Thiostrepton Dosage Regimen

Abstract

Disclosed herein are methods of administering thiostrepton or a pharmaceutical composition thereof, and methods of treating cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 404,728, filed September 8, 2022, and U.S. Provisional Patent Application No. 63 / 403,553, filed September 2, 2022, each of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Thiostrepton is a cyclic oligopeptide antibiotic also known as briamycin, tiactin, alaninamide, and HR4S203Y18. Thiostrepton has the following structure: [ka] or a pharmaceutically acceptable salt thereof. Recent studies have shown that thiostrepton, in addition to its antibiotic properties, also has promising anticancer activity. There remains a need for a safe and effective method of administering thiostrepton to treat cancer. Summary of the Invention

[0003] In certain aspects, provided herein are methods for treating cancer, comprising administering thiostrepton to a subject in need thereof in a single dose of about 50 mg to about 500 mg once a week, thereby treating the cancer.

[0004] In certain aspects, provided herein is a pharmaceutical composition comprising thiostrepton and at least one pharmaceutically acceptable carrier, the pharmaceutical composition comprising from about 50 mg to about 500 mg of thiostrepton.

[0005] In certain embodiments, the present disclosure provides for the administration of any of the thiostrepton or pharmaceutical compositions comprising thiostrepton disclosed herein.

[0006] Also provided herein are methods for treating cancer, comprising administering thiostrepton, or a pharmaceutical composition comprising thiostrepton, as described herein, to a subject in need thereof. In certain preferred embodiments, the cancer is malignant mesothelioma. In certain embodiments, thiostrepton is administered intraperitoneally, intrapleurally, subcutaneously, or intratumorally. In certain embodiments, thiostrepton is administered intraperitoneally, e.g., using an indwelling intraperitoneal catheter (IPC) or a drainage port catheter. In certain embodiments, the method further comprises removing fluid from the body cavity (e.g., pleural effusion or ascites from the peritoneal cavity), e.g., until dry, prior to administering thiostrepton. In some embodiments, thiostrepton is administered once weekly for at least three weeks. In preferred embodiments, a single dose of thiostrepton is administered weekly at about 90 mg to about 450 mg, e.g., about 90 mg, about 180 mg, about 270 mg, about 360 mg, and about 450 mg. [Brief explanation of the drawings]

[0007] [Figure 1A] The nucleus and mitochondria of a normal mesothelial cell are shown. [Figure 1B] Nuclei and mitochondria of malignant mesothelial cells are shown. [Figure 2A] EC50 of thiostrepton in normal mesothelial cell lines and various mesothelioma cell lines (various BAP1 expression) is shown. [Figure 2B] siRNA-mediated PRX3 knockdown significantly reduces proliferation of MM (malignant melanoma, HM cell line - pleural biphasic) (red squares). Co-expression of H2O2 scavenger catalase (CAT, green triangles) or mitochondrial-targeted catalase (mCAT, inverted blue triangles) rescues proliferation in cells lacking PRX3 expression. [Figure 2C] Shown is the weight (grams) of residual tumors excised from mice bearing intraperitoneal MM xenografts after treatment with 20 mg / ml thiostrepton composition twice weekly for 4 weeks. **p<0.01. [Figure 3A]A malignant pleural effusion (MPE) collected from a patient with metastatic disease is shown. [Figure 3B] Adherent tumor spheroids grown in MPE supernatant are shown. [Figure 3C] Non-adherent immune cells grown in MPE supernatant are shown. [Figure 3D] Figure 1 shows the relative PRX3 inactivation by thiostrepton in both tumor (adherent) and immune (non-adherent) cells. [Figure 3E] We show that MPE-derived tumor cells are equally sensitive to thiostrepton compared to established MM cell lines. [Figure 4A] Shows multiple exudates being drained and dried. [Figure 4B] 1 shows administration of thiostrepton using an intraperitoneal catheter (IPC). [Figure 4C] The IPC is shown secured onto the patient. [Figure 5] 1 shows a summary of a thiostrepton dose escalation study. [Figure 6] 1 shows an exemplary Phase 1 dose escalation study for treating cancer with compounds and / or compositions of the disclosure. [Figure 7] 1 shows a Phase 1 dose-expansion study at RP2D, where TS represents a compound or composition of the disclosure. [Figure 8] 1 is a swimmer plot containing three exemplary patient outcomes from the Phase 1 / 2 MITOPE trial. BOR indicates best overall response, PR indicates partial reduction in disease, and SD indicates stable disease. [Figure 9] An outline of the treatment for patient 1 is shown. [Figure 10] 1 is a chart showing the decrease in pleural fluid drainage for patient 1 as a function of time. [Figure 11A]

[0033] Figure 1 shows a cross-sectional CT scan of the CP node of Patient 1 before treatment. The scan confirms a partial response to treatment. [Figure 11B]

[0033] Figure 1 shows a cross-sectional CT scan of the CP node in patient 1 at week 6 of treatment. The scan confirms a partial response to treatment. [Figure 11C]

[0033] Figure 1 shows a cross-sectional CT scan of the CP node in patient 1 at week 12 of treatment. The scan confirms a partial response to treatment. [Figure 12A]

