Combinations of inhibitors of ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) with radiation for cancer therapy

Abstract

The present invention provides combinations of inhibitors of Ectonucleotide Pyrophosphatase / Phosphodiesterase (ENPP1) with a radiation therapy or a radioligand for the purposes of treating cancer. The invention includes both methods of treatment of cancer with the provided combinations and pharmaceutical compositions comprising such combinations. A preferred ENPP1 inhibitor is SR-8541A; and a preferred radioligand is PluvictoTM.

Description

COMBINATIONS OF INHIBITORS OF ECTONUCLEOTIDE PYROPHOSPHATASE / PHOSPHODIESTERASE 1 (ENPP1) WITH RADIATION FOR CANCER THERAPYFIELD OF THE INVENTION

[0001] The present invention generally relates to combinations of inhibitors of Ectonucleotide Pyrophosphatase / Phosphodiesterase (ENPP1), including but not limited to SR-8541 A, with radiation therapy, including but not limited to Pluvicto™, for the purposes of treating cancer.BACKGROUND OF THE INVENTION

[0002] Ectonucleotide Pyrophosphatase / Phosphodiesterase (ENPP) family members include seven isoforms, ENPP 1-7, which are type II transmembrane glycoproteins or ectoenzy mes. Mass spectrometry and proteomics analysis from more than 370 protein targets led to the identification of an extracellular protein ENPP1 as one of the top hits which exhibited high hydrolytic activity. ATP is an identified substrate of ENPP 1, which is hydrolyzed to AMP and PPi. CD73 converts AMP to adenosine and inorganic phosphate (Pi). The kinetic experimental data indicates that the ENPP1 is capable of hydrolyzing ATP. These ectonucleotide enzy mes are involved in the hydrolysis of pyrophosphate (PPi) and phosphodiester bonds in extracellular nucleotides: such as triphosphates, oligonucleotides and that generates nucleoside 5 ’-monophosphates. One of the key isoforms, ENPP1 (Plasma cell membrane gly coprotein- 1, PC-1), is involved in a number of physiological processes, such as development, formation and trafficking, as well as in pathophysiological conditions. Aberrant ENPP1 expression has been detected in breast cancers relative to normal mammary epithelium, an evidence of its potential in the development of bone metastasis (occurs in approximately 80% cases), Hodgkin’s lymphoma, hepatocellular carcinoma, follicular lymphoma, glioblastoma and in other malignant tumor tissues.

[0003] Recent reports suggest that the cyclic dinucleotides (CDNs), a substrate for ENPP1, stimulate innate immunity' via STING-dependent activation of interferon genes. ENPP1 inhibition and subsequent activation of STING pathway is critical for tumor control, similar to that of checkpoint inhibitors such as anti PD-1 or PD-L1 which are promising immunotherapeutics for various cancers. In addition, mutations in ENPP1 were associatedwith several disorders including infantile arterial calcification (generalized arterial calcification of infancy or GACI), ossification of the posterior longitudinal ligament of the spine and insulin signaling and resistance. ENPP1 expression is high in bone and cartilage and is implicated in lung and kidney fibrosis. A correlation was also found between expression of ENPP1 and the grade of astrocytic tumor. Another study reported that ENPP1 was required to maintain the undifferentiated and proliferative state of glioblastoma stem-like cells. Therefore, ENPP1 is an attractive druggable target for the development of novel anticancer, cardiovascular, diabetes, obesity, NASH, glaucoma, and anti -fibrotic therapeutics.

[0004] Importance of ENPP1 activity was further investigated from both direct binding assay and in vitro cellular efficacy on MDA-MB231 cells. The siRNA-based knock down of ENPP1 significantly reduced its catalytic activity both in cell specific and in vivo experiments. These experiments demonstrated that the ENPP1 activity was abolished on treatment with siRNA. This further supports the validity of this target in certain diseases. It has been shown recently that the bisphosphothionate analog of endogenous cGAMP is resistant to hydrolysis by ENPP1 phosphodiesterase, and particularly the cyclic dinucleotides (CDNs) are more potent at inducing IFN-0 secretion in human THP1 cells by a mechanism of inhibiting the ENPP1 activity' and simultaneous STING activation responses.

