis of hGIIA dynamics using imaging software Imaris (Bitplane) identified two distinct classes of hGIIA-positive vesicles based on colocalisation with vimentin; (i) those tightly associated with vimentin (vimentin positive, red), and (ii) those moving freely in the cytoplasm (vimentin free, yellow). Fluorescent dynamics showed that vimentin-associated hGIIA exhibit restricted movement, with slower average speed and smaller vesicle size than vimentin-free hGIIA (Fig. 5e), indicating vimentin acts as a cage. Further live cell imaging highlights vimentin also facilitates the movement, fusion and division of hGIIA-positive vesicles. This interaction highlights that vimentin is able to modulate intracellular hGIIA movement and localisation – confirming its involvement in hGIIA’s catalytically independent interactions. c2 blocks hGIIA / vimentin interaction, modulating vimentin structure and hGIIA trafficking. Given the above findings, it was next investigated whether c2 perturbs the above mentioned hGIIA / vimentin interaction as its mechanism of action for inhibiting tumour growth and hGIIA catalysis-independent activity. Firstly, an enzyme immunoassay was used to confirm that c2 inhibits the interaction between hGIIA and vimentin in vitro, with an IC50 of 56.5 µM, whereas hGIIA inhibitor LY311727 and vimentin binding compound withaferin A were also tested and did not inhibit this interaction (Fig. 6a). Next, molecular docking studies predicted that c2 binds to the second coil of vimentin, forming well-defined hydrophobic interactions with Met347 and Phe351 respectively, as well as charge-charge interactions with Glu354, sterically inhibiting hGIIA interaction with vimentin (Fig. 6b). Next, to investigate c2’s effect on hGIIA and vimentin localisation, c2 (10 µM) was incubated onto cells for one or 24 hours and hGIIA and vimentin imaged via immunofluorescence. After one hour, c2 reduced hGIIA intensity and localisation (Fig.6c) as well as vimentin expression, with modest reductions in vimentin network size, known as vimentin bundling.24-hour incubation of c2 significantly increased hGIIA signal (Fig.6c). c2 also greatly inhibited hGIIA trafficking, as co-incubation of hGIIA / AF568 at 2 µg / mL with c2 at 100 µM for 24 hours significantly reduced hGIIA displacement and mean speed in all tested cell lines (P < 0.0001, Kruskal-Wallis test) (Fig. 6d-f). The cell-wide hGIIA-positive vesicle movement and fusion and division events under vehicle treatment were almost completely stagnated by c2, with hGIIA localisation identified as predominantly perinuclear. c2 treatment also reduces size of hGIIA-positive vesicles in PC-3 cells, while increasing them in LNCaP and DU145 (Fig.6d). Since vimentin is involved in hGIIA trafficking (Fig. 5e) and c2 inhibits the hGIIA / vimentin interaction in vitro (Fig. 6a, 6b), vimentin targeting by c2 was investigated as the potential mechanism of action for impeding hGIIA trafficking. A vimentin knockout DU145 cell line was constructed using CRISPR-Cas9 (Fig. 12). hGIIA displacement and mean speed were significantly lower in vimentin knockout DU145 than wtDU145 with c2 reducing hGIIA movement similarly in both cell lines (Fig. 6h). As c2 still greatly reduced intracellular trafficking of hGIIA in the vimentin knockout, it is likely that this is a result of c2 targeting another protein other than vimentin, such as EGFR, as EGFR activation is known to trigger its endocytosis, as well as increased trafficking by Rab proteins such as Rab 522. Separate from trafficking, hGIIA-positive vesicle area was significantly larger in the vimentin knockout than wtDU145 (P = 0.0002, one-way ANOVA), and unlike wtDU145, was unaffected by c2 treatment (P = 0.8172) (Fig. 6i). The loss of c2 function in vimentin knockout DU145 confirms that c2 mediates vesicle size through targeting vimentin. c2’s ability to increase vesicle size indicates aggresome formation – a process tightly controlled by vimentin23. The build-up of aggresomes leads to apoptosis, which was observed in c2 treated tumours (Fig. 3f) confirming c2’s second mechanism of action (Fig.7). hGIIA binds to epidermal growth factor receptor (EGFR) and is inhibited by c2. hGIIA has been recently identified as a ligand for the epidermal growth factor receptor (EGFR), providing a potential mechanism for hGIIA to initiate ERK phosphorylation, activation of cPLA2-α and subsequent eicosanoid production. As c2 is derived from the structure of hGIIA, its ability to potentially inhibit the hGIIA / EGFR interaction was investigated. Lysates from PC-3 cells pre-incubated with c2 (100 μM, 2 hours) followed by hGIIA (2 μg / mL, 2 hours) were immunoprecipitated with anti-hGIIA and anti-EGFR antibody and coimmunoprecipitated EGFR and hGIIA was detected using western blot, respectively (Fig. 22a). c2 reduced EGFR signal (P = 0.0141, unpaired t-test, Fig. 22b-c). Modelling of the c2 analogue cFLSFR binding to EGFR revealed that the lowest energy binding conformation is located close to the ligand binding domain of EGFR (Fig. 22d). hGIIA interaction was observed in live PC-3 cells which were transfected with EGFR-EGFP and Rab5-mCherry, then exogenous hGIIA / AF647 was added for 24 hours. hGIIA / showed close colocalization with Rab5-mCherry, as well as colocalization between all three shown in white (Fig. 22e). These results indicate that c2 inhibits hGIIA’s catalysis independent mechanism through blocking hGIIA binding to EGFR, thereby inhibiting downstream signalling and resulting in decreased PGE2 production. To investigate this, PC-3 cells were incubated with combinations of DMSO (0.5%), TNF (10 ng / mL), hGIIA (2 μg / mL), H48Q (2 μg / mL) and c2 (100 μM) for 10 mins before fixing and cells immunofluorescently labelled with either pEGFR, pERK or pcPLA2-α antibodies. hGIIA alone and H48Q resulted in a non-significant increase in pEGFR fluorescence (P = 0.1507 and P = 0.9455, respectively, one- way ANOVA), however were able to significantly increase pERK fluorescence (both P < 0.0001) and pcPLA2-α (P = 0.0452 and P = 0.0003, respectively). In comparison to TNF alone, co-incubation of TNF with hGIIA significantly increased pEGFR signal (P < 0.0001), with non- significant changes for hGIIA + TNF in pERK and pcPLA2-α (P = 0.3990 and P = 0.7039, respectively). Co-incubation of TNF with H48Q also significantly increased pEGFR signal (P = 0.0003), decreasing pERK signal (P = 0.0369) and increasing pcPLA2-α signal (P = 0.0055). With the addition of c2 to TNF + hGIIA, pEGFR and pERK signal was significantly reduced (P < 0.0001 and P = 0.0082, respectively) with no-significant in pcPLA2-α (P > 0.9999). Collectively, these results indicate that hGIIA’s ability to increase PGE2 production via a catalytically-independent mechanism is through binding EGFR and initiating signalling, which can be inhibited by c2. c2 initiates PCa apoptosis via a vimentin-mediated pathway To confirm that c2 initiates apoptosis, PCa cell lines PC-3, LNCaP, DU145 WT and vimentin knockout DU145 were treated with either nothing (control), DMSO (0.5%) or c2 (100 μM) for 72 hours. Cells were then analysed stained with Annexin V-FITC and propidium iodide, markers of apoptosis and necrosis, respectively. In comparison to DMSO, c2 significantly increased the population of apoptotic cells in PC-3, LNCaP and DU145 WT cells (all P < 0.0001, two-way ANOVA) (Fig. 6j-l). However, in DU145 vimentin KO cells, there is no significant difference in the number of apoptotic cells between DMSO and c2 treated cells (P = 0.7055, 2- way ANOVA) (Fig.6l, scatter plots, Fig.23). This loss of function of c2 in DU145 KO confirms that c2 causes apoptosis of cells via a vimentin-mediated pathway, confirming c2’s multimodal function. Conclusion The present Example has identified that hGIIA’s role in promoting PCa tumour progression is due to its non-catalytic function rather than its enzymatic activity, which was thetarget of previous failed clinical trials15,24. hGIIA’s non-catalytic function involves the activationof cPLA2-α, as confirmed with the use of a catalytically-inactive hGIIA mutant H48Q (Fig. 4c). In addition, the calcium / hGIIA imaging data established that exogenously added hGIIA is only found in low calcium intracellular environments where it is has no enzymatic activity (Fig. 4d), further supporting a hGIIA catalysis-independent intracellular role. Unlike previous structure-based designed inhibitors including those trialled in the clinic, c2 and cF are selective for the catalysis-independent function of hGIIA relative to inhibition of catalytic mechanisms5,8. In addition, pre-clinical testing indicates that unlike most cyclic peptides25, cF and c2 are orally absorbed, bioavailable, orally effective and cell permeable (Fig. 1d and Fig 24). c2 is extremely well tolerated with no observable toxicity at high dosage, another key difference from other clinically tested hGIIA inhibitors such as Varespladib methyl15(Fig. 1j). Through characterisation of c2’s unique autofluorescence, the compound was observed to be cell permeable, colocalising with hGIIA in vesicles identified as caveolae in real time, in situ, in living cells (Fig. 1k, Fig. 11a). Furthermore, unlike previous inhibitors26, c2 was able to enter cells in the absence of hGIIA. c2 competitively inhibited hGIIA sequestration into cells – indicating c2 enters the cell via the same pathway as hGIIA –identified to be through a charge interaction with heparan sulfate proteoglycans (HSPG) (Fig.11b). Both cF and c2 reduced tumour volume in androgen dependent xenograft models (Fig.2a and 2d) and retained efficacy in castrated animals (Fig. 3a). In androgen independent xenograft models, cF and c2 increased survival and in some cases, resulted in complete tumour regression (Fig.3b-d). c2 was effective at concentrations of 0.1 mg / kg thrice weekly and cF was effective at concentrations of 2 mg / kg, both significantly less than the maximum observed dosage with no toxicity (40 mg / kg, Fig. 1j), highlighting their potential usefulness as a therapeutic for prostate cancer. c2 was also observed to inhibit hGIIA’s catalytically independent eicosanoid production (Fig. 4c), likely through its ability to inhibit hGIIA binding to EGFR (Fig. 4f), and subsequent observed activation of cPLA2-α (Fig.4e). The present Example therefore highlights that hGIIA’s pro-tumorigenic role is a result of its catalysis-independent mechanism. Moreover, the cyclic peptide c2 exhibits in vivo effectiveness at inhibiting hGIIA’s non-catalytic function at nanomolar concentrations. The lack of toxicity and oral effectiveness of c2 and cF demonstrates their advantage over previous hGIIA inhibitors that target the catalytic function of hGIIA and potential as anticancer therapeutics.