[0033] Figure 1 shows a cross-sectional CT scan of a right mediastinal pleural nodule in patient 1 before treatment. The scan confirms a partial response to treatment. [Figure 12B]

[0033] Figure 1 shows a cross-sectional CT scan of a right mediastinal pleural nodule in patient 1 at week 6 of treatment. The scan confirms a partial response to treatment. [Figure 12C]

[0033] Figure 1 shows a cross-sectional CT scan of a right mediastinal pleural nodule in patient 1 at week 12 of treatment. The scan confirms a partial response to treatment. [Figure 13] An outline of the treatment for patient 2 is shown. [Figure 14A] 1 shows a cross-sectional CT scan of the right pleural nodule in patient 2 before treatment. The scan confirms stable disease. [Figure 14B]

[0033] Figure 1 shows a cross-sectional CT scan of a right pleural nodule in patient 2 at week 6 of treatment. The scan confirms stable disease. [Figure 14C]

[0033] Figure 1 shows a cross-sectional CT scan of a right pleural nodule in patient 2 at week 12 of treatment. The scan confirms stable disease. [Figure 15A] 1 shows a cross-sectional CT scan of the GB base lesion in patient 2 before treatment. The scan confirms stable disease. [Figure 15B]

[0033] Figure 1 shows a cross-sectional CT scan of the GB base lesion in patient 2 at week 6 of treatment. The scan confirms stable disease. [Figure 15C]

[0033] Figure 1 shows a cross-sectional CT scan of the GB base lesion in patient 2 at week 12 of treatment. The scan confirms stable disease. [Figure 16] 1 is a chart showing the decrease in pleural fluid drainage for patient 2 as a function of time. [Figure 17] An outline of the treatment for patient 3 is shown. [Figure 18] 1 is a chart showing the decrease in pleural fluid drainage in patient 3 as a function of time. [Figure 19A]

[0033] Figure 1 shows a cross-sectional CT scan of the tumor of patient 3 before treatment. The scan confirms stable disease by week 12 of treatment. [Figure 19B] (B) Cross-sectional CT scan of the tumor from patient 3 at week 6 of treatment. (C) The scan confirms stable disease by week 12 of treatment. [Figure 19C]

[0033] Figure 1 shows a cross-sectional CT scan of the tumor from patient 3 at week 12 of treatment. The scan confirms stable disease by week 12 of treatment. [Figure 20] Cross-sectional CT scan of new liver metastases from patient 3 is shown, demonstrating disease progression at the time of the 12-week scan. [Figure 21] CT scan of new lytic bone metastases from patient 3 is shown, demonstrating disease progression at the time of the 12-week scan. DETAILED DESCRIPTION OF THE INVENTION

[0008] Tumor cells generate high levels of reactive oxygen species (ROS) and therefore exhibit increased expression and activity of key ROS scavenging pathways, including the mitochondrial peroxide scavenging enzyme peroxiredoxin 3 (PRX3). PRX3 is a peroxidase responsible for metabolizing approximately 90% of mitochondrial ROS, primarily H2O2. PRX3 transcript levels are upregulated in approximately 50% of cancers compared with normal tissues (data from the GEPIA2 database). Genetic knockdown of PRX3 in human tumor cells results in increased sensitization to apoptosis. Mitochondria in malignant mesothelioma (MM) cells are structurally and functionally altered, leading to metabolic abnormalities that support tumor growth and may serve as therapeutic targets (see Figures 1A and 1B).

[0009] Thiostrepton is a covalent inhibitor that inactivates PRX3 peroxidase activity through direct addition of an active-site cysteine ​​residue, thereby inducing oxidative stress to levels incompatible with tumor cell survival. Figure 2A shows the EC50 of thiostrepton in normal mesothelial cell lines and various mesothelioma cell lines with varying BAP1 expression. As shown in Figure 2B, siRNA-mediated PRX3 knockdown significantly reduces MM (HM cell line—pleural biphasic) proliferation. Coexpression of the H2O2 scavenger catalase rescues proliferation in cells lacking PRX3 expression. After treatment with 20 mg / ml of thiostrepton composition twice weekly for 4 weeks, tumor weights were significantly lower than control weights (Figure 2C) in residual tumors resected from mice bearing intraperitoneal MM xenografts, thereby demonstrating the preclinical rationale for thiostrepton's bioactivity.

[0010] A small amount of pleural fluid in the pleural cavity is physiologically normal. Mesothelioma and metastatic disease to the lungs often result in excessive fluid accumulation (approximately 15% of cancers). Malignant pleural effusions (MPEs) are routinely drained using an intrapleural catheter. Thiostrepton retains activity in patient-derived MPEs. MPEs contain tumor and immune cells, allowing for the evaluation of thiostrepton's efficacy in this disease, where both cell types are inhibited by thiostrepton. Specifically, adherent tumor spheroids and nonadherent immune cells can be grown in medium containing MPE supernatant (Figures 3A, 3B, and 3C). PRX3 is inactivated by thiostrepton in both tumor (adherent) and immune (nonadherent) cells (Figure 3D). Furthermore, as shown in Figure 3E, MPE-derived tumor cells are equally sensitive to thiostrepton compared to established MM cell lines.

