Use of radionuclide pp-f11n in a chemotherapy like fast injection cycles

Abstract

The invention features dosing regimens and combination therapies utilizing radiolabeled gastrin analogues for the treatment of CCKB receptor positive diseases, including CCK2R-positive cancers and cancers at all stages of cancer spread.

Description

[0001] USE OF RADIONUCLIDE PP-F11N IN A CHEMOTHERAPY LIKE FAST INJECTION CYCLES

[0002] BACKGROUND OF THE INVENTION

[0003] Cholecystokinin B receptor, also known as CCKBR or CCK2R, has been linked to various diseases and plays an important role in both slow- and fast-growing tumors, particularly tumor infiltration and metastasis.

[0004] Targeted radionuclide therapy (TRT) delivers cytotoxic radioactivity specifically to cancer cells through tumor-targeting molecules. To date, beta particle-emitting radionuclides have been routinely employed for the development of TRT against malignant tumors. Lutathera® (lutetium-177oxodotreotide) for neuroendocrine tumors, Pluvicto® (lutetium Lu 177 vipivotide tetraxetan) for progressive Metastatic Castration-Resistant Prostate Cancer (mCRPCT), Zevalin® (yttrium-90 Ibritumomab Tiuxetan) for non-Hodgkin’s follicular lymphoma, and Azedra® (iodine-131 iobenguane) for advanced or metastatic pheochromocytoma or paraganglioma represent FDA-approved beta particle-emitting pharmaceuticals. TRT is a promising therapeutic modality for patients with disseminated diseases, nonoperative tumors, tumor metastasis, and for the removal of tumor residues that remain following early- stage operation, which can be combined with standard-of-care chemotherapy and external beam radiotherapy. TRT significantly reduces toxicity and improves efficacy through selectively targeting the receptors or antigens, which are exclusively present or overexpressed on the cancer cells.

[0005] The overexpression of cholecystokinin B receptor (CCKBR, also known as CCK2R) has been previously found in different types of tumors, including medullary thyroid carcinoma (MTC), stromal ovarian cancer, small-cell lung cancer, and astrocytoma (see, e.g., Qin, Yun, et al., Pharmaceutics 12.11 (2020): 1088). The expression of CCKBR was also identified in gastroenteropancreatic tumors, leiomyomas and leiomyosarcomas indicating wide application prospects of the radiolabeled minigastrin analogues for diagnosis and therapy of the CCKBR-positive cancers (see Roy et all Oncotarget 20.02.2016: Vol. 7, No 12).

[0006] New efficacious and safe therapies combined with new treatment regimens are needed for treating CCKB receptor positive diseases, including fast- and slow growing CCKBR-positive cancers at all stages of cancer spread.

[0007] SUMMARY OF THE INVENTION

[0008] This disclosure relates to gastrin analogues that bind to the CCK2 receptor (CCK2R). This disclosure also provides pharmaceutical compositions including such gastrin analogues and uses of such gastrin analogues in the treatment of disorders associated with dysregulation or overexpression of CCK2R (e.g., cancer).

[0009] In the first aspect, the invention features a method for treating a cancer characterized by overexpression of CCK2R in a subject comprising administering to the subject a therapeutic amount of a gastrin analogue complexed with a radionuclide, wherein the administering comprises: i. a treatment period in which the gastrin analogue administration is repeated about once every week to about once every six weeks (e.g., about once every week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, or about once every six weeks) for the duration of the treatment period; and ii. a maintenance period, wherein if the cancer enters remission, the gastrin analogue administration is repeated about once every week to about once every six weeks (e.g., about once every week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, or about once every six weeks) for the duration of the maintenance period.

[0010] In some embodiments, the treatment period comprises gastrin analogue administration about once every two weeks, and the maintenance period comprises gastrin analogue administration about once every four weeks.

[0011] In some embodiments, the treatment period comprises gastrin analogue administration about once every two weeks, and the maintenance period comprises gastrin analogue administration about once every four weeks.

[0012] In some embodiments, the subject receiving gastrin analogue administration has not concomitantly received any other anticancer treatment.

[0013] In a related aspect the invention features a method for treating a cancer characterized by overexpression of CCK2R in a subject, the method comprising the steps of: i. administering to the subject an anticancer treatment; and ii. administering a therapeutically effective amount of a gastrin analogue complexed with a radionuclide.

[0014] In some embodiments, the administration is repeated about once every week to about once every eight weeks (e.g., about once every week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, or about once every eight weeks) for the duration of the treatment period.

[0015] In some embodiments, the administration is repeated about once every two weeks to about once every four weeks for the duration of the treatment period.

[0016] In some embodiments, if the cancer enters remission, the administration is repeated about every four weeks for the duration of treatment period.

[0017] In some embodiment of any of the above aspects, prior to the gastrin analogue administration, a neprilysin inhibitor is administered to the subject.

[0018] In some embodiments, the neprilysin inhibitor is orally administered about two hours before the gastrin analogue administration.

[0019] In some embodiments, the neprilysin inhibitor is sacubitril. In some embodiments, between about 50 mg and about 200 mg of sacubitril is administered.

[0020] In some embodiments, valsartan is administered concurrently with a neprilysin inhibitor.

[0021] In some embodiments, the cancer is selected from pancreas adenocarcinoma, colon adenocarcinoma, primary liver cancer, astrocytoma, glioma, colorectal carcinoma, esophageal carcinoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, stomach carcinoma, ovarian cancer, medullary thyroid cancer, neuroendocrine tumors, bronchial carcinoids, carcinoids of the bowels and stomach, gastrointestinal stromal tumors, pancreatic neuroendocrine tumors, cholangiocarcinoma, fibrolamellar carcinoma, or non-medullary thyroid carcinoma.

[0022] In some embodiments, the cancer is somatostatin negative.

[0023] In some embodiments, the subject has at least one measurable, histologically proven, or radiodiagnostically proven site of disease. In some embodiments, the subject has a histologically proven Grade 1 or higher tumor. In another embodiment, the cancer is metastatic.

[0024] In some embodiments of any of the above aspects, the cancer is non-operable.

[0025] In some embodiments of any of the above aspects, the cancer is non-responsive to treatment with177lutetium oxodotreotide.

[0026] In some embodiments, the method includes administering to the subject an anticancer treatment selected from immune checkpoint inhibitors, chemotherapeutic agents, PARP inhibitors, antibody drug conjugates, a cytotoxic agent, an antimetabolite, an alkylating agent, an anthracycline, an antibiotic, an anti-mitotic agent, a hormone therapy, a signal transduction inhibitor, a gene expression modulator, an apoptosis inducer, an angiogenesis inhibitor, an immunotherapy agent, a DNA damage repair inhibitor, an mTOR inhibitor, and a kinase inhibitor.

[0027] In some embodiments, following the gastrin analogue administration, the subject experiences an increase in Progression Free Survival, Tumor Response, or Overall Survival Benefit.

[0028] In some embodiments, the subject is human.

[0029] In some embodiments, the gastrin analogue is administered intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraocularally, orally, locally, by inhalation, by injection, or by infusion.

[0030] In some embodiments, the gastrin analogue is a compound described by the formula (I): or a pharmaceutically acceptable salt thereof, wherein

[0031] R1is a chelating group complexed with a radionuclide selected from225Ac,212Bi,213Bi,62Cu.64Cu,

[0032] 67Cu,69Cu.66Ga,67Ga,68Ga,111In,113mIn,177Lu,186Re,188Re,43Sc,44Sc,47Sc,155Tb,161Tb,99mTc.86Y.90Y, 59Yb,175Yb,18Fe,11C,123l,131l,13N and212Pb; R2is optionally present, and is selected from

[0033] R3is OH or NH2;

[0034] X1is optionally present, and is an amino acid selected from β-alanine, D-glutamate and L- glutamate; m is 0, 1 , 2, 3, 4, 5, 6, 7, or 8;

[0035] X2optionally present, and is an amino acid selected from glycine, N-methyl glycine, L-alanine, D- alanine, L-tyrosine, D-tyrosine, D-proline, L-proline, (2S,4S)-4-fluoroproline, and (2S,4R)-4- fluoroproline; n is 0, 1 , 2, 3, or 4;

[0036] X3is an amino acid selected from L-methionine, N-methyl L-methionine, L-norleucine, and N- methyl L-norleucine;

[0037] X4an amino acid amide selected from L-phenylalanine, N-methyl L-methionine, 3-(1-naphthyl)-L- alanine, and N-methyl 3-(1-naphthyl)-L-alanine; optionally wherein any (C=O)NH moiety may be substituted for a 1 ,4-disubstituted-1 ,2,3-triazole, provided: at least one of R2and X2must be present; ii. If X2is present, then R2is not iii. If R2is then X1is β-alanine.

[0038] In some embodiments, the gastrin analogue is selected from a compound of Table A, or any pharmaceutically acceptable salt thereof:

[0039] Table A

[0040] 5

[0041]

[0042] In some embodiments, the gastrin analogue administered is Gastrin analogue 1 , in which R1is DOTA, R2is absent, R3is NH2, X1is only D-glutamate, n is 6, X2is L-alanine - L-tyrosine - glycine, m is 3, X3is L-methionine, and X4is L-phenylalanine.

[0043] In some embodiments, the gastrin analogue administered is Gastrin analogue 2, in which R1is DOTA, R2is absent, R3is NH2, X1is only D-glutamate, n is 6, X2is L-alanine - L-tyrosine - glycine, m is 3, X3is L-norleucine, and X4is L-phenylalanine.

[0044] In some embodiments, the gastrin analogue administered is Gastrin analogue 4, in which R1is DOTA, R2is absent, R3is NH2, X1is D-glutamate, n is 1 , X2is L-alanine - L-tyrosine - glycine, m is 3, X3is N-methyl L-norleucine, and X4is 3-(1-naphthyl)-L-alanine.

[0045] In some embodiments, the gastrin analogue administered is Gastrin analogue 15, in which R1is

[0046] DOTA, R2is present, and is R3is NH2, X1only D-glutamate and X1is connected by isopeptide linkages, m is 8, X2is L-alanine - L-tyrosine - glycine, n is 3, X3is L-norleucine, and X4is L- phenylalanine.

[0047] In some embodiments, the gastrin analogue administered is Gastrin analogue 27, in which R1is R3is NH2, X1is absent, n is 2, X2is absent,

[0048] X3is N-methyl L-norleucine, and X4is 3-(1-naphthyl)-L-alanine.

[0049] In some embodiments, the gastrin analogue administered is Gastrin analogue 28, in which R1is

[0050] DOTA, R2is R3is NH2, X1is absent, m is 1 , n is 2, X2is absent, X3is N-methyl L-norleucine, and X4is 3-(1-naphthyl)-L-alanine.

[0051] In some embodiments, the gastrin analogue administered is Gastrin analogue 29, in which R1is

[0052] DOTA, R2is R3is NH2, X1is β-alanine, m is 1 , n is 2, X2is absent, X3is N- methyl L-norleucine, and X4is 3-(1-naphthyl)-L-alanine.

[0053] In some embodiments, a gastrin analogue complexed with225Ac is administered. In some embodiments, doses ≤500 kBq are administered with each gastrin analogue administration.

[0054] In some embodiments, a gastrin analogue complexed with177Lu is administered. In some embodiments, a dose of about 8 GBq is administered with each gastrin analogue administration.

[0055] In some embodiments, the administered gastrin analogue complexed with212Bi,213Bi,11C62Cu,64Cu,67Cu,69Cu,18Fe,66Ga,67Ga,68Ga,123l,131l,111ln,113mln,13N186Re,188Re,43Sc,44Sc,47Sc,155Tb,161Tb99mTc86Y90Y169Yb175Yb or212Pb In some embodiments, prior to the gastrin analogue administration, the subject is administered a gastrin analogue complexed with68Ga and PET imaging is acquired at least once every eight weeks. It is contemplated that PET imaging is acquired at least once every eight weeks with imaging agents other than those utilizing a68Ga radionuclide, such as those that make use of18F. For example, [18F]- fluorodeoxyglucose may be utilized.

[0056] In another aspect, the disclosure provides a pharmaceutical composition including a gastrin analogue or a gastrin analogue complex, or a pharmaceutically acceptable salt thereof, described herein and a pharmaceutically acceptable excipient.

[0057] In another aspect, the disclosure provides a method of treating cancer in a subject, the method including administering to the subject a gastrin analogue, gastrin analogue complex, or pharmaceutical composition described herein.

[0058] In some embodiments, the cancer is selected from selected from pancreas adenocarcinoma, colon adenocarcinoma, primary liver cancer, astrocytoma, glioma, colorectal carcinoma, esophageal carcinoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, stomach carcinoma, ovarian cancer, medullary thyroid cancer, neuroendocrine tumors, bronchial carcinoids, carcinoids of the bowels and stomach, gastrointestinal stromal tumors, pancreatic neuroendocrine tumors, cholangiocarcinoma, fibrolamellar carcinoma, or non-medullary thyroid carcinoma. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer overexpresses or is known to overexpress CCK2R relative to a non-cancerous cell of the same tissue type.

[0059] In some embodiments, the method further includes administering to the subject an anticancer treatment in addition to a gastrin analogue. In some embodiments, the anticancer treatment is selected from immune checkpoint inhibitors, chemotherapeutic agents, PARP inhibitors, antibody drug conjugates, or a combination thereof.