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[0003] Example 2. Evaluation of c2 in the treatment of prostate cancer Materials and methods Patient population This was a Phase 0, open-label, single arm, non-randomised dose-escalation study of c2 in patients with advanced prostate cancer. To broaden the eligibility for this preliminary trial, patients were not required to have castrate-resistant disease. Eligible patients were aged at least 18 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, biopsy-proven adenocarcinoma of the prostate, adequate organ function, continued androgen-ablative therapy without changes in prior one month, and willing to use highly effective contraceptive if sexually active. Adequate organ function was defined as: absolute neutrophil count ≥1.5 x 109 / L; platelet count ≥100 x 109 / L; haemoglobin ≥ 9.0 g / dL; bilirubin ≤1.5 times upper limit of normal (ULN); alkaline phosphatase (ALP), aspartate transaminase (AST), and alanine transaminase (ALT) ≤3 × ULN (≤5 x ULN if liver metastases present); calculated creatinine clearance ≥50 mL / min per Cockcroft and Gault formula. Patients were not eligible for the trial if they met any of the following exclusion criteria: anti-tumour therapy (chemotherapy, radiotherapy, targeted therapies or experimental therapies) within 30 days prior to study entry (concurrent GnRH agonists or oral anti-androgens for prostate cancer at stable doses excepted); serious concomitant disorders (e.g. heart failure); uncontrolled, active infection requiring therapy; central nervous system (CNS) metastases (unless completed local therapy and off corticosteroids for at least 4 weeks before starting study therapy); or inability to comply with protocol or study procedures. Study design The primary objective was to examine the safety and tolerability of c2. Secondary objectives were to evaluate the preliminary efficacy of c2 by monitoring PSA levels, determine its pharmacokinetics (PK), and explore potential biomarkers. Four cohorts of patients were treated with each cohort consisting of 3 subjects which could be expanded to 6 subjects if needed. If there was no dose-limiting toxicity (DLT) in any patients in a given dose cohort, after a meeting of the Data and Safety Monitoring Board (DSMB), patients were enrolled in the next cohort and administered a higher dose of c2. If one of the first three patients within a cohort experienced a DLT, an additional 3 patients were recruited to that cohort. If <33% patients within a dose cohort experienced a DLT, the next highest dose cohort was opened for recruitment. If >=2 of 3 patients had a DLT, the MTD was defined as the preceding dose level. DLT was defined as any Grade 4 haematological or Grade 3 non-haematological event (excluding alopecia, nausea and vomiting) judged by the investigator to be possibly related to the study drug. Drug manufacture and validation c2 was manufactured by Bachem AG in Bubendorf, Switzerland using solid phase peptide chemistry. Bachem is a licensed manufacturer of new clinical entities (NCE’s) and complies with Good Manufacturing Practices (GMP). Annual testing was performed on the manufactured peptide to ensure purity and that degradation had not occurred. Stability studies were performed at room temperature and at 4 °C for two weeks duration to ensure c2 would remain stable when dispensed to patients to take at home. In preparation for the clinical trial, c2 peptide was compounded along with an excipient (microcrystalline cellulose 102) in cellulose capsules by Compounded Pty Ltd, Alexandria. Capsules were prepared containing doses of 5 mg, 20 mg and 60 mg of c2. Capsules of each strength were subsequently tested at the Western Sydney University NATA accredited analytical lab to confirm their c2 content. Safety evaluations Safety was assessed via regular assessment of vital signs, physical examination, performance status, laboratory studies, ECG’s, review of concomitant medications, and questioning for adverse events. Subjects were encouraged to report any adverse events experienced at any time after the initial dose or during continuous dosing. Subjects were provided with a diary to record any symptoms experienced and any changes to their usual medications. Any observed toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All adverse events occurring after enrolment were reported on the case report form for each participant. Any serious adverse event (SAE) was required to be reported immediately. An SAE included any event resulting in death, initial or prolonged inpatient hospitalisation, persistent or significant disability / incapacity, or congenital anomaly / birth defect. Pharmacokinetics Blood samples for pharmacokinetic analyses were collected from participants in Part 1 of the study at pre-dosing, 30 mins, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours and 24 hours. In Part 2, pharmacokinetic sampling was conducted at baseline (pre-dose) and 2 hrs post-dose on day 1, and then on days 8, 15, 22 and 43. All patients who received c2 and had at least four measured c2 levels over a 24-hour period were included in the pharmacokinetic analysis. Pharmacokinetic samples were assayed using a liquid chromatography–tandem mass spectrometry (LC-MSMS) assay which was previously validated for the quantitation of c2 in rat plasma in accordance with acceptance criteria set out in the document “Guidance to validation of bioanalytical methods” USFDA 2001. A known quantity of the compound cF was spiked into each sample as an internal standard. Samples were analysed at SCIEX, Melbourne, Australia. PSA responses and biomarker testing A baseline serum PSA level was measured during screening, at the commencement of Part 2, and every 3 weeks for the duration of the study. PSA responses were assessed over the continuous dosing portion of the study (Part 2). Plasma and urine samples were collected for sPLA2-IIA measurements during screening, days 1 and 2 of Part 1, and weekly throughout Part 1 and 2 of the study. Plasma and urine samples were assayed for sPLA2-IIa using an enzyme- linked immunosorbent assay (ELISA) kit (Cayman Chemical, Ann Arbor, MI). Urine samples were also assayed for creatinine concentration using a colorimetric kit (Cayman Chemical). Lipidomic profiling was performed by measuring plasma concentrations of 773 lipids (from 39 non-singleton lipid classes) using a high-performance liquid chromatography (HPLC) system coupled to an electrospray ionisation triple quadrupole mass spectrometer in Prof. Meikle’s laboratory at the Baker Institute, Melbourne, Australia. Data analysis and statistical methods All patients treated with c2 were evaluated for safety, and all treatment emergent adverse events were documented and causality assigned. PSA responses were determined from the change in serum PSA level from the commencement of continuous c2 dosing until the end of study (six weeks later). Change in plasma and urinary sPLA2-IIA levels was determined over the duration of the study time period. Basic descriptive statistics were performed on these data. The sample size for this study was selected