[0011] In certain aspects, provided herein are methods for treating cancer, comprising administering thiostrepton to a subject in need thereof in a single dose of about 50 mg to about 500 mg once a week, thereby treating the cancer.

[0012] In certain embodiments, the single dose is from about 90 mg to about 450 mg. In some such embodiments, the single dose is selected from about 90 mg, about 120 mg, about 180 mg, about 270 mg, about 360 mg, and about 450 mg.

[0013] In some embodiments, the single dose is administered to the subject once a week for at least 3 weeks.In certain embodiments, the single dose in a certain week is the same amount as the single dose administered in different weeks.In various embodiments, the first single dose is administered for 3 weeks, and then the second single dose is administered for the next 3 weeks, and the first single dose and the second single dose are different.In certain such embodiments, the second single dose is larger than the first single dose.In other embodiments, the second single dose is smaller than the first single dose.

[0014] In certain embodiments, the thiostrepton is present in a pharmaceutical composition that further comprises at least one pharmaceutically acceptable carrier.

[0015] In some embodiments, thiostrepton is administered locally, hi certain embodiments, thiostrepton is administered intraperitoneally, intrapleurally, subcutaneously, or intratumorally.

[0016] In certain embodiments, thiostrepton is administered by a catheter, tube, or needle. In some embodiments, thiostrepton is administered by an indwelling intraperitoneal catheter (IPC).

[0017] In some embodiments, the cancer is selected from lung cancer, breast cancer, prostate cancer, melanoma, esophageal cancer, leukemia, cervical cancer, liver cancer, colon cancer, gastric cancer, colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, mesothelioma, and ovarian cancer. In further embodiments, the cancer is malignant mesothelioma. In still further embodiments, the cancer is malignant pleural mesothelioma. In still further embodiments, the cancer is malignant epithelioid pleural mesothelioma. In other embodiments, the cancer is malignant peritoneal mesothelioma. In particular embodiments, the cancer is lung cancer. In certain such embodiments, the lung cancer is adenocarcinoma. In some embodiments, the cancer is metastatic.

[0018] In certain embodiments, the subject experiences stable disease for at least 12 weeks after administration of the first dose of thiostrepton. In some such embodiments, the subject experiences stable disease for at least about 12 weeks to about 52 weeks after administration of the first dose of thiostrepton. In some embodiments, the subject experiences stable disease for at least 18 weeks after administration of the first dose of thiostrepton. In certain such embodiments, the subject experiences stable disease for at least about 18 weeks to about 52 weeks after administration of the first dose of thiostrepton. In certain embodiments, the subject experiences stable disease for at least 24 weeks after administration of the first dose of thiostrepton. In some such embodiments, the subject experiences stable disease for at least about 24 weeks to about 52 weeks after administration of the first dose of thiostrepton.

[0019] In some embodiments, the subject experiences progression-free survival for at least 12 weeks after administration of the first dose of thiostrepton. In some such embodiments, the subject experiences progression-free survival for at least about 12 weeks to about 52 weeks after administration of the first dose of thiostrepton. In some embodiments, the subject experiences progression-free survival for at least 18 weeks after administration of the first dose of thiostrepton. In certain such embodiments, the subject experiences progression-free survival for at least about 18 weeks to about 52 weeks after administration of the first dose of thiostrepton. In certain embodiments, the subject experiences progression-free survival for at least 24 weeks after administration of the first dose of thiostrepton. In some such embodiments, the subject experiences progression-free survival for at least about 24 weeks to about 52 weeks after administration of the first dose of thiostrepton.

[0020] In certain embodiments, the subject experiences a partial response for at least 12 weeks after administration of the first dose of thiostrepton. In some such embodiments, the subject experiences a partial response for at least about 12 weeks to about 52 weeks after administration of the first dose of thiostrepton. In some embodiments, the subject experiences a partial response for at least 18 weeks after administration of the first dose of thiostrepton. In certain such embodiments, the subject experiences a partial response for at least about 18 weeks to about 52 weeks after administration of the first dose of thiostrepton. In certain embodiments, the subject experiences a partial response for at least 24 weeks after administration of the first dose of thiostrepton. In some such embodiments, the subject experiences a partial response for at least about 24 weeks to about 52 weeks after administration of the first dose of thiostrepton.

[0021] In certain embodiments, a partial response comprises at least a 10% reduction in tumor size compared to the tumor size before thiostrepton administration. In further embodiments, a partial response comprises at least a 30% reduction in tumor size compared to the tumor size before thiostrepton administration. In yet further embodiments, a partial response comprises at least a 60% reduction in tumor size compared to the tumor size before thiostrepton administration.

[0022] In certain embodiments, the subject experiences pleural effusion.In some such embodiments, the volume of pleural effusion is reduced 10 weeks after the administration of the first dose of thiostrepton, compared to the volume of pleural effusion before thiostrepton administration.In certain embodiments, the volume of pleural effusion is reduced 5 weeks after the administration of the first dose of thiostrepton, compared to the volume of pleural effusion before thiostrepton administration.In some embodiments, the volume of pleural effusion is reduced 1 week after the administration of the first dose of thiostrepton, compared to the volume of pleural effusion before thiostrepton administration.