[0005] There is ample evidence that ENPP1 expression is prominent in human primary breast tumors relative to normal mammary epithelium, with highest levels observed in breastbone metastasis. These data not only support a potential role for ENPP1 in breast-bone metastasis, but also support as a potential prognostic marker for breast cancer. More recently, ENPP1 was shown to be upregulated in lung cancer. Knockdown of ENPP1 in lung cancer cell lines HCC827 and A549 resulted in suppressed colonogenic formation, anchorageindependent grow th in vitro, and tumorigenicity in vivo. These results from target validation experiments clearly support the pharmacological role of ENPP1 for the development of novel immunotherapeutics for cancers.

[0006] SR-8541A (also known as 4-(6,7-dimethoxyquinazolin-4-yl)-l,4-diazepane-I- sulfonamide hydrochloride salt) is one example of an ENPP1 inhibitor, described in WO 2021 / 158829, Example 5).

[0007] While ENPP1 inhibitors are potent inhibitors of ENPP1 and exhibit single agent activity, the relative potency and / or observed maximal effect of any given ENPP1 inhibitorcan vary between various cell lines. The reasons for the range of potencies and observed maximal effect is not fully understood. Thus, there is a need to develop alternative approaches to maximize the potency, efficacy, therapeutic index and / or clinical benefit of ENPP1 inhibitors in vitro and in vivo.

[0008] Radiation therapy (RT), a fundamental component of standard-of-care treatment, is received by more than half of all cancer patients. Because of its ability to induce double stranded DNA damage, RT can lead to cancer cell death via apoptosis, necrosis, senescence, or mitotic catastrophe. RT can also modulate several systemic biological effects, prominent among them is the anti-tumor immune response that includes enhanced tumor antigen release and presentation, priming and activation of immune cells, increased migration and infiltration of lymphocytes into the tumors, facilitation of tumor cell recognition, and augmentation of anti-tumor effects by T cells. Besides provoking systemic anti-tumor immune response, RT can exert immunoinhibitory effects through modulation of regulatory T cell (Treg) and myeloid derived suppressor cell (MDSC) activities, and elevating immunosuppressive cytokines such as TGF . In addition, several preclinical studies have shown that the radiation dose and fractionation schedule can negatively impact the RT-mediated anti-tumor immune response. Conventional RT (single high tumoricidal dose) can increase antigen release and presentation but the induction of TREX1 and mobilization of Tregs and MDSCs dampens the overall tumor immunogenicity. In contrast, fractionated low dose RT (doses below the threshold thought to physically damage DNA or kill cancer cells directly) has been shown to produce greater anti-tumor immunity. Additionally, the advent of targeted radionuclide therapy (TRT) has changed the dynamics of radiation therapy, and it is now7possible to deliver continuous low doses systemically and target disseminated or metastatic tumors.

[0009] Many cancer cells accumulate nucleic acids in the cytoplasm in response to radiation induced DNA damage, and nucleic acids released by dying cancer cells can be taken up or sensed as DAMPs by surviving cancer or bystander cells (e.g., dendritic cells). This leads to activation of several nucleic acid-sensing pathways, including the evolutionarily conserv ed cGAS-STING pathway that promotes innate immunity. ENPP1 blocks activation of STING by hydrolyzing 2'3'-cGAMP, which is the natural ligand for STING. Therefore, combining radiation therapy and ENPP1 inhibition has the potential to strongly remodel the tumor-associated immune landscape and produce a superior outcome for cancer patients.SUMMARY OF THE INVENTION

[0010] In one embodiment, the invention provides a method for treating cancer in a subject comprising administering an effective amount of an ENPP1 inhibitor or a pharmaceutically acceptable salt thereof and a radiation therapy or a radioligand.

[0011] In a preferred embodiment, said ENPP1 inhibitor is SR-8541 A (4-(6,7- dimethoxy quinazolin-4-yl)- 1 ,4-diazepane- 1 -sulfonamide hydrochloride salt).