without performing a power calculation and was intended to provide descriptive information on safety, tolerability, pharmacokinetics and exploratory biomarkers following administration of c2. It was assumed that the effect of treatment on lipid levels was linear on the log scale, and since there were repeated measures (each patient acting as their own control) it was considered reasonable not to include age and BMI as covariates. The 3-week and 6-week time point lipidomes in Part 2 were considered representative of the “daily treated lipidome”. A mixed effects model was used to test for significant differences in lipid levels before and after drug treatment. Benjamini-Hochberg multiple testing correction was performed to control the false discovery rate. A p-value at or below 5% was considered significant for the nominal and corrected p-values. Results Patient characteristics A total of 12 men with prostate cancer were included in the study across 4 dose cohorts of c2. All had metastases to bone and / or lymph nodes but were not necessarily castrate-resistant. Participants in the trial were of typical age for men with advanced prostate cancer (median age 73 years), predominantly Caucasian and of good performance status. All participants were on established androgen deprivation therapy receiving a gonadotropin releasing hormone agonist or antagonist, apart from one who was on an oral anti-androgen (cyproterone) alone. There was a wide range in baseline serum PSA levels ranging from 0.01 – 243 mg / L, reflecting a broad range in the burden of disease of participants. The patient demographics and baseline characteristics are summarised in Table 1. Table 1: Dose escalation cohorts Dose level Cohort number Part 1 (n=3 per cohort) (Single dose) (Continuous dosing) 1 5 mg 5 mg 2 10 mg 10 mg 3 40 mg 10 mg 4 60 mg 10 mg Table 2: Patient demographics and baseline characteristics Characteristic No. of patients (%) (N=12) Age (years) Median 73 Range 60-81 Race White 10 (83) Hispanic 2 (17) ECOG performance status 0 11 (92) 1 1 (8) Concurrent prostate cancer therapy GnRH agonist 9 (75) GnRH antagonist 2 (17) Oral antiandrogen alone 1 (8) Sites of metastatic disease Bone only 6 (50) Lymph nodes only 3 (25) Bone and lymph nodes 3 (25) Prostate-specific antigen ( g / L) Median 2.3 Range 0.01 - 243.1 Abbreviations: ECOG, Eastern Cooperative Oncology Group; GnRH, gonadotropin-releasing hormone Table 3: PSA responses from commencement of continuous c2 dosing PSA change Number of patients (%) Response*0 (0) Progression†2 (17) Stable 10 (83) *PSA response defined as > 50% decline from baseline. †PSA progression defined as ≥ 25% increase, and an absolute increase of 2 ug / L or more, from the baseline or nadir Do se escalation Dose escalation proceeded through the four cohorts as planned and no cohorts required expansion beyond 3 patients. No changes were made to the planned dosing levels at the scheduled safety review meetings. There were no DLTs observed in any of the cohorts and the MTD was not reached. Safety and tolerability All patients except one experienced an adverse event during the study (Table 4). The majority of AE’s were considered by the investigators unlikely to be related to the study drug. The majority of AE’s were Grade 1 and a small number of Grade 2 events occurred. One grade 3 event of appendicitis occurred which was also an SAE, and was considered unlikely to be related to c2. There were no concerning laboratory test abnormalities seen in any participants. Grade 2 neutropaenia occurred in one patient and Grade 2 thrombocytopaenia in another, and may have been related to the subjects’ multiple bone metastases with possible bone marrow infiltration. Overall c2 was very well tolerated at the doses studied, since nearly all adverse events experienced by participants in the trial were likely due to other causes including their underlying prostate cancer (e.g. bone pain, fatigue), concurrent medications (e.g. constipation from opiates), co-morbidities (e.g. hypertension), or intercurrent illness (e.g. respiratory tract infection). Table 4: Treatment emergent adverse events Adverse event Number of patients (%)*5 mg qd 10 mg qd†Total (n=3) (n=9) (N=12) All grades Grade ≥3 Any TEAE 12 24 35 (92) 1 (8) TEAEs leading to treatment discontinuation 0 0 0 (0) 0 (0) Any SAE 0 1 1 (8) 1 (8) Drug-related SAEs 0 0 0 (0) 0 (0) Haematological disorders Neutropaenia 1 1 2 (17) 0 (0) Thrombocytopaenia 0 1 1 (8) 0 (0) Gastrointestinal disorders Nausea 1 0 1 (8) 0 (0) Constipation 2 1 3 (25) 0 (0) Diarrhoea 0 1 1 (8) 0 (0) Gastro-oesophageal reflux 0 1 1 (8) 0 (0) Dental abscess 0 1 1 (8) 0 (0) Appendicitis 0 1 0 (0) 1 (8) Cardiovascular disorders Hypertension 1 2 3 (25) 0 (0) Bradycardia 2 0 2 (17) 0 (0) QTc prolongation 0 1 1 (8) 0 (0) Respiratory disorders Respiratory tract infection 0 1 1 (8) 0 (0) Sore throat 0 1 1 (8) 0 (0) Wheeze 0 1 1 (8) 0 (0) Urinary disorders Haematuria 0 1 1 (8) 0 (0) Skin and musculoskeletal disorders Rash 1 0 1 (8) 0 (0) Arthralgia 1 1 2 (17) 0 (0) Bone pain 2 0 2 (17) 0 (0) Jaw pain 0 1 1 (8) 0 (0) Nervous system disorders Dizziness 0 2 2 (17) 0 (0) Headache 0 1 1 (8) 0 (0) Tinnitus 0 1 1 (8) 0 (0) Generalised and metabolic disorders Fatigue 0 1 1 (8) 0 (0) Somnolence 0 1 1 (8) 0 (0) Peripheral oedema 1 1 2 (17) 0 (0) Abbreviations: TEAE, treatment-emergent adverse event; qd, once daily; SAE, serious adverse event.*Recurring events are counted only once for each patient.†Of these 9 patients, 3 received a single dose of 40 mg, and 3 received a single dose of 60 mg in part 1 Pharmacokinetics In part 1 of the study, c2 was detectable in blood samples of patients. In cases where a peak was detectable after dosing, it occurred between 2 and 6 hours post-dose, which may reflect variable drug absorption between patients. PSA responses PSA response was assessed over the 6-week period participants received c2 continuously in Part 2 of the study. PSA levels were measured at baseline (prior to first dose), at 3 weeks and at 6 weeks (end of study). Although no patients achieved an objective PSA response (> 50% decline from baseline), ten patients had PSA stability with three of those having a PSA decrease that was <50% from baseline. The waterfall plot of PSA changes in Part 2 is shown in Figure 14, and PSA changes tabulated by response criteria in Table 3. Biomarker analyses The role of sPLA2 as a potential biomarker for response to treatment with c2 was assessed by measuring sPLA2 levels in plasma and urine samples from participants at several planned timepoints during the trial. In those patients that had a reduction in serum PSA over the 6-week continuous dosing period (patients 3, 8 and 12 had PSA declines of 28%, 43% and 21% respectively), plasma sPLA2 levels remained relatively steady over this period with minor reductions over this period. Patient 3 did have a significant reduction in plasma sPLA2 level after a single dose of c2 on Day 2 in Part 1 of the study, with minor reductions for patients in 8 and 12 after single doses in Part 1 (Figure 16). Plasma sPLA2 levels increased in patients 1, 2, 5 and 6 over the 6-week