[0023] In certain embodiments, the volume of the pleural fluid is about 30% less than the volume of the pleural fluid before administration of thiostrepton. In some embodiments, the volume of the pleural fluid is about 60% less than the volume of the pleural fluid before administration of thiostrepton. In certain embodiments, the volume of the pleural fluid is about 90% less than the volume of the pleural fluid before administration of thiostrepton.

[0024] In certain aspects, provided herein is a pharmaceutical composition comprising thiostrepton and at least one pharmaceutically acceptable carrier, the pharmaceutical composition comprising from about 50 mg to about 500 mg of thiostrepton.

[0025] In certain embodiments, the composition comprises about 90 mg to about 450 mg of thiostrepton, hi some embodiments, the composition comprises about 90 mg, about 180 mg, about 270 mg, about 360 mg, or about 450 mg of thiostrepton.

[0026] The compositions and methods described herein can be utilized to treat individuals in need thereof. The term "pharmaceutical composition" refers to a composition comprising thiostrepton and at least one pharmaceutically acceptable carrier. The terms "active compound" and "active ingredient" refer to thiostrepton. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. In certain preferred embodiments, the subject or mammal is a human. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, an active compound described herein and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, by way of non-limiting example, aqueous solutions such as water or physiologically buffered saline, or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are intended for human administration, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion across an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipients can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical compositions can be in dosage unit forms such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized products for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The compositions can also be present in transdermal delivery systems, for example, skin patches. The compositions can also be present in solutions suitable for topical administration, such as lotions, creams, or ointments.

[0027] Pharmaceutically acceptable carriers can contain physiologically acceptable agents that act to stabilize, increase solubility, or enhance absorption of active compounds, such as those described herein. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low-molecular-weight proteins; or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier containing a physiologically acceptable agent depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying or self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, which can incorporate, for example, a compound described herein. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to prepare and administer.

[0028] As used herein, the phrase "pharmaceutically acceptable" is used to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0029] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; and (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water; (17) isotonic saline, (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0030] Pharmaceutical compositions (preparations) can be administered to a subject by any of a number of routes of administration, including, for example, intraperitoneally; intrapleurally; subcutaneously; intratumorally; orally (e.g., drenches such as aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue), absorption through the oral mucosa (e.g., sublingually), transdermally (e.g., as a patch applied to the skin), and topically (e.g., as a cream, ointment, or spray applied to the skin). The compounds may also be formulated for inhalation. In some embodiments, the pharmaceutical compositions are administered topically. In some embodiments, the pharmaceutical compositions are administered by catheter, tube, or needle. In certain embodiments, the compounds may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, and the patents cited therein.

[0031] Preparation can be conveniently provided in unit dosage form, and can be prepared by any method known in the art of pharmacy.The amount of active ingredient that can be combined with carrier material to produce single dosage form varies depending on the host treated, specific administration method.The amount of active ingredient that can be combined with carrier material to produce single dosage form is generally the amount of compound that produces therapeutic effect.

[0032] Methods of preparing these formulations or compositions include the step of bringing into association the active compound, e.g., thiostrepton, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound described herein with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0033] Liquid dosage forms include pharmaceutically acceptable emulsions, lyophilized products for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0034] In addition to the inert diluents, the liquid compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming agents, and preservatives.

[0035] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0036] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intraperitoneal, intrapleural, subcutaneous, intratumoral, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. In some embodiments, the pharmaceutical composition is administered intraperitoneally, intrapleurally, subcutaneously, or intratumorally. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents, or sterile powders that can be reconstituted into a sterile injectable solution or dispersion immediately before use.

[0037] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions described herein include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate, etc. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0038] These compositions may contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the compositions. Furthermore, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0039] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug after injection, for example, subcutaneous injection.This can be achieved by using a liquid suspension of crystalline or amorphous material that is poorly water-soluble.In this case, the absorption rate of the drug depends on its dissolution rate, which may depend on crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0040] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0041] For use in the methods described herein, the active compound may be provided per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0042] The introduction method may also be provided by a rechargeable or biodegradable device. For the controlled delivery of drugs, including proteinaceous biopharmaceuticals, various sustained-release polymeric devices have been developed and tested in vivo in recent years. Various biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

[0043] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and method of administration without being toxic to the patient.

[0044] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts, or amides thereof, employed, the route of administration, the time of administration, the rate of excretion of the particular compound(s) employed, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health, and past medical history of the patient being treated, and similar factors well known in the medical arts.

[0045] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start by administering a pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" refers to the concentration of a compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary depending on the subject's weight, sex, age, and medical history. Other factors that affect the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, other therapeutic agents administered together with the compounds described herein. Multiple administrations of the drug can deliver a larger total dose. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, incorporated herein by reference).