[0060] In some embodiments of any of the methods of treatment described herein, the gastrin analogue, gastrin analogue complex, or pharmaceutical composition is administered intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically , intraocularally, orally, locally, by inhalation, by injection, or by infusion.

[0061] In another aspect, the invention features a method of treating cancer characterized by overexpression of CCK2R in a subject in need thereof, wherein the cancer is selected from medullary thyroid cancer, neuroendocrine tumors, bronchial carcionids, carcinoids of the bowels and stomach, gastrointestinal stromal tumors, pancreatic neuroendocrine tumors, pancreas adenocarcinoma, colon adenocarcinoma, primary liver cancer, ovarian cancer, astrocytoma, glioma, colorectal carcinoma, esophageal carcinoma, chlolangiocarcinoma, fibrolamellar carcinoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, stomach carcinoma, or non-medullary thyroid carcinoma, wherein the subject is administered a therapeutically effective amount of PP-F11 N complexed with a radionuclide selected from225Ac,212Bi,213Bi,11C62Cu,64Cu,67Cu,69Cu,18Fe,66Ga,67Ga,68Ga,123l,131l,111ln,113ml n ,177Lu,13N186Re,188Re,43Sc,44Sc,47Sc,155Tb,161Tb,99mTc,86Y,90Y,169Yb,175Yb, or212Pb and wherein the radionuclide administration is repeated about once every week to about once every six weeks for the duration of treatment.

[0062] In some embodiments, PP-F11 N complexed with225Ac is administered to the subject. In some embodiments, PP-F11 N complexed with225Ac is administered in doses of below 500 kBq with each treatment cycle.

[0063] In some embodiments, PP-F11 N complexed with177Lu is administered to the subject. In some embodiments, the PP-F11 N or gastrin analogue complexed with177Lu is administered in doses of about 8 GBq with each treatment cycle.

[0064] In some embodiments of any of the above, prior to the administration of PP-F11 N, the subject is administered a neprilysin inhibitor about two hours prior to the PP-F11 N administration. In one embodiment the neprilysin inhibitor is sacubitril. In some embodiments, from about 50 mg to about 150 mg of the sacubitril is orally administered. In one embodiment, 100 mg of the sacubitril is orally administered.

[0065] In some embodiments of any of the above, prior to the administration of PP-F11 N, a complex of PP-F11 N and68Ga is administered to the subject and PET imaging is performed on the subject. In some embodiments, for the duration of gastrin analogue administration,68Ga-PP-F11 N PET imaging is obtained every eight weeks. In some embodiments, the radionuclide administration is repeated about once every week. In some embodiments, the radionuclide administration is repeated about once every two weeks. In some embodiments, the radionuclide administration is repeated about once every four weeks. In some embodiments, the radionuclide administration is repeated about once every six weeks.

[0066] In some embodiments, the subject is human.

[0067] In some embodiments, the subject has a local, metastasized or locally advanced, histologically proven Grade 1 or higher tumor.

[0068] In some embodiments, the subject has at least one measurable or histologically or radio- diagnostically proven site of disease.

[0069] In another aspect, the invention features a method of treating cancer characterized by overexpression of CCK2R in a subject in need thereof, the method comprising the steps of: i. Administration of a neprilysin inhibitor to the subject, and ii. Following about two hours after completion of step (i), administration of therapeutically effective amount of PP-F11 N complexed with a radionuclide177Lu or225Ac to the subject, wherein steps i. and ii. are repeated about once every two to about once every ten weeks for the duration of treatment.

[0070] In some embodiments, the cancer overexpressing CCK2R is medullary thyroid cancer, lung neuroendocrine tumors, or gastro-enteropancreatic neuroendocrine tumors. In one embodiment the cancer overexpressing CCK2R is medullary thyroid cancer. In another embodiment, the cancer overexpressing CCK2R is lung neuroendocrine tumors. In another embodiment, the cancer overexpressing CCK2R is gastro-enteropancreatic neuroendocrine tumors.

[0071] In some embodiments, the cancers are somatostatin negative. In some embodiments, the cancers are non-responsive to treatment with177lutetium- oxodotreotide.

[0072] In some embodiments, the neprilysin inhibitor is sacubitril. In some embodiments, between about 50 mg and about 200 mg of sacubitril is administered.

[0073] In some embodiments, steps i. and ii. are repeated about once every week for the duration of treatment. Alternatively, in some embodiments the repetition occurs every two weeks, every four weeks, or every six weeks. In some embodiments, prior to the repetition of steps i. and ii., the subject is administered PP-F11 N or any gastrin analogue complexed with68Ga.

[0074] In some embodiments, after administering the PP-F11 N or any gastrin analogue complexed with68Ga, a PET imaging scan of the subject is obtained. In some embodiments, for the duration of treatment, PP-F11 N complexed with68Ga PET imaging scans are obtained at least every eight weeks.

[0075] In some embodiments of any of the above, the subject is human.

[0076] In some embodiments of any of the above, the subject has a local or metastasized or locally advanced, histologically proven Grade 1 or higher tumor.

[0077] In some embodiments of any of the above, the subject has at least one measurable or histologically or radio-diagnostically proven site of disease.

[0078] In some embodiments of any of the above, wherein the PP-F11 N is administered intravenously.

[0079] In some embodiments of any of the above, following the administration the subject experiences an increase in Progression Free Survival, Tumor Response or Overall Survival Benefit.

[0080] DEFINITIONS

[0081] To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a,” “an,” and “the” are not intended to refer to only a singular entity but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.

[0082] The terms “CCKBR” or “CCK2R” as used interchangeably herein, refer to the cholecystokinin B receptor protein. CCK2R is encoded by the CCKBR gene and is a G protein-coupled receptor with affinity for gastrointestinal peptide hormones such as cholecystokinin or gastrin; the binding of gastrin, as well as other gastrin analogues, to CCK2R influences neurotransmission in the brain to regulate feeding behavior and simultaneously helps to regulate digestion. CCK2R is overexpressed in endocrinological tumors such as medullary thyroid carcinoma, neuroendocrine tumors, or carcinoids. CCK2R is also overexpressed in many fast-growing, solid tumors such as those found in pancreatic cancers, small cell- and non-small cell lung cancers, hepatocellular cancers, gliomas, or ovarian cancers.

[0083] As used herein, the term “gastrin analogue” refers to a class of compounds (peptides) structurally related to the endogenous peptide hormone gastrin, which can bind to CCK2R. The term “gastrin analogue” as used herein is meant to encompass all compounds containing the C-terminal amino acid sequence Gly-Trp-Dxx-Asp-Phe-NH2, wherein Dxx is Met or an amino acid isosteric with Met, as found in CCK2R-binding endogenous peptide hormones including e.g. gastrin and cholecystokinin (CCK). Gastrin is a linear peptide hormone produced by G cells of the duodenum and in the pyloric antrum of the stomach. It is secreted into the bloodstream. The encoded polypeptide is pre-progastrin, which is cleaved by enzymes in posttranslational modification to produce progastrin and then gastrin in various forms, including primarily big gastrin (G-34), little gastrin (G-17), and minigastrin (Leu-Glu-Glu-Glu-Glu-Glu-Ala- Tyr-Gly-Trp-Met-Asp-Phe-NH2) which all represent “gastrin analogues” in the sense of the present invention. CCK is a peptide hormone structurally related to gastrin in that both compounds share five C- terminal amino acids i.e. Gly-Trp-Met-Asp-Phe-NH2(wherein Met can be replaced by an amino acid isosteric with Met such as norleucine). CCK exists naturally in several forms including e.g. CCK (Asp-Tyr- Met-Gly-Trp-Met-Asp-Phe-NH2). The gastrin analogue can be chemically modified, e.g. at its N-terminus, for covalent attachment to a linker or a moiety that is able to chelate radiometals, such as 1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA), or a moiety that (covalently) bond a radionuclide such as18F or iodine isotopes. In some instances, the gastrin analogue can be modified for covalent attachment to an imaging moiety for medical applications such as Alexa Fluor 647, IRDye 680RD or DY-700, or to a photosensitizer such as Photofrin, Forscam, or Photochlor. In some cases, gastrin analogues with distinct peptide sequences may be referred to using alternative names. For example, in Table A, Gastrin analogue 1 is representative of the sequence and chelating moiety found in “PP-F11 ,” Replacement of the methionine X3motif in PP-F11 with norleucine yields “PP-F11 N.”

[0084] The term “covalently attached” refers to two parts of a gastrin analogue that are linked to each other by a covalent bond formed between two atoms in the two parts of the gastrin analogue.

[0085] The term “linker” as used herein, refer to a covalent linkage or connection between two or more components in a gastrin analogue (e.g., between two separated parts of a gastrin analogue described herein, between a CCK2R ligand and a polypeptide fragment of a gastrin analogue described herein, between a chelating group and a gastrin analogue described herein, and between a radionuclide and a gastrin analogue described herein). Linkers of the disclosure may be linear or branched. In some embodiments, molecules that may be used as linkers include at least two functional groups, which may be the same or different, e.g., two carboxylic acid groups, two amine groups, two sulfonic acid groups, a carboxylic acid group and a maleimide group, a carboxylic acid group and an alkyne group, a carboxylic acid group and an amine group, a carboxylic acid group and a sulfonic acid group, an amine group and a maleimide group, an amine group and an alkyne group, or an amine group and a sulfonic acid group. The first functional group may form a covalent linkage with a first component in the gastrin analogue and the second functional group may form a covalent linkage with the second component in the gastrin analogue. In some embodiments, a molecule containing one or more maleimide groups may be used as a linker, in which the maleimide group may form a carbon-sulfur linkage with a cysteine in a component in the gastrin analogue. In some embodiments, a molecule containing one or more alkyne groups may be used as a linker, in which the alkyne group may form a 1 ,2,3-triazole linkage with an azide in a component in the gastrin analogue. In some embodiments, a molecule containing one or more azide groups may be used as a linker, in which the azide group may form a 1 ,2,3-triazole linkage with an alkyne in a component in the gastrin analogue. In some embodiments, a molecule containing one or more bis-sulfone groups may be used as a linker, in which the bis-sulfone group may form a linkage with an amine group in the gastrin analogue. In some embodiments, a molecule containing one or more sulfonic acid groups may be used as a linker, in which the sulfonic acid group may form a sulfonamide linkage with a component in the gastrin analogue. In some embodiments, a molecule containing one or more isocyanate groups may be used as a linker, in which the isocyanate group may form a urea linkage with a component in the gastrin analogue. In some embodiments, a molecule containing one or more haloalkyl groups may be used as a linker, in which the haloalkyl group may form a covalent linkage, e.g., C-N and C-0 linkages, with a component in the gastrin analogue. In some embodiments, a molecule containing one or more phenyl ester groups (e.g., trifluorophenyl ester groups or tetrafluorophenyl ester groups) may be used as a linker, in which the phenyl ester group (e.g., trifluorophenyl ester group or tetrafluorophenyl ester group) may form an amide with an amine in a component (e.g., a fusion protein) in the gastrin analogue. In some embodiments, a linker provides space, rigidity, or flexibility between the two or more components. In some embodiments, a linker may be a bond, e.g., a covalent bond. The term “bond” refers to a chemical bond, e.g., an amide bond, a disulfide bond, a C-0 bond, a C-N bond, a N-N bond, a C-S bond, or any kind of bond created from a chemical reaction, e.g., chemical conjugation. In some embodiments, a linker includes no more than 20 atoms. In some embodiments, a linker includes no more than 10 non-hydrogen atoms. In some embodiments, the backbone of a linker includes no more than 5 atoms. The “backbone” of a linker refers to the atoms in the linker that together form the shortest path from one part of a gastrin analogue to another part of the gastrin analogue (e.g., the shortest path between two separated parts of the gastrin analogue structure). The atoms in the backbone of the linker are directly involved in linking one part of a gastrin analogue to another part of the gastrin analogue. For example, hydrogen atoms attached to carbons in the backbone of the linker are not considered as directly involved in linking one part of the gastrin analogue to another part of the gastrin analogue.

[0086] The term “amino acid,” as used herein, means naturally occurring amino acids and non-naturally occurring amino acids.

[0087] The term “isopeptide bond,” as used herein, refers to an amide bond between two fragments of a compound containing multiple peptide bonds, in which said amide bond is covalently linked through atoms other than the N-terminal amine or C-terminal carboxylate. Isopeptide bonds generally refer to amino acids in a peptide sequence which are connected through functional groups of the amino acid side chain, such as those of lysine, glutamate, or aspartate. For example, the isopeptide bonds of glutamate, as used herein, refers to usage of glutamate in a peptide sequence wherein the side chain carboxylate serves as the site of covalent attachement.