continuous dosing period, with patients 5 and 6 meeting criteria for PSA progression (increases of 95% and 71% respectively). Plasma sPLA2 levels trended down in most patients receiving 10 mg daily continuously, but sPLA2 increased in patients 5 and 6 over this period (Figure 17). Since these patients had confirmed PSA progression, this is in keeping with sPLA2 as a prognostic biomarker for prostate cancer, with increasing levels indicative of tumour burden. When plasma sPLA2 levels at the end of the trial (Day 43 of Part 2) were plotted against percentage change in PSA level over the trial, a trend towards a positive correlation was seen (r = 0.53, p = 0.08; Figure 18). sPLA2 was detectable in urine of three participants at baseline (patients 3, 6 and 10), and subsequent samples from these patients collected throughout the trial were analysed. A significant drop in urinary sPLA2 concentration occurred in the samples taken at 6 hours after the c2 dose in Part 1 (Figure 19). This drop was most evident in patient 3 due to the relatively high pre-dose level. In the other two patients, the baseline urinary sPLA2 level was relatively lower but dropped to zero at 6 hours post-dose, before increasing again. This could represent an acute drop in sPLA2 excretion via urine due to the c2 dose. During Part 2, urinary sPLA2 levels were relatively stable over time, apart from a peak after 3 weeks of treatment in patient 10. Lipidomic profiling Lipidomic analysis was performed to assess whether there was any impact of c2 at various doses on the blood plasma lipidome. A mixed effects model was used to analyse the repeated measures of participants’ lipid profiles at different time points. The model was simplified for analysis of Part 1 data by assuming that lipidomes at time points other than the 6- hour post-dose sample were representative of the baseline lipidome. In Part 2, the patients took a daily dose of either 5 mg (cohort 1) or 10 mg (remaining cohorts) and samples were collected at baseline (pre-dosing), 3 weeks and 6 weeks. The 3- and 6-week time point lipidomes were considered representative of the daily-treated lipidome. The model tested whether there was a significant difference (on the log scale) between the ‘on-treatment’ lipid concentrations and the ‘baseline’ concentrations. Given the number of related tests (>700 lipids), Benjamini-Hochberg multiple testing correction was applied to control the false discovery rate. In Part 1, 461 of 773 lipids were nominally significant at the 5% level in at least one dose level or for the full model (Figure 20). There were generally higher numbers of significant lipids for higher dose levels (35 for 5 mg, 32 for 10 mg, 167 for 40 mg, and 294 for 60 mg). The significances and direction of changes were not consistent across dose levels with results for 10 mg and 60 mg looking more similar than with those for 40 mg. The post-treatment sample was collected 6 hours after the morning c2 dose, after the subjects had lunch, and hence there may be post-prandial effects on the lipidome that differed between groups. There were fewer repeated measures for each participant in Part 2, leading to reduced statistical power, and only 80 of 773 lipids were nominally significant for either of the two dose levels or for the full model (Figure 21). There were slightly more significant lipids for the 10 mg daily dose compared to the 5 mg daily dose (41 versus 32, respectively). Following treatment with a PLA2 inhibitor it would be expected that the lipid profile may alter with increased phosphatidylcholines (PCs) and decreased lysophosphatidylcholines (LPCs). In Part 1, no consistent alterations were observed in the post-dose samples compared to baseline samples. In Part 2, PCs did show a trend towards increasing for both 5 mg and 10 mg dose levels, though LPCs did not show a consistent trend. Discussion This trial was designed to investigate the potential feasibility of administering the peptide c2 to patients with prostate cancer. The specific doses tested were demonstrated to be safe and tolerable. Observed adverse events were all attributable to the patients’ prostate cancer or other causes unrelated to the study drug. The compound was detectable at low concentrations after dosing in some patients, with peaks occurring between 2 to 6 hours post-dose. Conclusion This first-in-human study showed that the cyclic peptide c2 can be administered orally to patients with prostate cancer and was detectable in patients at low concentrations. The compound was well tolerated and the MTD was not reached. Example 3. Rat toxicity studies The inventors determined the effects of repeated oral administration of c2 in male Sprague Dawley rats. c2 was administered orally to one group of three animals once every 2 days over 7 days at three escalating dose levels. Three groups of three animals were dosed once every 3 days over 28 days at three dose levels. A further group of four animals was dosed at 10 mg / kg once on Day 1 and blood samples taken at specific intervals. All animals were observed for signs of toxicity daily and a gross necropsy performed at sacrifice (Day 7 or Day 29). Methods c2 (Cyclo(2-Nal-leu-Ser-2-Nal-Arg) acetate salt was administered orally by gavage to groups of rats once every 3 days over 28 days (total 10 doses) at three dose levels (10, 30 and 100 mg / kg). One group of 3 rats (Group 5) received c2 every 2 days over 7 days at escalating dose levels (total 3 doses). A further group (Group 6) was given a single dose of 10 mg / kg, blood samples collected at 1, 4 and 8 hours after dosing and plasma and major organs are frozen. All animals were observed for signs of toxicity daily over the experimental period. Clinical examinations were performed daily on all animals. Body weight was determined immediately prior to the first test item administration, and then daily or weekly. Necropsy was conducted in all animals. Major organs (liver, kidneys, heart, lung, spleen and brain) were weighed wet immediately following dissection. All carcasses were discarded. A total of 19 outbred albino SD male rats were used in the study. The rats weighed between 183 and 207 g upon receipt. All animals were housed on bedding of recycled paper pellets in groups of 3 / sex / cage, in polyethylene boxes with stainless steel lids. Each animal was uniquely identified by tail marking. The rats were acclimatised to the experimental conditions for at least 5 days before commencement of the test. All animals were examined during the acclimatisation period to confirm suitability for the study. Animals were allocated to groups as shown in Table 5. Table 5. Animal allocation Feed and water The rats were fed on a diet of Rat & Mouse pellets (Gordon’s Specialty Stock Feeds) and provided with tap water ad libitum. Water was analysed regularly for bacterial contaminants. Water quality was within acceptable quality range. Environment Environmental controls for the animal room were set to maintain a temperature of 22 ± 3°C. The relative humidity (RH) ranged between 30 - 70%. The automated light / dark cycle was 12 hours light / 12 hours