[0046] In general, an appropriate dosage of an active compound used in the compositions and methods described herein will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0047] If desired, an effective dose of the active compound may be administered as one, two, three, four, five, six, or more separate doses administered at appropriate intervals, optionally in unit dosage form. In some embodiments, thiostrepton is administered once a week. In certain embodiments, thiostrepton is administered for 2, 3, 4, 5, or 6 consecutive weeks. In some embodiments, thiostrepton is administered every other week, every three weeks, or every four weeks, once or twice each week.

[0048] The patient receiving this treatment may be any animal in need of treatment, including primates, particularly humans, as well as mammals such as horses, cows, pigs, sheep, cats, and dogs, poultry, and common pets.

[0049] In certain embodiments, the compounds described herein may be used alone or may be administered in combination with another type of therapeutic agent.

[0050] The present disclosure includes the use of pharmaceutically acceptable salts of the compounds described herein in the compositions and methods described herein. In certain embodiments, contemplated salts include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, contemplated salts include, but are not limited to, L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.In certain embodiments, contemplated salts include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptan-1,2-one ... and d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0051] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0052] Wetting agents, emulsifying agents, and lubricating agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0053] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0054] definition Unless otherwise defined herein, scientific and technical terms used herein shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0055] The methods and techniques of the present disclosure are generally carried out according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout the specification, unless otherwise indicated.

[0056] All of the above, as well as any other publications, patents, and published patent applications mentioned in this application, are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0057] The term "agent" is used herein to refer to a chemical compound (e.g., an organic or inorganic compound, a mixture of compounds), a biological macromolecule (e.g., nucleic acids, antibodies containing portions thereof, as well as humanized, chimeric, and human antibodies, and monoclonal antibodies, proteins or portions thereof, e.g., peptides, lipids, carbohydrates), or an extract prepared from biological material such as bacterial, plant, fungal, or animal (especially mammalian) cells or tissues. Agents include, for example, agents whose structures are known and agents whose structures are unknown.

[0058] The terms "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including cattle, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats). A subject can be male or female. In some embodiments, a subject is over 18 years of age. In certain embodiments, a subject preferably has an ECOG (Eastern Cooperative Oncology Group) score of 0 to 1. In certain embodiments, a patient may have a histological diagnosis of MPE caused by a non-mesothelioma solid tumor or mesothelioma. In some embodiments, a patient has received at least one prior standard-of-care treatment regimen with documented progression and no available approved alternatives. In some embodiments, a patient has resolution of all acute reversible toxic effects of prior therapy to Grade 1 or less. In certain embodiments, a patient has a paraffin block of their most recent biopsy. In some embodiments, the patient has adequate organ function as defined by laboratory values ​​prior to thiostrepton administration. In some embodiments, the subject is postmenopausal, surgically sterilized, or uses effective contraception.

[0059] In some embodiments, the patient has not received prior systemic anti-cancer therapy or radiation therapy prior to thiostrepton administration. In some embodiments, the patient has not undergone surgery within 3 weeks or 5 half-lives prior to thiostrepton administration. In some embodiments, the patient has not received treatment with an investigational drug / device within 30 days prior to thiostrepton administration. In certain embodiments, the patient has not had a malignancy other than the cancer being treated prior to thiostrepton administration. In certain embodiments, the patient has no tumors or vesicles that would render intrapleural administration incomplete or ineffective. In certain embodiments, the patient has no known hypersensitivity to thiostrepton or the excipients of the pharmaceutical composition. In some embodiments, the patient has no surgical or medical conditions that could interfere with thiostrepton treatment. In some embodiments, the patient has no active infection with human immunodeficiency virus (HIV), or hepatitis B, or hepatitis C without a sustained virologic response. In certain embodiments, the patient is not pregnant or breastfeeding. In some embodiments, the patient does not have symptomatic or unstable CNS tumors or metastases or carcinomatous meningitis. In some embodiments, the patient has not used systemic corticosteroids within 15 days prior to thiostrepton administration or other immunosuppressive drugs within 3 weeks prior to thiostrepton administration.

[0060] "Treating" a condition or patient refers to taking measures to achieve beneficial or desired results, including clinical results. As used herein, and as well understood in the art, "treatment" is an approach for achieving beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, reduction in the extent of disease, stabilization of the disease state (i.e., not worsening), prevention of disease spread, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or total). "Treatment" can also mean prolonging survival compared to expected survival if not receiving treatment.

[0061] The term "prevention," when used in reference to a condition such as local recurrence (e.g., pain), a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition, is art-recognized and well understood in the art and includes administration of a composition that reduces the frequency of, or delays the onset of, symptoms of, a medical condition in a subject compared to subjects not administered the composition. Thus, cancer prevention, by way of example, includes reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population relative to an untreated control population, by a statistically and / or clinically significant amount.

[0062] "Administering" or "administration" of a substance, compound, or agent to a subject can be accomplished using one of a variety of methods known to those skilled in the art. For example, the compound or agent can be administered intraperitoneally, intrapleurally, subcutaneously, intratumorally, intravenously, intraarterially, intradermally, intramuscularly, subcutaneously, intraocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intrathecally, intracerebrally, and transdermally (e.g., by absorption through cutaneous channels). The compound or agent can also be suitably introduced via rechargeable or biodegradable polymeric or other devices, e.g., patches and pumps, or formulations that provide extended, slow, or controlled release of the compound or agent. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods of time.