[0088] The term “chelating group,” as used herein, refers to a moiety present in the chemical structure that can bind a positively charged metal ion. In some embodiments the metal ion is a radioactive isotope. The chelating group may be present in the structure of a linker. Examples of chelating groups include

[0089] 1 .4.7.10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA), 1 ,4,7,10-tetrakis(carboxymethyl)-

[0090] 1 .4.7.10-tetraazacyclododecane glutaric acid (DOTAGA), 2,2,2,2-(1 ,4,7,10-tetraazacyclododecane-

[0091] 1 .4.7.10-tetraacetamide (TCMC), diethylenetriaminepentaacetic acid (DTPA), 1 ,4,7-triazacyclononane-

[0092] 1 ,4,7-triacetic acid (NOTA), 2-(4,7-bis(carboxymethyl)-1 ,4,7-triazonan-1-yl)pentanedioic acid (NODAGA), 2-(4,7-bis(carboxymethyl)-1 ,4,7-triazonan-1-yl) succinic acid (NODASA), 2,20-((2-(4,7- bis(carboxymethyl))-1 ,4,7-triazonan-1-yl)ethyl)azanediyl)diacetic acid (NETA), 1 ,4,8,11- tetraazacyclotetradecane-1 ,4,8,11 -tetraacetic acid (TETA), and para-isothiocyanato-benzyl-3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-1 (15),11 ,13-triene-3,6,9-triacetic acid (PCTA-NCS) . It is contemplated that in some embodiments of the invention, a separated gastrin analogue that contains a chelating group is treated with a reagent that then generates the pharmaceutical composition for use in the methods of treatment described herein. For example, use of DOTA as a chelating group in gastrin analogues described herein would enable mixing of the radiopharmaceutical precursor with isotopically enriched177LuCl3, thereby exchanging the chloride ligands of lutetium for the carboxylates of DOTA and generating the radionuclide complex described herein.

[0093] The term “treating” or “to treat,” as used herein, refers to a therapeutic treatment of a disease (e.g., cancer) in a subject. In some embodiments, a therapeutic treatment may slow the progression of the disease, improve the subject’s outcome, or eliminate tumors. In some embodiments, a therapeutic treatment of the disease in a subject may alleviate or ameliorate of one or more symptoms or conditions associated with the disease, diminish the extent of the symptoms, stabilize (i.e., not worsening) the state of the disease, prevent the spread of the disease, or delay or slow the progress of the disease, as compared the state or the condition of the disease in the absence of the therapeutic treatment. The results of “treating” encompass but are not limited to: alleviation of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilizing (i.e., not worsening) state of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable. “Palliating” a disease, disorder, or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder, or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.

[0094] As used-herein, “remission” is defined as a reduction or disappearance of the signs or symptoms of disease. For example, in a cancer characterized by overexpression of CCK2R, remission could be demonstrated by the subject experiencing a reduction in the number of cells abnormally expressing CCK2R relative to a previous timepoint. The method of detection may be selected between, for example, positron emission tomography (PET) scan of the diseased area, an assay for tumor biomarkers (e.g. calcitonin), computed tomography (CT), or magnetic resonance imaging (MRI). The remission may be either partial, indicating a non-complete reduction in the amount of rapidly growing cells, or complete, indicating the absence of detectable cancer by any of the above methods. Other methods for monitoring tumor growth and progression may be utilized as recognized by one skilled in the art.

[0095] The term “subject,” as used herein, can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, goat, monkey, rat, mouse, and sheep. In preferred embodiments, the subject is a human.

[0096] As used herein, the term “effective amount” refers to an amount sufficient to effect beneficial or desired results, such as diagnostic results of determining disease activity, and / or determining the therapeutically effective amount, such as ameliorating one or more symptoms of disease, which may depend upon the context in which treatment is being applied. For example, in the context of administering a radionuclide complexed gastrin analogue according to the methods of the invention, the amount administered is an amount sufficient to improve the efficacy and / or safety of ionization radiation in the treatment of, e.g., a cancer or a tumor. The methods of the invention can include systemic (e.g., intravenous) or local administration (e.g., topical or local injection) of radionuclide complexed gastrin analogue, as needed depending upon the nature of the condition being treated. It is also to be understood herein that a “therapeutically effective amount” may be interpreted as an amount giving a desired therapeutic or preventative effect, taken in one or more doses or in any dosage or route, or taken alone or in combination with other therapeutic agents. For example, in the context of administering a gastrin analogue described herein that is used for the treatment of a disease described herein, an effective amount of a gastrin analogue can be an amount sufficient to slow down or reverse the progression of the disease as compared to the response obtained without administration of the gastrin analogue.

[0097] As used herein, the term “pharmaceutical composition” refers to a medicinal or pharmaceutical formulation that contains at least one active ingredient as well as one or more excipients and diluents to enable the active ingredient suitable for the method of administration. The pharmaceutical composition of the present disclosure includes pharmaceutically acceptable components that are compatible with a gastrin analogue described herein.

[0098] The term “anticancer agent,” as used herein and interchangeably with “anticancer treatment,” refers to any anticancer compound or composition used in a subject to slow, halt, or reduce the proliferation of cells in a population, given that said cells are experiencing uncontrolled or accelerated growth relative to normal cells within the same cell population.

[0099] As used herein, the term “pharmaceutically acceptable carrier” refers to an excipient or diluent in a pharmaceutical composition. For example, a pharmaceutically acceptable carrier may be a vehicle capable of suspending or dissolving the active gastrin analogue. The pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient. In the present disclosure, the pharmaceutically acceptable carrier must provide adequate pharmaceutical stability to a gastrin analogue described herein. The nature of the carrier differs with the mode of administration. For example, for oral administration, a solid carrier is preferred; for intravenous administration, an aqueous solution carrier (e.g., WFI, or a buffered solution) is generally used.

[0100] The term “pharmaceutically acceptable salt,” as used herein, represents salts of the gastrin analogues described herein that are, within the scope of sound medical judgment, suitable for use in methods described herein without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Pharmaceutical Salts: Properties, Selection, and Use (Eds. P.H. Stahl and C.G. Wermuth), Wiley- VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the gastrin analogues described herein or separately by reacting the free base group with a suitable organic acid. The term “pharmaceutically acceptable excipient,” as used herein, refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) that is biocompatible and suitable for administration to a subject. Acceptable carriers and excipients may include buffers such as phosphate, citrate, HEPES, and TAE, antioxidants such as ascorbic acid and methionine, preservatives such as hexamethonium chloride, octadecyldimethylbenzyl ammonium chloride, resorcinol, and benzalkonium chloride, proteins such as human serum albumin, gelatin, dextran, and immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acid residues such as glycine, glutamine, histidine, and lysine, and carbohydrates such as glucose, mannose, sucrose, and sorbitol. Nonlimiting examples of other excipients include, but are not limited to, antiadherents, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, sorbents, suspensing or dispersing agents, or sweeteners. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients.

[0101] The term “about,” as used herein, indicates a deviation of ±10%. For example, about 10% refers to from 9.0% to 11 .0%. Any values provided in a range of values include both the upper and lower bounds, and any values contained within the upper and lower bounds.

[0102] The term “radionuclide”, as used herein, indicates an unstable chemical isotope of an atom with an excess number of neutrons or protons that eventually undergoes emission of a particle and converts to a more stable chemical isotope. Examples include but are not limited to225Ac,212Bi,213Bi,62Cu,64Cu,67Cu,69Cu,66Ga,67Ga,68Ga,111ln,113mln,177Lu,186Re,188Re,43Sc,44Sc,47Sc,155Tb,161Tb,99mTc,18Fe,11C,123l,131I,1 3N,86Y,90Y,169Yb,175Yb, and212Pb.

[0103] The term “neprilysin inhibitor,” as used herein, refers to any compound or pharmaceutical composition which can inhibit the activity of neutral endopeptidase (NEP). Nonlimiting examples include sacubitril, sacubitrilat, RB-101 , UK-414495, omapatrilat, ecadotril, and candoxatril.

[0104] The term “ionizing radiation” means any radiation where a nuclear particle has sufficient energy to remove an electron or proton or other particle from an atom or molecule, thus producing an ion and a free electron or radical. Examples of such ionizing radiation include, but are not limited to, gamma rays, X- rays, protons, electrons, alpha particles, carbon atoms, or particles emitted from a radioactive source including, but not limited to, yttrium and radium. Radiation from implanted material is included. Ionizing radiation is commonly used in medical radiotherapy and the specific techniques for such treatment will be apparent to a person of ordinary skill in the art. Other examples of radiation suitable for use in the present methods are provided elsewhere in the specification. Other features and advantages of the gastrin analogues described herein will be apparent in the following Detailed Description, the drawings, and the claims.

[0105] BRIEF DESCRIPTION OF THE DRAWINGS

[0106] FIG. 1 is a graph depicting the concentration of68Ga- PP-F11 N after a single dose injection comparing three PP-F11 minigastins in different mouse organs and the tumor.

[0107] FIG. 2 are graphs depicting tissue and plasma concentration of177Lu-PP-F11 N with and without Entresto®.

[0108] FIG. 3 graphs depict (A) carcinoembryonic antigen (CEA) and (B) calcitonin responses of patients in a Phase I study following 3 cycles of 6 GBq177Lu-PP-F11 N treatment.

[0109] FIG. 4 graphs depict (A) change in calcitonin levels and (B) progression free survival in 6 patients in a Phase I study following 3 cycles of 6 GBq177Lu-PP-F11 N treatment.

[0110] FIG. 5 depicts (A) single photon emission computed tomography (SPECT) image of a lung carcinoid patient following treatment with 8 GBq177Lu-PP-F11 N in three cycles, supplemented in later cycles with Entresto® and everolimus; and (B) the change in chromogranin A levels following each cycle of treatment.

[0111] DETAILED DESCRIPTION OF THE INVENTION

[0112] The invention features dosing regimens and combination therapies utilizing radiolabeled gastrin analogues for the treatment of CCKB receptor positive diseases, including CCKBR-positive cancers and cancers at all stages of cancer spread.

[0113] The invention also features the use of PP-F11 N as radionuclide which can be used in short treatment cycles to kill fast- and slow growing tumors. These short treatment cycles mimic anti-cancer chemotherapy. The ability to use radiolabeled PP-F11 N in these chemotherapy-like treatment cycles (of up to four weeks repetitive injections of radiolabeled PP-F11 N) is due to the combination of i) a short plasma half-life of the PP-F11 N minigastrin, ii) a high therapeutic window of radiolabeled PP-F11 N with high tumor radiation load, but low kidney and bone marrow radiation dosages and iii) a low side effect profile in treated patients.

[0114] PP-F11N Therapy

[0115] Some of the advantages when using PP-F11 N radionuclide therapy in the methods of the invention include the following.

[0116] PP-F11 N has a short plasma half-life. After an IV injection, rapid elimination of radioactivity from blood occurred via the kidneys. Elimination kinetics followed a two-phase process with respective halflives of 21 min (68% of exposure) and 5.4 hours (remaining 32% of exposure). Following intravenous (IV) administration, the bioavailability of the peptide may be dramatically limited by high proteolytic turnover in serum. One of the amino acids found in minigastrin is methionine (Met). To overcome a possible Met oxidation and enzymatic hydrolysis at the Met-Asp bond, the amino acid residue Met is replaced by the non-oxidizable amino acid norleucine, which does not change peptide binding affinity or internalization. The resulting minigastrin analogue ((DGIu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2), is characterized by favorable pharmacokinetics (PK), relatively low kidney uptake, and improved metabolic stability, and, when attached to the chelating agent DOTA, it is called PPF11 N. By attaching a radionuclide chelator to the N-terminus of peptide analogues, these reagents can be used for tumor imaging and radiotherapy.

[0117] Radiolabeled PP-F11 N has a high tumor uptake, due to a high CCK2 receptor affinity. PP-F11 N specifically binds to CCK2 receptor with an affinity (Ki value) of 0.81 nM. The tumor-targeting ability of PPF11 N was demonstrated in tumor-xenografted mice administered IV with177Lu-PP-F11 N: the highest accumulation of radioactivity was detected in the CCK2 receptor-expressing tumors.

[0118] Further, PP-F11 N is designed to protect kidneys from radio-damage. PPF11 N has been designed, to reduce the kidney re-uptake as compared to older minigastrin analogs. Lysine residues seem to be responsible for the relatively high re-uptake of other minigastrins or the other peptides in the proximal tubular of the kidneys. PP-F11 N doesn’t contain any lysine residues, and therefore has a relatively low exposure of the kidney with radio-nuclide linked to PP-F11 N.

[0119] Bone marrow exposure of PP-F11 N is low. In a single dose biodistribution study with68Ga- PP- F11 N, bone marrow exposure was low (Figure 2). Such low exposure to radiation will translate into low probability of developing myelosuppression under therapy with labeled PP-F11 N.

[0120] PP-F11 N has been designed to achieve highest efficacy in the destruction of tumors independent of the tumor growth rate by simultaneously protecting kidneys and bone marrow from radiation damage. Thereby, this unique product profile allows to expose tumor cells more often to deadly radiation which reduces the time tumor recovery. This tumor destruction is accomplished with PP-F11 N without causing major toxicities. Therefore, PP-F11 N allows for the first time for a radionuclide to be dosed in short-term treatment cycles to undercut the tumor growth rate with the goal to eliminate this tumor rather than just suppressing its growth.

[0121] The invention features the use of PP-F11 N, a minigastrin which binds with high affinity to the CCK2R. Due to its low kidney and bone marrow toxicity PP-F11 N can be used in fast treatment cycles, which are similar to anticancer chemotherapy, of less than 4 weeks. These fast treatment cycles allow to move ahead the tumor growth of several targeted cancers and thereby bring treated patients into remission. CCK2R is expressed on several slow-growing and fast-growing tumors, such as pancreatic cancer, colorectal cancer, ovarian cancer, liver cancer, and lung cancer.