dark. Administration of c2 c2 was prepared as a suspension at the required concentration immediately prior to administration and administered to each rat by oral gavage using a plastic intragastric cannula attached to a 3 mL syringe. Three dose levels of 10, 30 and 100 mg / kg of the test item suspension were administered in a single dose to 3 rats every 3 days (total 10 doses) for 28 days (Groups 2, 3 and 4). The dose volumes on Day 1 were 5.08, 5.13 and 10.31 mL / kg, for concentrations of 0.2%, 0.6%, and 1.0%, respectively. On subsequent days, concentrations of 0.1%, 0.3% and 1.0% were administered at 10.09, 10.17 and 10.24 mL / kg, respectively. The control animals received 10.24 mL / kg of the vehicle. Three rats (Group 5) received the test item every 2 days at 3 escalating doses (10, 30 and 100 mg / kg) over 7 day period (total 3 doses). Four rats (Group 6) received the test item once at dose of 10 mg / kg. Observation of animals The rats were observed at frequent intervals (30 min, 1 hr, 2 hrs and 3 hrs) on each day of test item administration and daily throughout the rest of the experimental period. Individual body weights of all animals were determined immediately prior to the first test item administration and then daily for Group 5 and weekly for Groups 1-4. Blood sampling Blood samples were taken from four rats 1, 4 and 8 hours after dosing at 10 mg / kg. Approximately 1 mL blood was taken through the tail vein at each time point. Blood was placed into lithium heparin collection tubes. Plasma was separated by centrifugation at 3000 rpm for 10 minutes. Plasma was transferred into 1.5 mL polypropylene tubes and frozen at -20°C. At sacrifice, 8 hours after dosing, the animals were anaesthetised by intraperitoneal injection of sodium pentobarbitone using a 2 mL sterile plastic syringe attached to a 26-gauge needle (Terumo). Approximately 4 mL of blood was taken from each animal by cardiac puncture using a 10 mL syringe and 21-gauge needle. Blood was placed into lithium heparin collection tubes. Plasma was separated by centrifugation at 3000 rpm for 10 minutes. Plasma was transferred into 1.5 mL polypropylene tubes and frozen at -20°C. The liver, kidneys, heart, lung, spleen and brain are weighed wet immediately following dissection and frozen at -20°C. Gross necropsy At sacrifice, all animals were subjected to a full gross necropsy, which included careful examination of the external surface of the body, all orifices, and the thoracic, cranial and abdominal cavities and major organs. This included determination of the wet weight of the liver, kidneys, heart, lung, spleen and brain. Statistical analyses Statistical analyses, consisting of unpaired t-tests, were performed on measured variables: percentage body weight gains, organ weight as a percentage of bodyweight. A significance level of P < 0.05 was used for all tests. Clinical observations and gross necropsy were summarised by descriptive analysis. Results Mortality No mortalities related to the treatment were observed during the study period. Body weights and clinical observations Group 5 (3 escalating doses over 7 days) Individual body weights were recorded every day for 7 days. No apparent treatment- related changes in body weight gain were observed. Grs 2 - 4 (3 dose levels over 28 days) vs Vehicle (Gr 1) Individual body weights were recorded weekly for 28 days (Days 1, 8, 15, 22, 28 and at sacrifice 29). The treated animals (Group 4, high dose) had a statistically significantly lower percentage body weight gain in Week 1 when compared with vehicle control animals (22.0 ± 1.14 vs 25.1 ± 0.96%). There were no other statistically significant differences between the treated and vehicle control animals over the 28-day experimental period. Decrease of body weight gain was observed only on Week 1 in the high dose treated animals. No deleterious effects of the test item on body weight gain were observed in any animals in any treated groups. No abnormal clinical signs were observed in any of the treated animals over the 28-day experimental period. Organ weights and gross necropsy (Group 5) A gross necropsy was performed on each animal at sacrifice. No obvious macroscopic abnormalities were seen at gross necropsy. Organ weights and gross necropsy (Groups 1 - 4) – Day 29 Gr 2 (10 mg / kg / every 3 days) vs Gr 1 (Vehicle) Statistically significant increase in spleen weight of treated male was seen when compared to the male vehicle control group when expressed as a percentage of body weight (0.224 ± 0.0053 vs 0.202 ± 0.0008 %). No other differences were observed between the organ weights of the treated and control group when expressed as a percentage of body weight. Gr 3 (30 mg / kg / every 3 days) vs Gr 1 (Vehicle) Statistically significant increase in spleen weight of treated male was seen when compared to the male vehicle control group when expressed as a percentage of body weight (0.217 ± 0.0045 vs 0.202 ± 0.0008 %). No other differences were observed between the organ weights of the treated and control group when expressed as a percentage of body weight. Gr 4 (100 mg / kg / every 3 days) vs Gr 1 (Vehicle) No statistically significant differences were observed between the organ weights (liver, kidneys, heart, lung, spleen and brain) of the treated and control group when expressed as a percentage of body weight. Drug treatment had no obvious effects on organ weights when expressed as a percentage of body weight. A gross necropsy was performed on each animal at sacrifice. No obvious macroscopic abnormalities were seen at gross necropsy. Conclusion Under the conditions of the study, c2, administered repeatedly by the oral at doses of 10, 30 and 100 mg / kg in the Sprague Dawley rat, produced no toxic effects. Example 4. Rat toxicity studies with a recovery period Groups of male SD rats were administered the test item over 28 days as a suspension at doses of 1 and 20 mg / kg / every three days. A vehicle control group was administered the vehicle only (1% Carboxymethylcellulose in distilled water). The dose levels were selected based on the results of Example 3 above. Three groups of 10 rats (Vehicle, Low dose and High dose) were treated over a period of 28 days and sacrificed on Day 29 (main study). Two additional groups of 5 rats from the vehicle and high dose treated group were observed for a treatment-free period of 14 days and sacrificed on Day 43 to assess reversibility of any toxicity observed by Day 29 (recovery study). Methods A total of 40 young adult Specific Pathogen Free Male Sprague Dawley rats weighing between 189 and 212 grams the beginning of the experiment were used for the study. The animals were acclimatised to the laboratory conditions for at least 5 days before commencement of the study. All animals were examined during the acclimatisation period. The rats were housed on bedding of recycled paper pellets in groups of five in polyethylene boxes with stainless steel lids. Animals were identified with a unique identification number by marking their tails with permanent marker pens. Animals were allocated to groups as shown in Table 6. Table 6. Animal allocation