[0063] In certain embodiments, administration of thiostrepton or any of the pharmaceutical compositions comprising thiostrepton disclosed herein can be performed using an indwelling intraperitoneal catheter (IPC). In some embodiments, administration is performed once or twice weekly, preferably once weekly. In some embodiments, the method further comprises removing fluid from the pleural effusion, e.g., prior to administration of thiostrepton (FIG. 4A). In certain embodiments, after administration of thiostrepton (FIG. 4B), the IPC is fixed until the next dosing time (FIG. 4C).

[0064] In certain embodiments, a single dose of thiostrepton ranges from about 50 mg to about 500 mg. In some embodiments, a single dose of thiostrepton ranges from about 90 mg to about 450 mg. In preferred embodiments, the single dose is selected from about 90 mg, about 180 mg, about 270 mg, about 360 mg, and about 450 mg. In some embodiments, the single dose is administered to a subject, for example, once a week for at least three weeks.

[0065] In some embodiments, a single dose of thiostrepton may be increased, for example, every three weeks, such that a patient receives 90 mg once weekly for weeks 1-3, optionally followed by 180 mg once weekly for weeks 4-6, optionally followed by 270 mg once weekly for weeks 7-9, optionally followed by 360 mg once weekly for weeks 10-12, and finally, optionally, by 450 mg once weekly for weeks 13-15. Each patient may complete any or all of the three-week sessions (FIG. 5). In some embodiments, the dosing regimen may be paused, discontinued, or the patient may be transitioned to a lower dose, for example, in the event of toxicity or adverse events.

[0066] In some embodiments, the method further comprises obtaining a tumor biopsy from the patient prior to administering thiostrepton, hi some embodiments, the method further comprises obtaining a tumor biopsy after administering a third dose of thiostrepton.

[0067] In other embodiments, the pharmaceutical composition contains about 5 mg thiostrepton / mL to about 50 mg thiostrepton / mL. In some embodiments, the pharmaceutical composition contains about 10 mg thiostrepton / mL, about 20 mg thiostrepton / mL, about 30 mg thiostrepton / mL, about 40 mg thiostrepton / mL, and about 50 mg thiostrepton / mL. In a preferred embodiment, the pharmaceutical composition contains 20 mg thiostrepton / mL.

[0068] Suitable methods of administering a substance, compound, or agent to a subject also depend, for example, on the age and / or health of the subject, as well as the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or agent is administered orally to the subject, for example, by ingestion. In some embodiments, the orally administered compound or agent is in a sustained- or extended-release formulation or is administered using a device for such sustained- or extended-release.

[0069] As used herein, the phrase "co-administration" refers to any form of administration of two or more different therapeutic agents, such that a second agent is administered while a previously administered therapeutic agent is still effective in the body (e.g., if at least 5% of the formulation is detected systemically by industry-accepted methods, or if the two agents have an effect in the patient simultaneously, this may include a synergistic effect of the two agents). For example, different therapeutic compounds may be administered simultaneously or sequentially, either in the same formulation or in separate formulations. In certain embodiments, different therapeutic compounds may be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week of each other. Thus, individuals receiving such treatment may benefit from the combined effects of the different therapeutic agents.

[0070] In some embodiments, the first single dose in a certain week is the same amount as the single dose administered in a different week.In certain embodiments, the first single dose is administered for 3 weeks, and then the second single dose is administered for the next 3 weeks, and the first single dose and the second single dose are different.In some embodiments, the second single dose is larger than the first single dose.In other embodiments, the second single dose is smaller than the first single dose.

[0071] A "therapeutically effective amount" or "therapeutically effective dose" of a compound or other agent described herein is an amount that, when administered to a subject, causes the drug or agent to have its intended therapeutic effect. The full therapeutic effect does not necessarily occur with the administration of a single dose of such drug or agent, but may occur only after the administration of a series of doses (multiple consecutive administrations). Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount required for a subject will depend, for example, on the subject's size, health, and age, as well as the nature and extent of the condition, such as cancer, being treated.

[0072] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes examples when the event or circumstance occurs and examples when it does not occur.

[0073] As used herein, the term "modulate" includes inhibiting or suppressing a function or activity (eg, cell proliferation), as well as enhancing a function or activity.

[0074] The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, this term includes compositions, excipients, adjuvants, polymers, and other materials and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0075] Disclosed herein in certain embodiments are methods of treating cancer (e.g., a solid tumor or a hematological cancer), comprising administering to a subject in need of cancer treatment a therapeutically effective amount of any of the compounds described herein, or a composition of the compounds. In certain embodiments, the cancer (solid tumor or hematological cancer) is selected from lung cancer, breast cancer, prostate cancer, melanoma, esophageal cancer, leukemia, cervical cancer, liver cancer, colon cancer, gastric cancer, colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, mesothelioma, and ovarian cancer. In certain embodiments, the cancer is selected from mesothelioma, lung cancer, ovarian cancer, and breast cancer. In some embodiments, the cancer is malignant mesothelioma. [Example]

[0076] Exemplary Phase 1 / 2 Dose Escalation and Expansion Study A Phase 1 / 2 dose escalation and expansion study was conducted to determine the safety, tolerability, and recommended Phase 2 dose of an exemplary thiostrepton composition in patients with malignant pleural effusion due to advanced / metastatic solid tumors, including mesothelioma. Preliminary results for three patients (Patient 1, Patient 2, and Patient 3) are provided herein. Figures 6-20 provide a study summary, treatment details, and exemplary preliminary data for these three patients.