[0122] Targeted Radionuclide Therapy

[0123] In targeted radionuclide therapy, the biological effect is obtained by energy absorbed from the radiation emitted by the radionuclide. Radionuclides used for targeted radionuclide therapy emit radiation with a relatively short path length. There are two types of particulate radiation of consequence for targeted radionuclide therapy — beta particles and alpha particles. Moreover, within each of these categories, there are multiple radionuclides with a variety of tissue ranges, half-lives, and chemistries, offering the attractive possibility of tailor-making the properties of a targeted radionuclide therapeutic to the needs of an individual patient, which impact only the targeted tissues. PP-F11 N, a gastrin analogue, is a minigastrin that binds to the CCK2 receptor (CCK2R). The gastrointestinal hormones gastrin and cholecystokinin (CCK) have a C-terminal pentapeptide in common but have different biological roles. The biological effects of gastrin and CCK are mediated by the activation of distinct types of receptors located on target cells. CCK receptors are members of the superfamily of G-protein-coupled receptors (GPCRs) with 7 transmembrane domains and have been classified as CCK1 R and CCK2R based on their affinity for structurally and functionally related peptides (Roosenburg et al., Amino Acids. 2011 Nov;41 (5):1049-58).

[0124] A number of CCK and minigastrin analogs have been synthesized and tested for their potential use in peptide receptor radionuclide imaging and / or therapy of cancer (see, e.g., Kaloudi et al., EJNMMI Res. 2016 Dec;6(1):15; Klingler et al., Theranostics. 2018 Apr 16;8(11):2896-2908; Roosenburg et al., Amino Acids. 2011 Nov;41 (5):1049-58; Laverman et al., Eur J Nucl Med Mol Imaging. 2011 Aug;38(8):1410-6; Rangger et al., Mol Pharm. 2017 Sep 5;14(9):3045-3058; and Gunther et al., J Nucl Med. 2024 Jan 2;65(1):33-39). Most of these attempts had drawbacks due to high kidney uptake, low enzymatic stability of the radioligands, or changes in the affinity for the receptor.

[0125] Physiologically CCK2 receptor is predominantly expressed in the stomach, gut mucosa, and brain (Reubi 2003).

[0126] The CCK2 receptor is also highly expressed in several tumor types such as i) Neuroendocrine / carcinoid tumors: medullary thyroid cancer (MTC), neuroendocrine tumors (NETs), Bronchial carcinoids, Carcinoids of the bowels and stomach, gastrointestinal stromal tumor (GIST), Lung (non-small cell neuroendocrine tumors), Lung (small cell), Pancreatic neuroendocrine tumors, and Paraganglioma; as well as ii) Non-neuroendocrine tumors: Astrocytomas, Glioma, Colorectal Ca, Esophageal Ca, Liver (cholangiocarcinoma, fibrolamellar carcinoma and hepatocellular carcinoma), Lung (small and non-small cell), Ovarian Ca, Pancreatic Adeno-Ca, Stomach Ca, Thyroid (non-medullary carcinoma) (Roy et al., Oncotarget. 2016 Mar 22;7(12):14605-15).

[0127] PP-F11 N can be labeled with every available beta, alpha ray or positron emitting radionuclide such as177Lu,225Ac,68Ga,212Pb,64Cu,1111n , etc. Also provided herein are gastrin analogues that include a CCK2R targeting polypeptide complexed with a radionuclide; similarly, all gastrin analogues described herein can be labeled with emitting radionuclides and are envisioned to be interchangeable with PP-F11 N via the methods described herein. One with skill in the art understands the applicability of the present invention to extend to all gastrin analogues capable of both binding to CCK2R and chelating a radionuclide. For example, select gastrin analogues containing a silyl-fluoride moiety have been previously described and are envisioned to be within the scope of the present invention (Gunther et al., Pharmaceutics. 2023 Mar 3;15(3):826). Such gastrin analogues, exemplified by Gastrin analogue 12, could be utilized as a theranostic tool due to covalent exchange with18F providing a source for positron emission; the chelating moiety present in Gastrin analogue 12 simultaneously enables therapeutic effect by forming a complex between the analogue and a radionuclide such as177Lu,225Ac, among others. It is understood by the inventors that the motif necessary for obtaining CCK2R selectivity is the C-terminal tetrapeptide; other amino acids connecting this targeting motif to the radionuclide chelating group may be substituted in a variety of ways, either by replacement with a linker or by modification of the amino acid (Holzleitner et al., EJNMMI Res. 2023 Jul 8; 13(1 ):65). Non-canonical amino acids such as sarcosine or p- alanine may be used, for example (Hormann et al., Pharmaceutics. 2023 Feb 28;15(3):796). The amide moiety may also be exchanged for a triazole as an isosteric replacement (Grob et al., J Med Chem. 2020 May 14;63(9):4484-4495). Non-limiting examples of other gastrin analogues for use in the present invention include those described in U.S. Patent Nos. 18,263,797, which is incorporated by reference herein.

[0128] Methods of treatment

[0129] This disclosure provides uses of gastrin analogues and pharmaceutical compositions described herein in the treatment of disorders associated with dysregulation or overexpression of CCK2R.

[0130] Cancer

[0131] The gastrin analogues and pharmaceutical compositions described herein can be used to treat a cancer in a subject. In some embodiments, the cancer overexpresses or is known to overexpress CCK2R, also known as CCKBR, relative to a non-cancerous cell of the same tissue type. In some embodiments, the subject has been determined to have a cancer that overexpresses CCK2R relative to a non-cancerous cell of the same tissue type. In some embodiments, the method further comprises a step of determining whether the cancer overexpresses CCK2R relative to a non-cancerous cell of the same tissue type and administering the gastrin analogue only if the cancer overexpresses CCK2R.

[0132] In some embodiments, the cancer is pancreas adenocarcinoma, colon adenocarcinoma, primary liver cancer, astrocytoma, glioma, colorectal carcinoma, esophageal carcinoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, stomach carcinoma, or ovarian cancer. In some embodiments, the cancer is medullary thyroid cancer, neuroendocrine tumors, bronchial carcionids, carcinoids of the bowels and stomach, gastrointestinal stromal tumors, pancreatic neuroendocrine tumors, cholangiocarcinoma, fibrolamellar carcinoma, or non-medullary thyroid carcinoma. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is of a tumor grade 1 or higher.

[0133] Combination Therapies

[0134] In some embodiments, one or more anticancer agents (e.g., immune checkpoint inhibitors, chemotherapeutic agents, PARP inhibitors, antibody drug conjugates, or a combination thereof) may be administered in combination (e.g., administered substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions) or administered separately) at different times with a gastrin analogue described herein (e.g., a gastrin analogue of formula (I) or from Table A). In some embodiments, one or more anticancer agents may be administered in combination with a gastrin analogue described herein to treat cancer.

[0135] The anticancer agent may be administered substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions) as the gastrin analogues or may be administered prior to or following the gastrin analogues (e.g., within a period of 1 day, 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 6 months, or 12 months, or more). i. Immune checkpoint inhibitors

[0136] In some embodiments, the method further includes administering to the subject an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is an inhibitor of any one of more of the following immune checkpoint targets: CTLA-4, PD-1 , PD-L1 , LAG-3, B7.1 , B7-H3, B7-H4, TIM3, VISTA, CD137, OX-40, CD40, CD27, CCR4, GITR, NKG2D, and KIR. In some embodiments, the immune checkpoint inhibitor is a monoclonal antibody selected from one or more of an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG3 antibody, an anti-B7.1 antibody, an anti-B7H3 antibody, an anti-B7H4 antibody, an anti-TIM3 antibody, an anti-VISTA antibody, an anti-CD137 antibody, an anti- 0X40 antibody, an anti-CD40 antibody, an anti-CD27 antibody, an anti-CCR4 antibody, an anti-GITR antibody, an anti-NKG2D antibody, and an anti-KIR antibody.

[0137] Immune checkpoint inhibitors approved or in development include, but are not limited to, YERVOY® (ipilimumab), OPDIVO® (nivolumab), KEYTRUDA® (pembrolizumab), tremelimumab, galiximab, MDX-1106, BMS-936558, MEDI4736, MPDL3280A, MEDI6469, BMS-986016, BMS-663513, PF-05082566, IPH2101 , KW-0761 , CDX-1127, CP-870, CP-893, GSK2831781 , MSB0010718C, MK3475, CT-011 , AMP-224, MDX-1105, IMP321 , MGA271 , dostarlimab, and cemiplimab, as well as numerous other antibodies or polypeptides directed to immune checkpoint proteins described herein. In some embodiments, the immune checkpoint inhibitor is pembrolizumab, nivolumab, dostarlimab, dostarlimab, or cemiplimab.

[0138] In some embodiments, the method includes administering to said subject (1) a gastrin analogue described herein and (2) an immune checkpoint inhibitor. In some embodiments, the gastrin analogue described herein is administered first, followed by administering of the immune checkpoint inhibitor alone. In some embodiments, the immune checkpoint inhibitor is administered first, followed by administering of the gastrin analogue described herein alone. In some embodiments, the gastrin analogue described herein and the immune checkpoint inhibitor are administered substantially simultaneously (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions). In some embodiments, when a gastrin analogue described herein and an immune checkpoint inhibitor are administered together (e.g., substantially simultaneously in the same or separate pharmaceutical compositions, or separately in the same treatment regimen), tumor growth suppression of each of the gastrin analogue and the immune checkpoint inhibitor may be greater (e.g., occur at a lower concentration) than inhibition of tumor growth suppression of each of the gastrin analogue and the immune checkpoint inhibitor when each is used alone in a treatment regimen. ii. Chemotherapeutic agents

[0139] In some embodiments, the method includes administering to the subject one or more chemotherapeutic agents, e.g.,:

[0140] (a) a cytotoxic agent; (b) an antimetabolite;

[0141] (c) an alkylating agent;

[0142] (d) an anthracycline;

[0143] (e) an antibiotic;

[0144] (f) an anti-mitotic agent;

[0145] (g) a hormone therapy;

[0146] (h) a signal transduction inhibitor;

[0147] (i) a gene expression modulator;

[0148] (j) an apoptosis inducer;

[0149] (k) an angiogenesis inhibitor;

[0150] (l) an immunotherapy agent;

[0151] (m) a DNA damage repair inhibitor;

[0152] (n) an mTOR inhibitor

[0153] (o) a kinase inhibitor; or a combination thereof.

[0154] The cytotoxic agent may be, e.g., actinomycin-D, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, amphotericin, amsacrine, arsenic trioxide, asparaginase, avapritinib, azacitidine, azathioprine, Bacille Calmette-Guerin (BCG), belzutifan, bendamustine, bexarotene, bevacuzimab, bleomycin, bortezomib, busulphan, capecitabine, carboplatin, carfilzomib, carmustine, cetuximab, cisplatin, chlorambucil, cladribine, clofarabine, colchicine, crisantaspase, cyclophosphamide, cyclosporine, cytarabine, cytochalasin B, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, 1 -dehydrotestosterone, denileukin, dexamethasone, dexrazoxane, dihydroxy anthracin dione, disulfiram, docetaxel, doxorubicin, liposomal doxorubicin, emetine, epirubicin, erlotinib, epigallocatechin gallate, epoetin alfa, estramustine, ethidium bromide, etoposide, everolimus, filgrastim, finasunate, floxuridine, fludarabine, flurouracil (5-FU), fruquintinib, fulvestrant, ganciclovir, geldanamycin, gemcitabine, glucocorticoids, gramicidin D, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib, irinotecan, interferons, interferon alfa-2a, interferon alfa-2b, ixabepilone, lactate dehydrogenase A (LDH-A), lenalidomide, letrozole, leucovorin, levamisole, lidocaine, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, methoxsalen, metoprine, metronidazole, mithramycin, mitomycin-C, mitoxantrone, nandrolone, nelarabine, nilotinib, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, nab-paclitaxel, pemetrexed, pentostatin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, procaine, procarbazine, propranolol, puromycin, quinacrine, radicicol, radioactive isotopes, raltitrexed, rapamycin, rasburicase, regorafenib, ripretinib, salinosporamide A, sargramostim, sunitinib, temozolomide, teniposide, tetracaine, 6-thioguanine, thiotepa, topotecan, toremifene, trastuzumab, treosulfan, tretinoin, tucatinib, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, zoledronate, or a combination thereof.

[0155] The antimetabolite may be, e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5- fluorouracil decarbazine, cladribine, pemetrexed, gemcitabine, capecitabine, hydroxyurea, mercaptopurine, fludarabine, pralatrexate, clofarabine, cytarabine, decitabine, floxuridine, nelarabine, trimetrexate, thioguanine, pentostatin, or a combination thereof.

[0156] The alkylating agent may be, e.g., mechlorethamine, thiotepa, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP) cisplatin, altretamine, cyclophosphamide, ifosfamide, hexamethylmelamine, altretamine, procarbazine, dacarbazine, temozolomide, streptozocin, carboplatin, cisplatin, oxaliplatin, uramustine, bendamustine, trabectedin, semustine, or a combination thereof.

[0157] The anthracycline may be, e.g., daunorubicin, doxorubicin, aclarubicin, aldoxorubicin, amrubicin, annamycin, carubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, or a combination thereof.