[0004] Feed and water The rats were fed on a diet of Rat & Mouse pellets (Gordon’s Specialty Stock Feeds) and provided with tap water ad libitum. Water was analysed regularly for bacterial contaminants. Water quality was within acceptable quality range. Environment Environmental controls for the animal room were set to maintain a temperature of 22 ± 3°C and the relative humidity ranges from 30-70%. The automated light / dark cycle was 12 hours light / 12 hours dark. Administration of c2 and vehicle control c2 was prepared as a suspension at the required concentration immediately prior to administration and the weight / volume equivalence was calculated. The vehicle control, 1% carboxymethylcellulose (CMC) in distilled water was administered at a volume of 10.23 mL / kg. The calculated volumetric dose was administered to each rat orally by gavage, using a plastic intragastric cannula attached to a 3 mL syringe. Two dose levels of 1 and 20 mg / kg of the test item suspension were administered to each rat every 3 days (total 10 doses) for 28 days. This corresponded to volumetric dose of 10.09 and 10.23 mL / kg. Observation of animals Body weights were determined immediately prior to the first test item administration (Day 1), and weekly thereafter (Day 8, 15, 22 and 28 for all groups; and Days 36 and 42 for recovery groups). All animals were weighed after fasting i.e. on the day of sacrifice (main groups: Day 29; recovery groups: Day 43). Feed consumption was monitored weekly over the 28-day experimental period in all groups and was continued for a further 2 weeks in the recovery groups (42-day experimental period). Feed intake was monitored by providing a known mass of feed to each cage and subtracting the mass remaining at the end of the weekly period. Animals were fasted overnight on either Day 28 (main groups) or Day 42 (recovery groups). The animals were observed daily at approximately the same time each day, between 1 and 3 hours after dosing, for a period of 28 days for the main groups and 42 days for the recovery groups and on the day of sacrifice. Particular care was taken to look for signs of toxicity and abnormal behaviour. Skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behaviour patterns were monitored. Particular attention was paid to observation of tremor, convulsion, salivation, diarrhoea, lethargy, sleep and coma. Detailed clinical examinations were performed prior to commencement of the study and weekly thereafter (Weeks 1 to 4) of the study in the main groups and the recovery groups. The following parameters were assessed: posture, gait, clonic convulsion, tonic convulsions, biting, removing rat from cage, handing rat in hand, lacrimation, fur appearance, salivation, defecation, urination, grooming, palpebral closure, pupil response, eye, respiration, behaviour and rearing. Functional observation was performed in the last week of the 28-day experimental period for each animal. The following parameters are assessed: arousal, finger snap, approach response, touch response, tail pinch, extensor thrust, limb rotation, catalepsy, righting reflex, supine drop, grip strength test. Blood sampling Blood analyses (haematology and biochemistry) were performed on all animals on Day 29 (main groups) or Day 43 (recovery groups). Approximately 4 mL of blood was taken from each animal by cardiac puncture using a 10 mL syringe and 21-gauge needle. The procedure involved anaesthetising by intraperitoneal injection of sodium pentobarbitone using a 2 mL sterile plastic syringe attached to a 26-gauge needle (Terumo). For each blood sampling, the blood was divided into two aliquots: (i) one was placed into a tube containing EDTA (for whole blood and EDTA plasma), (ii) one aliquot into a Li-heparin tube. The following parameters were analysed: Red blood cell (RBC), haemoglobin (Hb), haematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), platelet count (PLT), mean platelet volume (MPV), white blood count (WBC), neutrophil (Neut), lymphocyte (Lymph), monocytes (Mono), eosinophil (Eos), basophil (Baso). The following parameters were also analysed: glucose (Glu), urea, creatinine (Creat), total protein (TP), albumin (ALB), albumin / globulin ratio (A:G), total bilirubin (TBil), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), cholesterol (Chol), calcium (Ca), phosphate (Phos), Ca:P ratio, sodium (Na), potassium (K), Na:K ratio, chloride (Cl), globulin (Glob), gamma glutamyl transferase (GGT) and triglycerides (Trig). Urinalysis Urine was collected at the end of the study (on Days 29 and 43 for main and recovery groups, respectively) by placing a urine collection tube at the opening of the urethra and any urine expressed by the animal was collected. If no urine came out, pressure was gently applied on the bladder area of the abdomen. Urine was also collected by bladder puncture at the time of death to maximise the volume collected. The animal was placed in lateral recumbency and the abdominal cavity opened. A needle attached to the syringe was inserted into the bladder and urine withdrawn with the plunger. The urine sample was expelled from the syringe into the collection tube. Gross necropsy Following sacrifice by intraperitoneal injection of sodium pentobarbitone a gross necropsy was performed. This included determination of the wet weight of the liver, kidneys, adrenals, testes, spleen, thymus, heart, epididymis, prostate + seminal vesicles with coagulating glands as whole and brain. Observations were recorded of the abdominal, thoracic and cranial cavities and major organs. Tissues and carcasses were placed in 10% formalin. The tissues to be processed for histopathological examinations were fixed for at least 48 hours prior to cassette preparation. Tissue processing / Slide preparation The tissues were placed in labelled cassettes and placed in an automated tissue processor and taken through several stages of alcohol dehydration, solvent clearing and wax infiltration. Infiltrated tissues were embedded in wax blocks, which were sectioned on a microtome at between 4 and 6 μm. Sections were placed on pre-labelled glass slides and stained with haematoxylin and eosin (H&E). Stained sections were dehydrated, then solvent cleared and cover slipped. Histopathology Histopathological examinations were performed on all animals in the vehicle control and high dose treated groups (main