[0077] The terms partial response ("PR"), stable disease ("SD"), and best overall response ("BOR") are used according to the definitions and criteria set forth in the RECIST guidelines, version 1.1 (Eur. J Cancer. 2009, 45, 228-247).

[0078] Patient 1: 84-year-old male, ECOG1 - Medical history: hypertension, hypercholesterolemia, benign prostatic hyperplasia Diagnosed with malignant epithelioid pleural mesothelioma in December 2020 Previous first-line (1L) treatment: carboplatin + pemetrexed BOR = stable disease Patient progressed to 1L therapy Treatment with thiostrepton at a dose of 90 mg administered once a week

[0079] As shown in the table in Figure 9, Patient 1 experienced a partial response (approximately 59% reduction in tumor size) for 18 weeks after initial thiostrepton treatment and stable disease through week 24. Figure 10 shows that Patient 1 experienced a significant reduction in pleural effusion throughout 30 weeks of thiostrepton treatment. Figures 11A-11C are CT scans of Patient 1 before treatment (11A), at week 6 of treatment (11B), and at week 12 of treatment (11C).

[0080] Patient 2: 75-year-old woman, ECOG1 · Diagnosed with malignant epithelioid pleural mesothelioma with subdiaphragmatic disease on April 12, 2019. · Underlying medical history: hypertension, previous TB - complicated by bronchiectasis 25 years ago. 1L: Chemocarboplatin + pemetrexed BOR = stable disease 2nd line: vinorelbine; BOR=PD 3rd line: nivolumab; BOR=SD 4th line: gemcitabine; BOR=PD 5th Level: Pem / Carbo (retry); BOR=PR Patient progressed to rechallenge Carb / Pem Treated with a 90mg thiostrepton dose administered once weekly

[0081] As shown in Figure 13, Patient 2 demonstrated stable disease throughout at least 18 weeks of treatment. Figure 16 shows that Patient 2 experienced a decrease in pleural fluid drainage throughout 18 weeks of treatment. Figures 14A-14C and 15A-15C are CT scans of Patient 2 before treatment (14A, 15A), at week 6 of treatment (14B and 15B), and at week 12 of treatment (14C and 15C).

[0082] Patient 3: 74-year-old male, ECOG1 ·Diagnosed with T4N2M1a adenocarcinoma of the lung on July 17, 2021 · Underlying medical history: glaucoma, atrial flutter (treated with ablation). First-line: Carboplatin + Pemetrexed + Pembro; BOR = stable disease The patient progressed on February 25, 2023 - Development of significant pleural effusion (MPE) An IPC was inserted on March 9, 2023, and a large amount of hemorrhagic pleural effusion (>4 liters) was drained in one week. -Trial treatment begins on March 17, 2023 Treated with a 90mg thiostrepton dose administered once weekly

[0083] As shown in Figure 17, Patient 3 demonstrated stable disease throughout at least 6 weeks of treatment, with disease progression observed at the time of the 12-week scan. Figure 18 shows that Patient 3 experienced a decrease in pleural fluid drainage throughout 12 weeks of treatment. Figures 19A-19C are CT scans of Patient 3 before treatment (19A), at week 6 of treatment (19B), and at week 12 of treatment (19C). Figures 20 and 21 are CT scans of Patient 3 obtained at week 12 of treatment.

[0084] Incorporation by Reference All publications and patents mentioned herein are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0085] equivalent The foregoing written specification is deemed sufficient to enable one skilled in the art to practice the invention. The present invention is not limited in scope by the examples provided, which are intended to be single illustrations of one aspect of the invention, and other functionally equivalent embodiments are also intended to be within the scope of the invention. Various modifications of the present invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. These modifications are intended to be included within the scope of the appended claims. The advantages and objectives of the present invention are not necessarily encompassed in each embodiment of the present invention.

Claims

1. A method for treating cancer, comprising administering thiostrepton to a subject in need thereof in a single dose of about 50 mg to about 500 mg once a week, thereby treating said cancer.

2. 10. The method of claim 1, wherein the single dose is from about 90 mg to about 450 mg.

3. 3. The method of claim 2, wherein the single dose is selected from about 90 mg, about 120 mg, about 180 mg, about 270 mg, about 360 mg, and about 450 mg.

4. 10. The method of any one of the preceding claims, wherein the single dose is administered to the subject once a week for at least three weeks.

5. 5. The method of claim 4, wherein the single dose in one week is the same amount as the single dose administered in a different week.

6. 5. The method of claim 4, wherein a first single dose is administered over a three-week period, followed by a second single dose administered over another three-week period, wherein the first single dose and the second single dose are different.