[0012] In one embodiment, said ENPP1 inhibitor comprises one more inhibitors selected from RBS2418, SR-8541A, TXN10128, ZX-8177, AVA-NP-695, AG-3132, STF-1623 / CM- 3163, ISM5939, GBD09259, LCB33-089. POM-1, VIR3. Ex54, QPS2, SK4A. and LCB33- 117.

[0013] In said ENPP1 inhibitor comprises one more ENPP1 inhibitors selected from all ENPP1 inhibitors disclosed in WO 2019 / 051269 Al, WO 2020 / 160333 Al, WO 2021 / 133915 Al, WO 2021 / 158829 Al. WO 2021 / 257614 Al. US 2019 / 0201423 Al, US 2021 / 0121484 Al , US 1 1,591 ,313 B2, and US 2023 / 0190927 Al , the contents of which are hereby incorporated by reference in their entirety.

[0014] In another preferred embodiment, the radioligand is selected from the group consisting of Pluvicto™ (lutetium Lu 177 vipivotide tetraxetan), zevalin, actimab-A, iomab- ACT, iomab-B, lutetium-177-DOTAGA-PEG-IAC, tozande, SS0110, BAY-2701439,177Lu- rhPSMA-10.1, CTT-1403, iopofosine, SAR-BBN, SAR-bisPSMA, SARTATE, FAP-2286, CONV-01-a.177Lu-PSMA-I&T. FPI-2059, FPI-1434. FPI-1966, [177LU] ludotadipep,161Tb- PSMA-I&T, ITM-31, ITM-11, JNJ-69086420, 1-131-1095, azedra, PSMA TTC / BAY- 2315497,177LU-DOTA-EB-TATE, betalutin, AAA817, AAA603, lutathera, PPMX-T002, 186RNL, PNT2003, CAM-H2, AlphaMedix, RYZ101, Sn-117m-DTPA, TLX592, TLX66, TLX250, TLX591. TLX101,124I-omburtamab, GD2-SADA,131I-omburtamab, and pharmaceutically acceptable salts thereof.

[0015] In one embodiment, radiation therapy is beam radiation therapy, also known as external beam radiation therapy (EBRT).

[0016] In another embodiment, radiation therapy is liquid radiation therapy, also known as systemic radiation therapy or radioisotope therapy, wherein the radioactive liquid is administered through a vein, by mouth, or as an injection.

[0017] In a preferred embodiment, the cancer is selected from the group consisting of breast cancer, lung cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, bladder cancer, colorectal cancer, endometrial carcinoma, kidney cancer, thyroid cancer, basal cell carcinoma, biliary tract cancer, bone cancer, brain and CNS cancer, choriocarcinoma, connective tissue cancer, esophageal cancer, eye cancer, cancer of the head and neck, gastric cancer, intra-epitheli al neoplasm, larynx cancer, lymphoma, melanoma, myeloma, neuroblastoma, oral cavity cancer, retinoblastoma, rhabdomyosarcoma, rectal cancer, cancer of the respiratory system, sarcoma, skin cancer, stomach cancer, testicular cancer, uterine cancer, and cancer of the urinary system.

[0018] The invention also provides pharmaceutical compositions comprising the combinations of the invention. In one embodiment, the combination pharmaceutical agent is itself a pharmaceutical composition.

[0019] In one embodiment, an ENPP1 inhibitor and a radioligand are formulated as a single composition.

[0020] In one embodiment, SR-8541 A and lutetium Lu 177 vipivotide tetraxetan are formulated as a single composition.

[0021] In another embodiment, an ENPP1 inhibitor and a radioligand are formulated as separate compositions.

[0022] The invention also provides methods for the treatment of cancers comprising administering to a patient in need thereof a therapeutically effective amount of the combination pharmaceutical agents of the invention.

[0023] The invention also provides methods for the treatment of cancers, wherein ENPP 1 inhibitors (for example, SR-8541 A) are administered prior to. or concurrently with administration of radioligands (for example, lutetium Lu 177 vipivotide tetraxetan).

[0024] In a preferred embodiment, the cancer is selected from the group consisting of prostate cancer, lung cancer, breast cancer, glioma, squamous cell carcinoma, melanoma, renal cancer, colorectal cancer, ovarian cancer, pancreatic cancer, sarcoma, and stomach cancer.