study) on the following tissues / organs: adrenal glands, bone marrow, brain, epididymis, heart, kidney, liver, lung, lymph node: mesenteric, prostate, seminal vesicles with coagulating glands, small and large intestine (including Peyer’s patches), spinal cord, spleen, stomach, thymus, thyroid gland, trachea, testes and urinary bladder. Slides were evaluated for histology changes under light microscopy at a magnification of 100 to 1000 times. Statistical analyses Clinical observations, detailed clinical observations, functional observations, blood and urine analyses and histopathology were summarised by descriptive analysis. Statistical analyses, consisting of unpaired t-tests, were performed on measured variables: percentage body weight gains, food consumption and organ weights as a percentage of body weight. A significance level of P < 0.05 was used for all tests. Results Results are presented as a 28-day experimental period (Main study groups): vehicle control - Group 1 and treated [Group 2, low dose - 1 mg / kg, and Group 3, high dose - 20 mg / kg,] and as a 42-day experimental period (Recovery groups): vehicle control - Group 4 and high dose - Group 5. Combined analyses of Main study and Recovery groups were made during the 28-day observation period for the following parameters: mortality, body weight, feed intake, clinical observation, detailed and functional clinical observations. Mortality No mortalities related to the treatment were observed during the study period. Body weights and clinical observations Main and Recovery Groups: Week 1-4 Treated (Gr 2 - 1 mg / kg) vs. Vehicle control (Grs 1 & 4) The treated males had a lower trend in body weight gain in Week 1, when compared to vehicle control males (19.6 ± 2.49 vs 22.4 ± 2.50%). Over the 4-week observation period the treated animals had a statistically significantly lower percentage body weight gain when compared with vehicle (Groups 1 and 4) control rats (55.4 ± 8.84 vs 63.8 ± 8.65%) Treated (Grs 3 & 5 - 20 mg / kg) vs. Vehicle control (Grs 1 & 4) Over the 4-week observation period no significant difference was found between treated animals and vehicle control animals. Recovery period: Week 5-6 Treated (Gr 5 - 20 mg / kg) vs. Vehicle control (Gr 4) Over the 6-week observation period no significant difference between treated animals and vehicle control animals was found during the recovery period. Over the 28-day observation period, a lower body weight gain was observed in the low dose treated animals when compared to the vehicle control animals. This observation was not considered to be of any clinical significance. After the recovery period, no statistical significant difference between test item and vehicle treated animals could be observed. On Day 21-22, one control rat in Vehicle control (Gr 1 & 4) had had porphyrin discharge around right eye. No other clinical signs were observed in any of the animals in the control groups over the 28-day observation period. There were no remarkable differences in clinical observations between vehicle and c2 treated animals. No abnormalities were detected in any of the treated rats. Thus, c2 administration had had no effect on any of the parameters measured in the functional observations tests performed during Week 4. Blood and blood biochemistry analysis One animal (R2414) in the Vehicle Control Group 1 had significantly lower WBC (and hence absolute numbers of various leukocytes from differential) than its group mates and was considered to be an outlier. There were no obvious effects related to administration of c2. Any differences were small and interpreted to be not clinically relevant. Urinalysis There were no obvious effects of c2 administration on the urine parameters analysed. Gross necropsy and histopathology c2 administration had no obvious effects on organ weight when expressed as a percentage of body weight. There were no treatment related differences observed between the treated and vehicle control groups. Conclusion Under the conditions of the study c2 administered at the two dose levels of 1 and 20 mg / kg for 28 days in the male Sprague Dawley rat, produced no toxic effects. c2 shows no sign of clinically relevant toxicity in male Sprague Dawley rats following a 28-day repeat dosing in a sighting study at doses up to 100 mg / kg. c2 shows no measureable toxicity in a full 28-day repeat dose toxicity study at either 1 mg / kg or 20 mg / kg in male Sprague Dawley rats. c2 is detectable in plasma following 28-day repeated dosing (10 mg / kg, po, thrice weekly) in rats Example 5. Beagle toxicity studies The inventors sought to determine the maximum tolerated dose of c2, following oral administration at 3 escalating doses with a washout period of 3 days between doses in the male beagle dog. Two male beagle dogs were administered c2 in gelatine capsules as a powder at three escalating doses of 3, 10 and 30 mg / kg on days 1, 5 and 9, respectively. Blood samples were taken for pharmacokinetic analysis 2 hours after administration of the 10 mg / kg dose; 2, 5 and 24 hours after the 30 mg / kg dose. The plasma was stored at -20º C. Body weights were recorded on Days 1, 5, 9, 16 and 23. Haematology, biochemistry and urine analyses were conducted prior to the first administration of the test item and 24 hours after the final dose, on days 1 and 10, respectively. The animals were observed at regular intervals on each day of test item administration, and daily during the 3-day washout periods for signs of toxicity. Fifteen days after administration of the last dose (Day 24), the animals were sacrificed and gross necropsy examination was performed. No mortalities occurred during the study. No weight loss was observed. Feed consumption was not affected by treatment. Dried vomitus consisting of a small amount of dried biscuits was found in the enclosure of one animal (C029) on Day 4, 3 days after the first dose of 3 mg / kg. No clinical abnormalities were seen between administrations of escalating doses. Blood and urine analyses did not show any changes of clinical significance. At necropsy, no gross abnormalities were seen in the major organs. Conclusion Under the conditions of the study, c2, administered at 3 escalating doses of 3, 10 and 30 mg / kg times over a period of 24 days in the Beagle dog produced no gross toxic effects. It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