[0158] The antibiotic may be, e.g., dactinomycin, bleomycin, mithramycin, anthramycin (AMC), ampicillin, bacampicillin, carbenicillin, cioxacillin, dicloxacillin, flucioxacillin, mezlocillin, nafcillin, oxacillin, piperacillin, pivampicillin, pivmecillinam, ticarcillin, aztreonam, imipenem, doripenem, ertapenem, meropenem, cephalosporins, clarithromycin, dirithromycin, roxithromycin, telithromycin, lincomycin, pristinamycin, quinupristin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, tobramycin, streptomycin, sulfamethizole, sulfamethoxazole, sulfisoxazole, demeclocycline, minocycline, oxytetracycline, tetracycline, penicillin, amoxicillin, cephalexin, erythromycin, clarithromycin, azithromycin, ciprofloxacin, levofloxacin, ofloxacin, doxycycline, clindamycin, metronidazole, tigecycline, chloramphenicol, metronidazole, tinidazole, nitrofurantoin, vancomycin, teicoplanin, telavancin, linezolid, cycloserine, rifamycins, polymyxin B, bacitracin, viomycin, capreomycin, quinolones, daunorubicin, doxorubicin, 4’-deoxydoxorubicin, epirubicin, idarubicin, plicamycin, mitomycin-c, mitoxantrone, or a combination thereof.

[0159] The anti-mitotic agent may be, e.g., vincristine, vinblastine, vinorelbine, docetaxel, estramustine, ixabepilone, paclitaxel, maytansinoid, a dolastatin, a cryptophycin, or a combination thereof.

[0160] The signal transduction inhibitor may be, e.g., imatinib, trastuzumab, erlotinib, sorafenib, sunitinib, sirolimus, everolimus, temsirolimus, ridaforolimus, umirolimus, zotarolimus vemurafenib, lapatinib, bortezomib, cetuximab panitumumab, matuzumab, gefitinib, STI 571 , rapamycin, flavopiridol, imatinib mesylate, vatalanib, semaxinib, motesanib, axitinib, afatinib, bosutinib, crizotinib, cabozantinib, dasatinib, entrectinib, pazopanib, lapatinib, vandetanib, or a combination thereof.

[0161] The gene expression modulator may be, e.g., a siRNA, a shRNA, an antisense oligonucleotide, an HDAC inhibitor, or a combination thereof. An HDAC inhibitor may be, e.g., trichostatin A, trapoxin B, valproic acid, vorinostat, belinostat, LAQ824, panobinostat, entinostat, tacedinaline, mocetionstat, givinostat, resminostat, abexinostat, quisinostat, rocilinostat, practinostat, CHR-3996, butyric acid, phenylbutyric acid, 4SC202, romidepsin, sirtinol, cambinol, EX-527, nicotinamide, or a combination thereof. An antisense oligonucleotide may be, e.g., custirsen, apatorsen, AZD9150, trabadersen, EZN- 2968, LErafAON-ETU, or a combination thereof. An siRNA may be, e.g., ALN-VSP, CALAA-01 , Atu-027, SPC2996, or a combination thereof.

[0162] The hormone therapy may be, e.g., a luteinizing hormone-releasing hormone (LHRH) antagonist.

[0163] The hormone therapy may be, e.g., firmagon, leuproline, goserelin, buserelin, flutamide, bicalutadmide, ketoconazole, aminoglutethimide, prednisone, hydroxyl-progesterone caproate, medroxy-progesterone acetate, megestrol acetate, diethy Istil-bestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, toremifine citrate, megestrol acetate, exemestane, fadrozole, vorozole, letrozole, anastrozole, nilutamide, tripterelin, histerelin, arbiraterone, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, tretinoin, fenretinide, troxacitabine, or a combination thereof.

[0164] The apoptosis inducers may be, e.g., a recombinant human TNF-related apoptosis-inducing ligand (TRAIL), camptothecin, bortezomib, etoposide, tamoxifen, or a combination thereof.

[0165] The angiogenesis inhibitors may be, e.g., bevacizumab, sorafenib, sunitinib, pazopanib, everolimus or a combination thereof.

[0166] The immunotherapy agent may be, e.g., a monoclonal antibody, cancer vaccine (e.g., a dendritic cell (DC) vaccine), oncolytic virus, cytokine, adoptive T cell therapy, Bacille Calmette-Guerin (BCG), GM- CSF, thalidomide, lenalidomide, pomalidomide, imiquimod, or a combination thereof. The monoclonal antibody may be, e.g., anti-CTLA4, anti-LAG3, anti-KIR, or a combination thereof. The monoclonal antibody may be, e.g., alemtuzumab, trastuzumab, ibritumomab tiuxetan, brentuximab vedotin, trastuzumab, ado-trastuzumab emtansine, blinatumomab, bevacizumab, cetuximab, pertuzumab, panitumumab, ramucirumab, obinutuzumab, ofatumumab, rituximab, pertuzumab, tositumomab, gemtuzumab ozogamicin, tositumomab, or a combination thereof. The cancer vaccine may be, e.g., Sipuleucel-T, BioVaxID, NeuVax, DCVax, SuVaxM, CIMAvax®, Provenge,®, hsp110 chaperone complex vaccine, CDX-1401 , MIS416, CDX-110, GVAX Pancreas, HyperAcute™ Pancreas, GTOP-99 (MyVax®), or Imprime PGG®. The oncolytic virus may be, e.g., talimogene laherparepvec. The cytokine may be, e.g., IL-2, IFNa, or a combination thereof. The adoptive T cell therapy may be, e.g., tisagenlecleucel, axicabtagene ciloleucel, or a combination thereof.

[0167] The DNA damage repair inhibitor may be, e.g., a PARP inhibitor, a DNA-dependent Protein Kinase (DNA-PK) inhibitor, a cell checkpoint kinase inhibitor, or a combination thereof. The PARP inhibitor may be, e.g., olaparib, rucaparib, veliparib (ABT-888), niraparib (ZL-2306), iniparib (BSI-201), talazoparib (BMN 673), 2X-121 , CEP-9722, KU-0059436 (AZD2281), PF-01367338, AZD5305, AZD9574, seneparib (IMP4297), fluzoparib (SHR-3162), XIN005104, NMS-293 or a combination thereof. The DNA- PK inhibitor may be AZD7648, nedisertib (M3814), M9831 , or BAY-8400. The cell checkpoint kinase inhibitor may be, e.g., RP-6306, MK-1775 or AZD1775, AZD7762, LY2606368, PF-0477736, AZD0156, GDC-0575, ARRY-575, CCT245737, PNT-737 or a combination thereof.

[0168] DNA-dependent Protein Kinase (DNA-PK) inhibitors that may be used in the present invention include compounds that upon contacting DNA-PK, whether in vitro, in cell culture, or in an animal, reduce the activity of DNA-PK, such that the measured DNA-PK IC50is 10 μM or less (e.g., 5 μM or less or 1 μM or less). For certain DNA-PK inhibitors, the DNA-PK IC50may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the DNA-PK IC50is 0.1 nM to 1 μM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). Examples of DNA-PK inhibitors include AZD-7648, Peposertib, M9831 , IMP11 , NU5455, BAY- 8400, ZL-2201 , adMare Bioinnovations DNA-PK Program, XRD-0394, Avadomide, NERx Ku program, CC-115, KU57788, ZSTK474, LY3023414, BR101801 , XRD-0394 and NK-314.

[0169] Another promising approach to increase PP-F11 N intracellularly is a combination therapy with mammalian target of rapamycin (mTOR) inhibitors (see, e.g., Michal Grzmil et al., Cancers (Basel). 2023 Jan; 15(1): 17). mTOR is a serine / threonine kinase, discovered as a mechanistic (or mammalian) target of rapamycin, and it functions in two distinct complexes. These complexes are distinguished by the interaction partners, subcellular localization, and substrate specificity, as well as by the sensitivity to rapamycin. It is suggested that mTORCI inhibition can increase the perfusion and delivery of the radiolabeled ligands into the tumors, such as PP-F11 N. Inhibitors of mTOR useful in this type of combination therapy include temsirolimus (CCI-779), rapamycin (sirolimus), everolimus (RAD001), ridaforolimus (AP-23573), umirolimus, and zotarolimus. Non-limiting examples of other mTOR inhibitors contemplated for use include torin-1 , torin-2, WAY-001 , WAY-600, WYE687, WYE-354, GDC-0349, GNE- 555, PF-05139962, KU0063794, AZD8055, AZD2014 (vistusertib), PP242, MLN0128, OSI-027, OXA-01, XL388, CC214-1, CC-223, CC-115, DHM25, Rapalink-1 , dactolisib (NVP-BEZ235), gedatolisib (PKI-587), omipalisib (GSK2126458), apitolisib (GDC-0980), bimiralisib (PQR309), and voxtalisib (XL765).

[0170] In some embodiments, the chemotherapeutic agent is selected from paclitaxel, docetaxel, liposomal doxorubicin, carboplatin, gemcitabine, nab-paclitaxel, doxorubicin, oxaliplatin, cisplatin, carboplatin, or a combination thereof. iii. PARP Inhibitors

[0171] In some embodiments, the method includes administering to the subject a PARP inhibitor. PARP inhibitors include compounds that upon contacting PARP, whether in vitro, in cell culture, in an animal or in a patient, reduce the activity of PARP, such that the measured PARP IC50is 10 μM or less (e.g., 5 μM or less or 1 μM or less). For certain PARP inhibitors, the PARP IC50may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the PARP IC50is 0.1 nM to 1 μM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM). For example, certain PARP inhibitors may be prepared using techniques and methods disclosed in, e.g., International Application No. PCT / US2022 / 025357, which is incorporated by reference herein. The PARP inhibitor may be, e.g., olaparib, rucaparib, veliparib (ABT-888), niraparib (ZL-2306), iniparib (BSI-201), talazoparib (BMN 673), 2X-121, CEP-9722, KU-0059436 (AZD2281), PF-01367338, AZD5305, AZD9574, seneparib (IMP4297), fluzoparib (SHR-3162), XIN005104, NMS-293 or a combination thereof.

[0172] Non-limiting examples of PARP inhibitors include those described in PCT applications PCT / CN2022 / 086311 , PCT / CN2022 / 115259, PCT / US2022 / 027334, PCT / CN2022 / 088989, and PCT / CN2022 / 087969 and U.S. Patent Nos. 11 ,325,906, 8,716,493, 8,236,802, 8,071,623, 8,012,976, 7,732,491, 7,550,603, 7,531,530, 7,151,102, and 6,495,541 , each of which is incorporated herein by reference herein. A PARP inhibitor may be isotopically enriched (e.g., enriched for deuterium). In some embodiments, the PARP inhibitor is olaparib or talazoparib. iv. Antibody drug conjugates

[0173] In some embodiments, the method includes administering to the subject an antibody drug conjugate (ADC). ADCs that may be used in the present invention include conjugates that upon contacting cancer cells, whether in vitro, in cell culture, or in an animal, inhibit the cancer cell, such that the measured IC50is 10 μM or less (e.g., 5 μM or less or 1 μM or less). For certain ADCs, the IC50may be 100 nM or less (e.g., 10 nM or less, or 1 nM or less) and could be as low as 100 pM or 10 pM. Preferably, the ADC IC50is 0.1 nM to 1 μM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM).

[0174] ADCs include Disitamab vedotin, Belantamab mafodotin, Trastuzumab deruxtecan, Ujvira, Mirvetuximab soravtansine, Gemtuzumab ozogamicin, Enfortumab vedotin, Inotuzumab ozogamicin, Trastuzumab emtansine, Tisotumab vedotin, Sacituzumab govitecan, Ladiratumab vedotin, Polatuzumab vedotin, Loncastuximab Tesirine, Brentuximab vedotin, PF-06804103, MGTA-117, FOR46, MRG001 , SOT102, ZV0203, AOC 1020, PRO1184, BAT8009, BB-1705, JS107, SHR-A1912, CMG901 , Ladiratuzumab vedotin, BAT8006, RC108, BAT8008, Mipasetamab Uzoptirine, NBE-002, Zanidatamab zovodotin, F0002-ADC, SKB315, GQ1001 , ABBV-637, XMT-2056, TORL-1-23, FDA022, DYNE-251 , STI- 6129, Ozuriftamab vedotin, Farletuzumab Ecteribulin, Trastuzumab vedotin, DB-1303, OMTX705, TRS005, Ispectamab debotansine, DXC-005, ESG-401 , ARX788, BAT8010, Tusamitamab ravtansine, ABBV-154, Naratuximab emtansine, PSMA ADC, TAK-164, ADCT-602, ADCT-901 , SHR-A1201 , GB251 , ABL202, SHR-A1921 , 9MW2821 , HS-20093, BIO-106, SKB264, Camidanlumab Tesirine, Datopotamab deruxtecan, Telisotuzumab vedotin, L-DOS47, AVID100, OBI-999, DP303c, AURIXIM, MT-8633, IMGC936, BB-1701 , AOC 1001 , JS108, TAC-001 , SYSA1801 , SHR-A2009, TORL-2-307-ADC, BL- M07D1 , STRO-001 , A166, Mecbotamab vedotin, Trastuzumab duocarmazine, ASN004, ABBV-011 , Mirzotamab clezutoclax, OBT076, HS630, SGN-STNV, FDA018, ABBV-400, AZD8205, IBI-343, SGN- ALPV, TAK-500, JBH492, ALT-P7, Ifinatamab deruxtecan, DXC-004, IMGN151 , XMT-1660, M1231 , LM- 102, ORM-5029, STI-3258, SGN-B7H4V, TPX-4589, IKS03, Zilovertamab Vedotin, ARX517, Pivekimab Sunirine, Lonigutamab Ugodotin, TRPH-222, MRG004a, DS-6000a, REGN5093-M114, Trastuzumab imbotolimod, RC88, HTI-1066, BI-CON-02, SGN-CD228A, AOC 1044, DB-1305, ABBV-319, Patritumab Deruxtecan, RC118, Trastuzumab rezetecan, ARX305, Upifitamab Rilsodotin, NBT828, TAA013, BL- B01 D1 , BL-M02D1 , GQ1007, DS-9606a, NBT508, B003, DX126-262, XB002, FS-1502, Praluzatamab ravtansine, AMT-151 , M9140, Indatuximab ravtansine, Cofetuzumab pelidotin, RG7861 , AGS62P1 , CX- 2029, SGN-B6A, Unspecified TROP2 ADC, Unspecified HER2 ADC, RC98 ADC, DYNE-101 , SHR- A1904, Anetumab ravtansine, Vobramitamab duocarmazine, Luveltamab tazevibulin, Serclutamab talirine, MRG003, SYD1875, BYON3521 , SGN-PDL1 V, JSKN-003, YL201 , HS-20089, DXC-007, SYS6002, and HDP-101 . In some embodiments, the antibody drug conjugate is Sacituzumab, govitecan, Trastuzumab deruxtecan, Datopotamab deruxtecan, Enfortumab vedotin, Tisotumab vedotin, Ladiratumab vedotin, M9140, or ASN004.