7. 7. The method of claim 6, wherein the second single dose is greater than the first single dose.

8. 7. The method of claim 6, wherein the second single dose is smaller than the first single dose.

9. The method of any one of claims 1 to 8, wherein the thiostrepton is present in a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier.

10. The method of any one of claims 1 to 9, wherein the thiostrepton is administered topically.

11. The method of any one of claims 1 to 10, wherein the thiostrepton is administered intraperitoneally, intrapleurally, subcutaneously, or intratumorally.

12. The method of any one of claims 1 to 11, wherein the thiostrepton is administered by a catheter, tube, or needle.

13. The method of any one of claims 1 to 10, wherein the thiostrepton is administered by an indwelling intraperitoneal catheter (IPC).

14. 11. The method of any one of claims 1 to 10, wherein the cancer is selected from lung cancer, breast cancer, prostate cancer, melanoma, esophageal cancer, leukemia, cervical cancer, liver cancer, colon cancer, gastric cancer, colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, mesothelioma, and ovarian cancer.

15. The method of any one of claims 1 to 10, wherein the cancer is malignant mesothelioma.

16. 16. The method of claim 15, wherein the cancer is malignant pleural mesothelioma.

17. 17. The method of claim 16, wherein the cancer is malignant epithelioid pleural mesothelioma.

18. 17. The method of claim 16, wherein the cancer is malignant peritoneal mesothelioma.

19. 15. The method of claim 14, wherein the cancer is lung cancer.

20. 20. The method of claim 19, wherein the lung cancer is an adenocarcinoma.

21. The method of any one of claims 14 to 20, wherein the cancer is metastatic.

22. 10. The method of any one of the preceding claims, wherein the subject experiences stable disease for at least 12 weeks after administration of the first dose of thiostrepton.

23. 10. The method of any one of the preceding claims, wherein the subject experiences stable disease for at least 18 weeks after administration of the first dose of thiostrepton.

24. 22. The method of any one of claims 1 to 21, wherein the subject experiences stable disease for at least 24 weeks after administration of the first dose of thiostrepton.

25. 10. The method of any one of the preceding claims, wherein the subject experiences progression-free survival for at least 12 weeks after administration of the first dose of thiostrepton.

26. 10. The method of any one of the preceding claims, wherein the subject experiences progression-free survival for at least 18 weeks after administration of the first dose of thiostrepton.

27. 22. The method of any one of claims 1 to 21, wherein the subject experiences progression-free survival for at least 24 weeks after administration of the first dose of thiostrepton.

28. 22. The method of any one of claims 1 to 21, wherein the subject experiences a partial response for at least 12 weeks after administration of the first dose of thiostrepton.

29. 22. The method of any one of claims 1 to 21, wherein the subject experiences a partial response for at least 18 weeks after administration of the first dose of thiostrepton.

30. 22. The method of any one of claims 1 to 21, wherein the subject experiences a partial response for at least 24 weeks after administration of the first dose of thiostrepton.

31. 31. The method of any one of claims 28 to 30, wherein the partial response comprises a decrease in tumor size of at least 10% compared to the tumor size before administration of thiostrepton.

32. 32. The method of any one of claims 28 to 31, wherein the partial response comprises a reduction in tumor size of at least 30% compared to the tumor size before administration of thiostrepton.

33. 33. The method of any one of claims 28 to 32, wherein the partial response comprises a reduction in tumor size of at least 60% compared to the tumor size before administration of thiostrepton.

34. 10. The method of any one of the preceding claims, wherein the subject is experiencing a pleural effusion.

35. 35. The method of claim 34, wherein the volume of the pleural effusion is reduced 10 weeks after administration of the first dose of thiostrepton compared to the volume of the pleural effusion before administration of thiostrepton.

36. 35. The method of claim 34, wherein the volume of the pleural effusion is reduced five weeks after administration of the first dose of thiostrepton compared to the volume of the pleural effusion before administration of thiostrepton.

37. 35. The method of claim 34, wherein the volume of the pleural effusion is reduced one week after administration of the first dose of thiostrepton compared to the volume of the pleural effusion before administration of thiostrepton.

38. 38. The method of any one of claims 35 to 37, wherein the volume of the pleural fluid is about 30% less than the volume of the pleural fluid before administration of thiostrepton.

39. 38. The method of any one of claims 35 to 37, wherein the volume of the pleural fluid is about 60% less than the volume of the pleural fluid before administration of thiostrepton.

40. 38. The method of any one of claims 35 to 37, wherein the volume of the pleural fluid is about 90% less than the volume of the pleural fluid before administration of thiostrepton.

41. A pharmaceutical composition comprising thiostrepton and at least one pharmaceutically acceptable carrier, the pharmaceutical composition comprising from about 50 mg to about 500 mg of thiostrepton.

42. 42. The pharmaceutical composition of claim 41, comprising about 90 mg to about 450 mg of thiostrepton.

43. 43. The pharmaceutical composition of claim 42, comprising about 90 mg, about 180 mg, about 270 mg, about 360 mg, or about 450 mg of thiostrepton.

Images