CLAIMS:

1. A pharmaceutical composition comprising: c2, or an analogue or derivative thereof, in an amount of about 5 mg to about 1500 mg; and a cellulose derivative.

2. The pharmaceutical composition of claim 1, wherein the cellulose derivative is microcrystalline cellulose.

3. The pharmaceutical composition of claim 1 or claim 2, formulated as a capsule.

4. The pharmaceutical composition of claim 3, formulated as a cellulose-based capsule.

5. A unit dosage form comprising c2, or an analogue or derivative thereof, in an amount of about 5 mg to about 1500 mg.

6. The pharmaceutical composition of any one of claims 1 to 4 or the unit dosage form of claim 5, wherein c2 or the analogue or derivative thereof is present in an amount of about 5 mg to about 100 mg.

7. The pharmaceutical composition or the unit dosage form of claim 6, wherein c2 or the analogue or derivative thereof is present in an amount of about 5 mg, about 10 mg, about 20 mg, about 40 mg or about 60 mg.

8. The pharmaceutical composition or the unit dosage form of any one of claims 1 to 7, formulated for oral administration to a subject.

9. A method of treating or preventing a cancer in a human subject, said method including the step of orally administering a therapeutically effective amount of cyclo-((2-Nal)-Leu-Ser-(2- Nal)-Arg) (c2) or an analogue or derivative thereof to the subject to thereby treat or prevent the cancer.

10. The method of claim 9, wherein c2 or the analogue or derivative thereof is orally administered at a dose of about 5 mg / day to about 1500 mg / day.

11. The method of claim 9 or claim 10, wherein c2 or the analogue or derivative thereof is orally administered at a dose of about 5 mg / day to about 100 mg / day.

12. The method of any one of claims 9 to 11, wherein c2 or the analogue or derivative thereof is orally administered daily for a period of at least about 2 weeks.

13. The method of any one of claims 9 to 12, wherein c2 or the analogue or derivative thereof is orally administered daily for a period of at least about 6 weeks.

14. The method of any one of claims 9 to 13, wherein the subject is receiving a further anti- cancer treatment.

15. The method of any one of claims 9 to 14, including the further step of administering a further anti-cancer treatment to the subject.

16. The method of claim 15, wherein the further anti-cancer treatment is selected from the group consisting of a chemotherapeutic agent, a radiation therapy, a molecularly targeted therapeutic agent and an immunotherapeutic agent.

17. The method of any one of claims 9 to 16, wherein the cancer is a prostate cancer.

18. A method of reducing a level of circulating hGIIA in a human subject, said method including the step of orally administering an effective amount of c2 or an analogue or derivative thereof to the subject to thereby reduce the level of circulating hGIIA.

19. The method of claim 18, further including the step of determining the level of circulating hGIIA before and / or after administration of c2 or the analogue or derivative thereof to the subject.

20. The method of claim 18 or claim 19, wherein the level of circulating hGIIA in the subject is elevated prior to orally administering the effective amount of c2 or the analogue or derivative thereof.

21. A method of selecting a human subject as being suitable for oral administration of c2, or an analogue or derivative thereof, said method including the step of determining a level of circulating hGIIA in the subject, wherein an elevated level of circulating hGIIA is indicative of the subject being suitable for oral administration of c2 or the analogue or derivative thereof.

22. The method of claim 21, further including the step of orally administering an effective amount of c2 or the analogue or derivative thereof to the subject if the level of circulating hGIIA in the subject is elevated.

23. The method of any one of claims 18 to 22, wherein the subject has a cancer.

24. The method of claim 23, wherein the cancer is a prostate cancer.

25. The method of any one of claims 18 to 24, wherein c2 or the analogue or derivative thereof is orally administered at a dose of about 5 mg / day to about 1500 mg / day.

26. The method of any one of claims 18 to 25, wherein c2 or the analogue or derivative thereof is orally administered at a dose of about 5 mg / day to about 100 mg / day.

27. The method of any one of claims 18 to 26, wherein c2 or the analogue or derivative thereof is orally administered daily for a period of at least about 2 weeks.

28. The method of any one of claims 18 to 27, wherein c2 or the analogue or derivative thereof is orally administered daily for a period of at least about 6 weeks.

29. The pharmaceutical composition or the unit dosage form of any one of claims 1 to 8, for use in the method of any one of claims 9 to 28.

30. A method of treating, preventing or ameliorating a hGIIA-dependent disease, disorder or condition in a human subject, said method including the step of administering a therapeuticallyeffective amount of an agent that selectively inhibits a non-catalytic activity of hGIIA to the subject to thereby treat, prevent or ameliorate the hGIIA-dependent disease, disorder or condition.

31. The method of Claim 30, wherein the agent induces little or no cardiotoxicity in the subject.

32. The method of Claim 30 or Claim 31, wherein the agent is orally administered to the subject.

33. The method of any one of Claims 30 to 32, wherein the agent is administered at a dose of about 5 mg / day to about 1500 mg / day.

34. The method of any one of Claims 30 to 33, wherein the agent is administered at a dose of about 5 mg / day to about 100 mg / day.

35. The method of any one of Claims 30 to 34, wherein the agent is administered daily for a period of at least about 2 weeks.

36. The method of any one of Claims 30 to 35, wherein the agent is administered daily for a period of at least about 6 weeks.

37. The method of any one of Claims 30 to 36, wherein the hGIIA-dependent disease, disorder or condition is a cancer.

38. The method of Claim 37, wherein the cancer is a prostate cancer.

39. The method of any one of Claims 30 to 38, wherein the agent is: (a) cyclo-((2-Nal)-Leu- Ser-(2-Nal)-Arg) (c2) or an analogue or derivative thereof; or (b) cFLSYR (cF) or an analogue or derivative thereof.

40. The method of any one of Claims 30 to 39, wherein a level of circulating hGIIA in the subject is elevated prior to administering the agent.

41. A method of inhibiting a non-catalytic activity of hGIIA in a cancer cell, said method including the step of contacting the cancer cell with an effective amount of: (a) c2 or an analogue or derivative thereof; or (b) cF or an analogue or derivative thereof.

42. The method of Claim 41, wherein the cancer cell is a prostate cancer cell.

43. A method of identifying, designing or producing an hGIIA inhibitor that induces little or no drug-induced toxicity in a human subject, said method including the steps of: (a) contacting hGIIA with a candidate hGIIA inhibitor; and (b) determining whether the candidate hGIIA inhibitor inhibits a non-catalytic activity of hGIIA.

44. The method of Claim 43, further including the step of determining whether the candidate hGIIA inhibitor inhibits a catalytic activity of hGIIA.

45. The method of Claim 43 or Claim 44, wherein the candidate hGIIA inhibitor is a cyclic peptide.

46. The method of Claim 45, wherein the candidate hGIIA inhibitor is a derivative or variant of c2 or cF.

47. The method of any one of Claims 43 to 46, further including the step of isolating and / or purifying an agent that inhibits the non-catalytic activity of hGIIA.

48. The method of Claim 47, wherein the isolated and / or purified agent does not inhibit or minimally inhibits the catalytic activity of hGIIA.

49. The method of Claim 47 or Claim 48, further including the step of formulating the isolated and / or purified agent into a pharmaceutically acceptable formulation.

50. The method of claim 49, further including the step of sterilising the formulation.

51. The method of Claim 49 or Claim 50, further including the step of filling the formulation into a container.

52. The method of Claim 51, wherein the container is any one or more of a vial, an ampoule, a bag, a blister pack, a bottle, a cartridge, an injection needle, an injection syringe, a single dose container, a strip of multiple single dose containers, or a tube.

53. An agent for use in treating, preventing or ameliorating a hGIIA-dependent disease, disorder or condition in a human subject, obtained by the method of any one of Claims 43 to 52.

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