[0175] Stand-alone Therapy

[0176] In some embodiments, the method includes administering to said subject as a stand-alone therapy to eliminate tumor residuals before or after a cancer operation, (i.e., to shrink the primary tumor to make it resectable or to eliminate metastases). During the treatment, a patient treated with a stand-alone therapy of the invention receives no other concomitant anticancer therapy.

[0177] Use in Combination with Neprilysin Inhibitors

[0178] The methods of the invention can include administration of a neprilysin inhibitor (e.g., 1-4 hours prior to administration of the radionuclide complexed gastrin analogue) to improve the safety of the treatment regimen by allowing more of the administered radionuclide to target CCKB receptors in CCKBR positive diseases, such as CCKBR positive cancers. Compounds which can inhibit the activity of neutral endopeptidase (NEP) include, without limitation, sacubitril (sold under the name Entresto®), sacubitrilat, RB-101 , UK-414495, omapatrilat, ecadotril, and candoxatril.

[0179] Pharmaceutical compositions

[0180] A gastrin analogue described herein may be formulated in a pharmaceutical composition for use in the methods described herein. In some embodiments, a gastrin analogue described herein may be formulated in a pharmaceutical composition alone. In some embodiments, a gastrin analogue described herein may be formulated in combination with a second therapeutic agent in a pharmaceutical composition. In some embodiments, a gastrin analogue described herein may be administered in combination with a second therapeutic agent as part of a dosing regimen (e.g., administered sequentially or simultaneously). In some embodiments, the pharmaceutical composition includes a gastrin analogue described herein and pharmaceutically acceptable carriers and excipients.

[0181] Depending on the route of administration and the dosage, a gastrin analogue herein or a pharmaceutical composition thereof used in the methods described herein will be formulated into suitable pharmaceutical compositions to permit facile delivery. A gastrin analogue or a pharmaceutical composition thereof may be formulated to be administered intramuscularly, intravenously (e.g., as a sterile solution and in a solvent system suitable for intravenous use), or by infusion (e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions).

[0182] A gastrin analogue described herein may be formulated in a variety of ways that are known in the art. For use as treatment of human and animal subjects, a gastrin analogue described herein can be formulated as pharmaceutical or veterinary compositions. Depending on the subject (e.g., a human) to be treated, the mode of administration, and the type of treatment desired, e.g., prophylaxis or therapy, a gastrin analogue described herein is formulated in ways consonant with these parameters. A summary of such techniques is found in Remington: The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilkins (2012); and Encyclopedia of Pharmaceutical Technology, 4th Edition, J. Swarbrick and J. C. Boylan, Marcel Dekker, New York (2013), each of which is incorporated herein by reference.

[0183] Formulations may be prepared in a manner suitable for systemic administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration. The formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, and preservatives. The pharmaceutical compositions can be administered parenterally in the form of an injectable formulation. Pharmaceutical compositions for injection can be formulated using a sterile solution or any pharmaceutically acceptable liquid as a vehicle. Formulations may be prepared as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions. Pharmaceutically acceptable vehicles include, but are not limited to, sterile water, physiological saline, and cell culture media (e.g., Dulbecco’s Modified Eagle Medium (DMEM), a-Modified Eagles Medium (a-MEM), F-12 medium). Such injectable compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, such as sodium acetate and sorbitan monolaurate. Formulation methods are known in the art, see e.g., Pharmaceutical Preformulation and Formulation, 2nd Edition, M. Gibson, Taylor & Francis Group, CRC Press (2009).

[0184] The pharmaceutical composition may be formed in a unit dose form as needed. The amount of active component, e.g., a gastrin analogue described herein, included in the pharmaceutical compositions are such that a suitable dose within the designated range is provided (e.g., a dose within the range of 0.00001-10 mg / kg of body weight).

[0185] Routes of administration and dosages

[0186] In any of the methods described herein, gastrin analogues herein may be administered by any appropriate route for treating or protecting against a disorder described herein (e.g., a cancer or viral infection). Gastrin analogues described herein may be administered to humans, domestic pets, livestock, or other animals with a pharmaceutically acceptable diluent, carrier, or excipient. In some embodiments, administering includes administration of any of the gastrin analogues described herein or compositions intramuscularly, intravenously (e.g., as a sterile solution and in a solvent system suitable for intravenous use), or by infusion (e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions). In some embodiments, if a second therapeutic agent is also administered in addition to a gastrin analogue described herein, the second therapeutic agent or a pharmaceutical composition thereof may also be administered in any of the routes of administration described herein.

[0187] The dosage of a gastrin analogue described herein or pharmaceutical compositions thereof depends on factors including the route of administration, the disease to be treated, and physical characteristics, e.g., age, weight, general health, of the subject. Typically, the amount of the gastrin analogue or the pharmaceutical composition thereof contained within a single dose may be an amount that effectively prevents, delays, or treats the disorder without inducing significant toxicity. A pharmaceutical composition may include a dosage of a gastrin analogue described herein ranging from 0.01 to 500 mg / kg (e.g., 0.01 , 0.1 , 0.2, 0.3, 0.4, 0.5, 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg / kg) and, in a more specific embodiment, about 0.1 to about 30 mg / kg and, in a more specific embodiment, about 1 to about 30 mg / kg. In some embodiments, when a gastrin analogue described herein and a second therapeutic agent, such as an anticancer treatment, are administered in combination (e.g., substantially simultaneously in the same or separate pharmaceutical compositions, or separately in the same treatment regimen), the dosage needed of the gastrin analogue described herein may be lower than the dosage needed of the gastrin analogue if the gastrin analogue was used alone in a treatment regimen. In some embodiments, the dosage may instead be measured as a function of radioactivity with respect to an emitting radionuclide. For example, the pharmaceutical composition may include a dosage of a gastrin analogue described herein ranging from 0.01 to 10 GBq (e.g. 10 kBq, 20 kBq, 30 kBq, 40 kBq, 50 kBq, 60 kBq, 70 kBq, 80 kBq, 90 kBq, 100 kBq, 200 kBq, 300 kBq, 400 kBq, 500 kBq, 600 kBq, 700 kBq, 800 kBq, 900 kBq, 1 GBq, 2 GBq, 3 GBq, 4 GBq, 5 GBq, 6 GBq, 7 GBq, 8 GBq, 9 GBq, or 10 GBq).

[0188] A gastrin analogue described herein or a pharmaceutical composition thereof may be administered to a subject in need thereof, for example, one or more times (e.g., 1 -10 times or more; 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 times) daily, weekly, monthly, biannually, annually, or as medically necessary. Dosages may be provided in either a single or multiple dosage regimens. The timing between administrations may decrease as the medical condition improves or increase as the health of the patient declines. The dosage and frequency of administration may be adapted by the physician in accordance with conventional factors such as the extent of the infection and different parameters of the subject.

[0189] The dosing of radiolabeled PP-F11 N depends on the nuclide which is bound to PP-F11 N. For example, the beta emitter177Lu-PP-F11 N is administered at a dose 8 GBq in combination with neutral endopeptidase 1 (NEP 1) inhibitor sacubitril. Sacubitril inhibits the break-down of177Lu-PP-F11 N and thereby leads to a doubling of the177Lu-PP-F11 N plasma dose (Figure 3). Sacubitril is given as single oral dose 2 hours before start of177Lu-PP-F11 N infusion. In some cases, sacubitril is given orally, with or without co-administration of valsartan. In another example, when225Ac is the radionuclide in complex with PP-F11 N, a dose of up to 500 kBq of the alpha emitter225Ac-PP-F11 N is administered. It is contemplated that the dose of radionuclide administered may differ based on the combination of radionuclide and gastrin analogue used to form the gastrin analogue complex.

[0190] The fast cycle administration regimen of PP-F11 N is the game changer in tumor treatment. Different to other radionuclide treatments, labeled PP-F11 N will be administered to stop the growth cycle of the treated tumor and thereby destroy tumor cells. Treatment cycles of PP-F11 N can be given in parallel to anticancer chemotherapy cycle as well as an independent radionuclide treatment. The goal of the PP-F11 N treatment is the destruction of the treated tumor and its metastases.

[0191] EXAMPLES

[0192] The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure.

[0193] Example 1. Treatment protocol with PP-F11 N, labeled with177Lu, in patients with gastro- enteropancreatic neuroendocrine tumors (GEP-NETs).

[0194] Some patients with GEP-NETs may be non-responsive to available treatments such as177lutetium-oxotreotide, which targets somatostatin-positive growths; for these patients with unresectable or metastatic, well differentiated grade 1 or grade 4 tumors, 8 GBq177Lu-PP-F11 N will be administered as an intravenous infusion every second week in four to six treatment cycles, for up to twelve weeks or until the treatment enters remission. Prior to initiation of treatment, patients will receive up to 250 MBq68Ga- PP-F11 N in order to image the diseased tissue with positron emission tomography; this would be supplementary to any previous diagnosis by computed tomography and magnetic resonance imaging. The imaging dose and analysis of growth would be repeated prior to every administration of177Lu-PP- F11 N. Tumor response for the treatment will be determined by these routine PET images as well as supplemental tumor biomarker measurement. If the patient shows a full remission or the patient is tumor free, the treatment with labeled PP-F11 N will be changed into a maintenance treatment with177Lu-PP- F11 N cycles every fourth week. This maintenance treatment will continue until the patient is either in i) in full remission, or ii) shows tumor growth progression. In the latter case, the two weeks cycle treatment will restart. If the patient cannot be brought back into remission, treatment with labeled PP-F11 N will be stopped. The treatment with177Lu-PP-F11 N as described above may be considered as a supplemental treatment to current standard of care; patients may also be undergoing treatment with an anticancer treatment (e.g. sunitinib) during gastrin analogue treatment.

[0195] Example 2. PP-F11 N has a high binding affinity to CCK2 receptors and a short plasma half-life of up to 5 hours.

[0196] PPF11 N specifically binds to the CCK2 receptor with an affinity (Ki value) of 0.81 nM. PPF1 1 N is a minigastrin analog with particular in vitro stability to human proteases. Plasma pharmacokinetics (PK) in mice were determined after IV administration of PPF11 N labeled with177Lutetium (177Lu). Radioactivity was rapidly eliminated from blood mostly via the kidneys, following typical two-phase kinetics with halflives of 1 .8-12.6 min and 60-325 min (Figure 1).

[0197] Example 3.177Lu-PP-F11 N given in a human Phase 0a study accumulates in close to efficacious doses in Medullary Thyroid Cancer without causing significant side effects.

[0198] In a Phase 0 study (Rottenburger C, Nicolas GP, McDougall L, Kaul F, Cachovan M, Vija AH, Schibli R, Geistlich S, Schumann A, Rau T, Glatz K, Behe M, Christ ER, Wild D. Cholecystokinin 2 Receptor Agonist177Lu-PP-F11 N for Radionuclide Therapy of Medullary Thyroid Carcinoma: Results of the Lumed Phase 0a Study. J Nucl Med. 2020 Apr;61 (4):520-526. doi, six consecutive patients with histologically proven MTC were screened and participated in the study. They all completed the study and were included in the proof-of-principle, safety, pharmacokinetic, and dosimetry evaluations. All patients had a thyroidectomy.

[0199] The patients received about 1 GBq of Lu-PP-F11 N with and without SG in a random crossover order within 4 wk. Dosimetry of tumors, the stomach, and kidneys with and without coadministration of SG was performed with Siemens Dosimetry Research Tool software version 5.4 (Siemens Medical Solutions). Tumors with Lu-PP-F11 N-positive results were identified on SPECT and correlated with CT images. Afterward, tumor volumes of interest were drawn on the basis of the CT volume. For kidney dosimetry, volumes of interest were defined on CT images by an automated segmentation algorithm. Dosimetry analyses shows (Table 1), that patients show a Median Tumor Dose of 0.88 (Gy / GBq), a Median Kidney Dose of 0.11 (Gy / GBq) and a Median Bone Marrow Dose of 0.022 (Gy / GBq). The Tumor to Kidney dose ratio was 11.6. These findings show that there is an enormous therapeutic window, as both the kidney and bone marrow were nearly not affected by the radiation of177Lu-PP-F11 N, whereas the radiation tumor load achieved with 1 GBq of of177Lu-PP-F11 N was already close to therapeutic levels. Reported side effects reported by the patients were low with only grade 1 toxicity.

[0200] Table 1 . Absorbed radiation doses of177Lu-PP-F11 N in Tumors, Kidneys, Bone Marrow and Stomach in

[0201] Phase 0 study, with and without co-administration of succinylated gelatin (SG).

[0202] Example 4.177Lu-PP-F11 N given in a human Phase 1 study accumulates into efficacious doses in Medullary Thyroid Cancer without causing significant side effects.

[0203] In a Phase 1 study performed by Rottenburger et al. three patients received three injections of 6.0-6.6 GBq177Lu-PP-F11 N with subsequent dosimetry in an interval of 8-10 weeks. Each patient received three infusions of 6.3 GBq within 15 min and in an interval of 8-10 weeks. Infusions were in general well tolerated and no patient suffered dose limiting toxicity. Minor toxicity at the time of infusion was similar to adverse events reported previously in the Phase 0 study and not higher than grade 2. Patients in this study received up to 8GBq without reaching a Maximum Tolerated Dose. Regular measurement of tumor markers showed biochemical response of at least one of the measured tumor markers in all patients (Table 2). The first dose escalation step with 3 x 6 GBq177Lu- PP-F11 N resulted in a stable disease according to RECIST 1.1 (Figure 2). As far as comparable regarding different study designs, response rates in this first dose escalation cohort are similar to those achieved by anti-CEA pretargeted radioimmunotherapy and PRRT with 177Lu-DOTATATE.

[0204] Table 2. Baseline characteristics, objective and biomarker response of Phase 0 study. As already observed in the Phase 0 study, side effects reported by the patients were low in severity. Most importantly the radiation dose of the Kidney was approximately 10% of the Tumor Dose (Table 3). The radiation dose of bone marrow with even below 5% of. the Tumor Dose. These data confirm a large therapeutic window of177Lu-PP-F11 N.

[0205] Table 3. Radiation dose in tumor, kidney, bone marrow and stomach measured at the 3 treatment cycles during the Phase I with177Lu-PP-F11 N.

[0206] Based on these findings, we conclude that177Lu-PP-F11 N combines a short plasma half-life of several hours with a therapeutic tumor load without exposing the kidney and bone marrow with toxic radiation doses. This means for the invention, that177Lu-PP-F11 N can be given theoretically consecutively daily without causing kidney or bone marrow damage. This also means, that177Lu-PP- F11 N can match the injection cycles of anti-cancer chemotherapies which are given in injection cycles of 2-3 weeks to undercut tumor recovery and growth, and thereby177Lu-PP-F11 N can be used to eliminate in combination with or without chemotherapies fast- and slow growing tumors by being able to intervene in their mitotic cycles and thereby kill and destroy those cancer cells.

[0207] The change in calcitonin and carcinoembryonic antigen (CEA) levels following 3 cycles of an about 6 GBq dose of177Lu-PP-F11 N was measured in 6 patients (Figure 3). Calcitonin is a biomarker for medullary thyroid cancer, and these patients typically experienced a proportional length of progression free survival corresponding to the change in calcitonin measured (Figure 4). Patient no. 1 was the only patient whose change in calcitonin level did not correlate with progression free survival. Example 5. Treatment protocol with Gastrin analogue 4, labeled with225Ac, in patients with pancreas adenocarcinoma receiving supplemental anticancer treatment.

[0208] Some patients with histologically proven pancreatic adenocarcinomas may be only partially responsive to anticancer treatments, including but not limited to everolimus, paclitaxel, capecitabine, erlotinib, fluorouracil, gemcitabine, irinotecan, Olaparib, mitomycin, or sunitinib. For these patients with unresectable or metastatic, well differentiated grade 1 to grade 4 tumors, up to 500 kBq [225Ac] -Gastrin analogue 4 will be administered as an intravenous infusion every second week for up to 56 weeks, while the patients simultaneously receive anticancer treatment. Prior to initiation of gastrin analogue treatment, patients will receive up to 250 MBq68Ga-PP-F11 N to image the diseased tissue with positron emission tomography; this would be supplementary to any previous diagnosis by computed tomography, magnetic resonance imaging, or CCK2R histological binding assay. The imaging dose and analysis of growth would be repeated at least once every four weeks during gastrin analogue treatment to determine if the cancer enters remission. Tumor response for the treatment will be determined by these routine PET images as well as supplemental tumor biomarker measurement. If after 16 weeks, an individual patient shows a clear trend towards remission, the patient will receive another up to six cycles. This pattern will continue if the tumor response supports the extension of the treatment. If the patient shows a full remission or the patient is tumor free, the treatment will be stopped. Treatment with [225Ac]-Gastrin analogue 4 will pause if a patient is showing side effects, such as high kidney or liver markers, or gastritis which cannot be managed with supportive medical treatments. In case of significant lymphocytopenia the patient will receive a hematopoietic growth factor, such as Neulasta to stimulate white blood cell regeneration.

[0209] Example 6. Treatment protocol with Gastrin analogue 15, labeled with177Lu, in patients with colon adenocarcinoma receiving supplemental anticancer treatment.

[0210] Some patients with previously measured colon adenocarcinomas may be only partially responsive to anticancer treatments, including but not limited to bevacizumab, irinotecan, capecitabine, cetuximab, ramucirumab, oxaliplatin, fluoruracil, fruquintinib, ipilimumab, pembrolizumab, leucovorin, trifluridine, tipiracil, nivolumab, panitumumab, regorafenib, or tucatinib. For any patient with a grade 1 to grade 4 growths that is simultaneously undergoing anticancer treatment, up to 8 GBq [177Lu]-Gastrin analogue 15 will be administered as an intravenous infusion every second week for up to 56 weeks. Patients receiving treatment will receive positron emission tomography scans to monitor tumor progression every four weeks; this would be supplementary to any previous diagnosis by computed tomography, magnetic resonance imaging, or CCK2R histological binding assay. The imaging dose and analysis of growth would be repeated at least once every four weeks during gastrin analogue treatment to determine if the cancer enters remission. Tumor response for the treatment will be determined by these routine PET images as well as supplemental tumor biomarker measurement. If after six cycles, totaling 12 weeks of treatment, the patient enters remission, the treatment with [177Lu]-Gastrin analogue 15 will be halted. Absence of remission at this stage will result in an additional four treatment cycles, or eight weeks of gastrin analogue treatment. If after any remission, a recurrence of tumor progression is observed, then the two week cycle will restart for six cycles, for 12 weeks total, and then switch to maintenance treatment dosing [177Lu]-Gastrin analogue 15 every four weeks until the end of treatment.

[0211] Example 7. Treatment protocol with sacubitril and Gastrin analogue 2, labeled with177Lu, in patients with medullary thyroid cancer. Includes maintenance treatment.

[0212] To improve the in vivo gastrin analogue stability, the efficacy of endopeptidase inhibitors as an adjuvant with peptide receptor radionuclide therapy will be pursued. Patients with metastatic medullary thyroid cancer will receive up to 150 mg oral sacubitril 2 hours prior to an additional treatment with 8 GBq [177Lu]-Gastrin analogue 2; sacubitril and [177Lu]-Gastrin analogue 2 will be administered as an intravenous infusion every second week for up to 72 weeks, and patients will always receive sacubitril prior to gastrin analogue administration, preferably two hours beforehand. Sacubitril may be administered in combination with valsartan. Prior to initiation of gastrin analogue treatment, patients will receive up to 250 MBq68Ga-PP-F11 N in order to image the diseased tissue with positron emission tomography; this would be supplementary to any previous diagnosis by computed tomography, magnetic resonance imaging, or CCK2R histological binding assay. The imaging dose and analysis of growth would be repeated at least once every eight weeks during gastrin analogue treatment to determine if the cancer enters remission. Tumor response for the treatment will be determined by these routine PET images as well as supplemental tumor biomarker measurement. If a patient enters remission, a maintenance period will begin, wherein sacubitril and [177Lu]-Gastrin analogue 2 are instead administered every four weeks. If a patient experiences full remission, the treatment will be stopped; however, upon observation of tumor progression, the treatment period administering sacubitril and [177Lu]-Gastrin analogue 2 every two weeks will be resumed.

[0213] Example 8. Treatment protocol with Gastrin analogue 28, labeled with225Ac, in patients with ovarian cancer.

[0214] Patients with metastatic ovarian cancer exper will receive up to 1 GBq [225Ac]-Gastrin analogue 28; sacubitril and [225Ac]-Gastrin analogue 28 will be administered as an intravenous infusion every second week for up to 72 weeks. Prior diagnosis by computed tomography, magnetic resonance imaging, or CCK2R histological binding assay will be required. Tumor response for the treatment will be determined by PET imaging with either18F-fluorodeoxyglucose or68Ga-labled gastrin analogue acquired every four weeks; MRI and CT scans will supplement determination of tumor progression. If a patient experiences full remission, the treatment will be stopped; however, upon observation of tumor progression, the treatment period administering [225Ac] -Gastrin analogue 28 every two weeks will be resumed.

[0215] Example 9. Treatment protocol with Gastrin analogue 29, labeled with177Lu, in patients with lung carcinoids. Includes sacubitril and maintenance treatments. Six week cycles.

[0216] Patients with well-differentiated lung carcinoids will receive up to 10 GBq [177Lu]-Gastrin analogue 29 will receive sacubitril and [177Lu]-Gastrin analogue 29 every four weeks for up to 72 weeks. Sacubitril administration will be up to 150 mg provided orally two hours prior to each administration of [177Lu]-Gastrin analogue 29. Prior diagnosis by computed tomography, magnetic resonance imaging, or CCK2R histological binding assay will be required. Tumor response for the treatment will be determined by PET imaging with either18F-fluorodeoxyglucose or68Ga-labled gastrin analogue acquired every four weeks; MRI and CT scans will supplement determination of tumor progression. In the event of the patient experience partial remission, a maintenance treatment will begin with sacubitril and [177Lu]-Gastrin analogue 29 administration occurring every six weeks. If a patient experiences full remission, the treatment will be stopped. Upon observation of tumor progression, the treatment period administering 10 GBq [177Lu]-Gastrin analogue 29 will be resumed with cycle frequency increasing to every two weeks for the remainder of treatment.

[0217] Example 10. Treatment of lung carcinoid patients with177Lu-PP-F11N and optional concurrent administration of sacubitril and everolimus over three treatment cycles.

[0218] A group of patients with well-differentiated lung carcinoids was treated with177Lu-PP-F11 N, seeking to evaluate benefits with concurrent neprilysin inhibitor and / or the anticancer therapeutic everolimus. Patients received an initial 8 GBq dose of177Lu-PP-F11 N, followed by an additional 8 GBq dose at 8 weeks concurrently with Entresto®, and were lastly treated with 8 GBq of177Lu-PP-F11 N with Entresto® and everolimus. A SPECT image of a single patient following this treatment protocol is depicted in Figure 5A, which shows localization of the emitter to the primary cancer site and sites of metastases. As a measure of treatment efficacy, the lung-cancer biomarker chromogranin A was measured in these patients, which in Figure 5B shows a 27% decrease in a single patient’s chromogranin A level after this treatment regimen.

[0219] OTHER EMBODIMENTS

[0220] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the invention that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. All publications, patents, and patent applications mentioned in the above specification are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[0221] Detailed descriptions of one or more preferred embodiments are provided herein. It is to be understood, however, that the present invention may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in any appropriate manner. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention. Other embodiments are in the claims.

Claims

CLAIMS1 . A method for treating a cancer characterized by overexpression of CCK2R in a subject comprising administering to the subject a therapeutic amount of a gastrin analogue complexed with a radionuclide, wherein the administering comprises: a) a treatment period in which the gastrin analogue administration is repeated about once every week to about once every six weeks for the duration of the treatment period; and b) a maintenance period, wherein if the cancer enters remission, the gastrin analogue administration is repeated about once every week to about once every six weeks for the duration of the maintenance period.

2. The method of claim 1 , wherein the treatment period comprises gastrin analogue administration about once every week, and the maintenance period comprises gastrin analogue administration about once every four weeks.

3. The method of claim 1 , wherein the treatment period comprises gastrin analogue administration about once every two weeks, and the maintenance period comprises gastrin analogue administration about once every four weeks.

4. The method of claims 1-3, wherein the subject receiving gastrin analogue administration has not concomitantly received any other anticancer treatment.

5. A method for treating a cancer characterized by overexpression of CCK2R in a subject, the method comprising the steps of: i. administering to the subject an anticancer treatment; and ii. administering a therapeutically effective amount of a gastrin analogue complexed with a radionuclide.

6. The method of claim 5, wherein the administration is repeated about once every week to about once every six weeks for the duration of the treatment period.

7. The method of claim 6, wherein the administration is repeated about once every two weeks to about once every four weeks for the duration of the treatment period.

8. The method of claim 7, wherein if the cancer enters remission, the administration is repeated about every four weeks for the duration of treatment period.

9. The method of any one of claims 1-8, wherein prior to the gastrin analogue administration, a neprilysin inhibitor is administered to the subject.

10. The method of claim 9, wherein the neprilysin inhibitor is orally administered about two hours before the gastrin analogue administration.

11. The method of claim 10, wherein the neprilysin inhibitor is sacubitril.

12. The method of claim 11 , wherein between about 50 mg and about 200 mg of sacubitril is administered.

13. The method of any of claims 8-11 , wherein valsartan is administered concurrently with the neprilysin inhibitor.

14. The method of any of claims 1-13, wherein the cancer is selected from pancreas adenocarcinoma, colon adenocarcinoma, primary liver cancer, astrocytoma, glioma, colorectal carcinoma, esophageal carcinoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, stomach carcinoma, ovarian cancer, medullary thyroid cancer, neuroendocrine tumors, bronchial carcinoids, carcinoids of the bowels and stomach, gastrointestinal stromal tumors, pancreatic neuroendocrine tumors, cholangiocarcinoma, fibrolamellar carcinoma, or non- medullary thyroid carcinoma.

15. The method of claim 14, wherein the cancer is somatostatin negative.

16. The method of claim 14, wherein the subject has at least one measurable, histologically proven, or radiodiagnostically proven site of disease.

17. The method of claim 14, wherein the subject has a histologically proven Grade 1 or higher tumor.

18. The method of claim 14, wherein the cancer is metastatic.

19. The method of claim 14, where the cancer is resectable, but tumor residuals need to be eliminated.

20. The method of any of claims 14-18, wherein the cancer is non-operable.21 . The method of any of claims 14-20, wherein the cancer is non-responsive to treatment with 177lutetium oxodotreotide.

22. The method of any of claims 1-21 , wherein the method further comprises administering to the subject an anticancer treatment selected from immune checkpoint inhibitors, chemotherapeutic agents, PARP inhibitors, antibody drug conjugates, a cytotoxic agent, an antimetabolite, an alkylating agent, an anthracycline, an antibiotic, an anti-mitotic agent, a hormone therapy, a signal transduction inhibitor, a gene expression modulator, an apoptosis inducer, an angiogenesis inhibitor, an immunotherapy agent, a DNA damage repair inhibitor, an mTOR inhibitor, and a kinase inhibitor.

23. The method of any of claims 1-22, wherein following the gastrin analogue administration, the subject experiences an increase in Progression Free Survival, Tumor Response, or Overall Survival Benefit.

24. The method of any of claims 1-23, wherein the subject is human.

25. The method of any of claims 1-24, wherein the gastrin analogue is administered intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraocularally, orally, locally, by inhalation, by injection, or by infusion.

26. The method of any of claims 1-25, wherein the gastrin analogue is a compound described by the formula (I):or a pharmaceutically acceptable salt thereof, whereinR1is a chelating group complexed with a radionuclide selected from225Ac,212Bi,213Bi,11C62Cu, 64Cu,67Cu,69Cu,18Fe,66Ga,67Ga,68Ga,123l,131l,1111n,113mln,177Lu,13N186Re,188Re,43Sc,44Sc, 47Sc,155Tb,161Tb,99mTc,86Y,90Y,169Yb,175Yb, and212Pb;R2is optionally present, and is selected fromR3is OH or NH2;X1is optionally present, and is an amino acid selected from β-alanine, D-glutamate and L- glutamate; m is 0, 1 , 2, 3, 4, 5, 6, 7, or 8;X2optionally present, and is an amino acid selected from glycine, N-methyl glycine, L-alanine, D- alanine, L-tyrosine, D-tyrosine, D-proline, L-proline, (2S,4S)-4-fluoroproline, and (2S,4R)-4- fluoroproline; n is 0, 1 , 2, 3, or 4;X3is an amino acid selected from L-methionine, N-methyl L-methionine, L-norleucine, and N- methyl L-norleucine;X4an amino acid amide selected from L-phenylalanine, N-methyl L-methionine, 3-(1-naphthyl)-L- alanine, and N-methyl 3-(1-naphthyl)-L-alanine; optionally wherein any (C=O)NH moiety may be substituted for a 1 ,4-disubstituted-1 ,2,3-triazole, provided: i. at least one of R2and X2must be present;ii. If X2is present, then R2is notiii. If R2isthen X1is β-alanine.

27. The method of claim 26, wherein the gastrin analogue is selected from a compound of Table A, or any pharmaceutically acceptable salt thereof:Table A4528. The method of claim 26, in which the gastrin analogue administered is Gastrin analogue 1 , in which R1is DOTA, R2is absent, R3is NH2, X1is only D-glutamate, n is 6, X2is L-alanine - L- tyrosine - glycine, m is 3, X3is L-methionine, and X4is L-phenylalanine.

29. The method of claim 26, in which the gastrin analogue administered is Gastrin analogue 2, in which R1is DOTA, R2is absent, R3is NH2, X1is only D-glutamate, n is 6, X2is L-alanine - L- tyrosine - glycine, m is 3, X3is L-norleucine, and X4is L-phenylalanine.

30. The method of claim 26, in which the gastrin analogue administered is Gastrin analogue 4, in which R1is DOTA, R2is absent, R3is NH2, X1is D-glutamate, n is 1 , X2is L-alanine - L-tyrosine - glycine, m is 3, X3is N-methyl L-norleucine, and X4is 3-(1-naphthyl)-L-alanine.

31. The method of claim 26, in which the gastrin analogue administered is Gastrin analogue 15, in which R1is DOTA, R2is present, and isR3is NH2, X1is only D- glutamate and X1is connected by isopeptide linkages, m is 8, X2is L-alanine - L-tyrosine - glycine, n is 3, X3is L-norleucine, and X4is L-phenylalanine.

32. The method of claim 26, in which the gastrin analogue administered is Gastrin analogue 27, in which R1is DOTA, R2isR3is NH2, X1is absent, n is 2, X2is absent, X3is N-methyl L-norleucine, and X4is 3-(1-naphthyl)-L-alanine.

33. The method of claim 26, in which the gastrin analogue administered is Gastrin analogue 28, in1 , n is 2, X2is absent, X3is N-methyl L-norleucine, and X4is 3-(1-naphthyl)-L-alanine.

34. The method of claim 26, in which the gastrin analogue administered is Gastrin analogue 29, in which R1is DOTA, R2isR3is NH2, X1is β-alanine, m is 1 , n is 2, X2is absent, X3is N-methyl L-norleucine, and X4is 3-(1-naphthyl)-L-alanine.

35. The method of any of claims 26-34, wherein a gastrin analogue complexed with225Ac is administered.

36. The method of claim 35, wherein doses ≤500 kBq are administered with each gastrin analogue administration.

37. The method of any of claims 26-34, wherein a gastrin analogue complexed with177Lu is administered.

38. The method of claim 36, wherein a dose of about 8 GBq is administered with each gastrin analogue administration.

39. The method of any of claims 26-34, wherein the administered gastrin analogue is complexed with 212Bi,213Bi,11C62Cu,64Cu,67Cu,69Cu,18Fe,66Ga,67Ga,68Ga,123l,131l,111ln,113mln,13N186Re, 188Re,43Sc,44Sc,47Sc,155Tb,161Tb,99mTc,86Y,90Y,169Yb,175Yb, or212Pb.

40. The method of any of claims 1-39, wherein prior to the gastrin analogue administration, the subject is administered a gastrin analogue complexed with68Ga and PET imaging is acquired at least once every eight weeks.41 . A method of treating cancer characterized by overexpression of CCK2R in a subject in need thereof, wherein the cancer is selected from medullary thyroid cancer, neuroendocrine tumors, bronchial carcionids, carcinoids of the bowels and stomach, gastrointestinal stromal tumors, pancreatic neuroendocrine tumors, pancreas adenocarcinoma, colon adenocarcinoma, primary liver cancer, ovarian cancer, astrocytoma, glioma, colorectal carcinoma, esophageal carcinoma, chlolangiocarcinoma, fibrolamellar carcinoma, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, stomach carcinoma, or non-medullary thyroid carcinoma, wherein the subject is administered a therapeutically effective amount of PP-F11 N complexed with a radionuclide selected from225Ac,212Bi,213Bi,11C62Cu,64Cu,67Cu,69Cu,18Fe,66Ga,67Ga, 68Ga,123l,131l,1111n,113mln,177Lu,13N186Re,188Re,43Sc,44Sc,47Sc,155Tb,161Tb,99mTc,86Y,90Y, 169Yb,175Yb, or212Pb and wherein the radionuclide administration is repeated about once every week to about once every six weeks for the duration of treatment.

42. The method of claim 41 , wherein PP-F11 N complexed with225Ac is administered to the subject.

43. The method of claim 42, wherein the PP-F11 N complexed with225Ac is administered in doses of below 500 kBq with each treatment cycle.

44. The method of claim 41 , wherein PP-F11 N complexed with177Lu is administered to the subject.

45. The method of claim 44, wherein the PP-F11 N complexed with177Lu is administered in doses of about 8 GBq with each treatment cycle.

46. The method of any one of claims 41-45, wherein about two hours prior to the administration of PP-F11 N, the subject is administered a neprilysin inhibitor.

47. The method of claim 46, wherein the neprilysin inhibitor is sacubitril.

48. The method of claim 47, wherein from about 50 mg to about 150 mg of the sacubitril is orally administered.

49. The method of claim 48, wherein about 100 mg of the sacubitril is orally administered.

50. The method of any of claims 41-49, wherein prior to the administration of PP-F11 N, a complex of PP-F11 N and68Ga is administered to the subject and PET imaging is performed on the subject.

51. The method of claim 50, wherein for the duration of treatment,68Ga-PP-F11 N or any gastrin analogue PET imaging is obtained every eight weeks.

52. The method of any of claims 41-51 , wherein the radionuclide administration is repeated about once every week.

53. The method of any of claims 41-51 , wherein the radionuclide administration is repeated about once every two weeks.

54. The method of any of claims 41-51 , wherein the radionuclide administration is repeated about once every four weeks.

55. The method of any of claims 41-51 , wherein the radionuclide administration is repeated about once every six weeks.

56. The method of any of claims 41-55, wherein the subject is human.

57. The method of any of claims 41-56, wherein the subject has a local, metastasized or locally advanced, histologically proven Grade 1 or higher tumor.

58. The method of any of claims 41-57, wherein the subject has at least one measurable or histologically or radio-diagnostically proven site of disease.

59. A method of treating cancer characterized by overexpression of CCK2R in a subject in need thereof, the method comprising the steps of: i. Administration of a neprilysin inhibitor to the subject, and ii. Following about two hours after completion of step (i), administration of therapeutically effective amount of PP-F11 N complexed with a radionuclide177Lu or225Ac to the subject, wherein steps i. and ii. are repeated about once every two to about once every ten weeks for the duration of treatment.

60. The method of claim 59, wherein the cancer overexpressing CCK2R is medullary thyroid cancer, lung neuroendocrine tumors, or gastro-enteropancreatic neuroendocrine tumors.61 . The method of claim 60, wherein the cancer overexpressing CCK2R is medullary thyroid cancer.

62. The method of claim 60, wherein the cancer overexpressing CCK2R is lung neuroendocrine tumors.

63. The method of claim 60, wherein the cancer overexpressing CCK2R is gastro-enteropancreatic neuroendocrine tumors.

64. The method of any of claims 59-63, wherein the cancers are somatostatin negative.

65. The method of any of claims 59-64, wherein the cancers are non-responsive to treatment with 177luteium-oxodotreotide.

66. The method of any of claims 59-65, wherein the neprilysin inhibitor is sacubitril.

67. The method of claim 66, wherein between about 50 mg and about 200 mg of sacubitril is administered.

68. The method of any of claims 59-67, wherein steps i. and ii. are repeated about once every week for the duration of treatment.

69. The method of any of claims 59-67, wherein steps i. and ii. are repeated about once every two weeks for the duration of treatment.

70. The method of any of claims 59-67, wherein steps i. and ii. are repeated about once every four weeks for the duration of treatment.71 . The method of any of claims 59-67, wherein steps i. and ii. are repeated about once every six weeks for the duration of treatment.

72. The method of any one of claims 59-71 , wherein prior to the repetition of steps i. and ii., the subject is administered PP-F11 N or any gastrin analogue complexed with68Ga.

73. The method of claim 71 , wherein after administering the PP-F11 N or any gastrin analogue complexed with68Ga, a PET imaging scan of the subject is obtained.

74. The method of any one of claims 59-73, wherein for the duration of treatment, PP-F11 N complexed with68Ga PET imaging scans are obtained at least every eight weeks.

75. The method of any of claims 59-74, wherein the subject is human.

76. The method of any of claims 59-75, wherein the subject has a local or metastasized or locally advanced, histologically proven Grade 1 or higher tumor.

77. The method of any of claims 59-76, wherein the subject has at least one measurable or histologically or radio-diagnostically proven site of disease.

78. The method of any of claims 41-77, wherein the PP-F11 N is administered intravenously.

79. The method of any of claims 41-78, wherein following the administration the subject experiences an increase in Progression Free Survival, Tumor Response or Overall Survival Benefit.

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