[0025] In one embodiment, the invention provides a kit for treating cancer in a subject comprising: an ENPP1 inhibitor and instructions for administering an ENPP1 inhibitor in combination with a radiation therapy or a radioligand.BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Fig. 1 A is a graph showing tumor growth inhibition (TGI) in various treatment groups (not treated (NT), ENPPli, radioligand therapy (RLT), RLT+ENPPli) in prostate cancer models.

[0027] Fig. IB is a graph of tumor volume vs time for the NT group.

[0028] Fig. 1C is a graph of tumor volume vs time for the ENPPli group.

[0029] Fig. ID is a graph of tumor volume vs time for the RLT group.

[0030] Fig. IE is a graph of tumor volume vs time for the combination of ENPPli andRLT group.

[0031] Fig. IF is a time to progression (TTP) graph of the NT, ENPP li, RLT, and the combination of RLT and ENPPli groups.

[0032] Fig. 2A is a graph of a normalized tumor volume vs time in the vehicle, radiation only, SR-8541 A only, and the combination of radiation and SR-8541 A groups.

[0033] Fig. 2B shows abscopal effect of administering a combination of radiation and SR-8541 A treatment.

[0034] Fig. 3A show-s results of a MC38 (murine colon carcinoma) efficacy study, where ARG1 expression, M2 marker, was measured for radiation only, SR-8541 A only, and the combination of radiation and SR-8541A groups.

[0035] Fig. 3B shows results of a MC38 efficacy study, where INOS expression, Ml marker, was measured for radiation only, SR-8541 A only, and the combination of radiation and SR-8541 A groups.DETAILED DESCRIPTION OF THE INVENTIONDEFINITIONS

[0036] As used in the specification and the appended claims, the singular forms ‘'a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0037] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0038] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0039] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0040] As used herein, the term “ENPP1” refers to Ectonucleotide Pyrophosphatase / Phosphodiesterase.

[0041] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0042] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow. cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects. In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment of a disorder of uncontrolled cellular proliferation associated with an ENPP1 dysfunction prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a need for inhibition of ENPP1 prior to the administering step.

[0043] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the termcovers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term "‘subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, zebra fish etc ).

[0044] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0045] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. For example, “diagnosed with a disorder of uncontrolled cellular proliferation” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by a compound or composition that can inhibit ENPP1. As a further example, “diagnosed with a need for inhibition of ENPP1” refers to having been subj ected to a physical examination by a person of skill, for example, a physician, and found to have a condition characterized by an ENPP1 dysfunction. Such a diagnosis can be in reference to a disorder, such as a disorder of uncontrolled cellular proliferation, cancer and the like, as discussed herein. For example, “diagnosed with a need for treatment of one or more disorders of uncontrolled cellular proliferation associated with an ENPP1 dysfunction” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have one or more disorders of uncontrolled cellular proliferation associated with an ENPP1 dysfunction.

[0046] As used herein, the phrase “identified to be in need of treatment for a disorder,” or the like, refers to selection of a subject based upon need for treatment of the disorder. For example, a subject can be identified as having a need for treatment of a disorder (e.g., a disorder related to a dysfunction of ENPP1) based upon an earlier diagnosis by a person ofskill and thereafter subjected to treatment for the disorder, ft is contemplated that the identification can, in one aspect, be performed by a person different from the person making the diagnosis. It is also contemplated, in a further aspect, that the administration can be performed by one who subsequently performed the administration.

[0047] As used herein, the terms "administering" and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, intraurethral administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0048] The term “contacting” as used herein refers to bringing a disclosed compound and a cell, target receptor, or other biological entity together in such a manner that the compound can affect the activity' of the target (e.g., receptor, cell, etc.), either directly; i.e., by interacting with the target itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the target is dependent.

[0049] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety' of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specificcompound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0050] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0051] The term “stable.” as used herein, refers to compounds that are not substantially- altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0052] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity-, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0053] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like),carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly (anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by fdtration through a bacterial-retaining fdter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0054] A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more -COfCFbhCO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0055] The term “SR-8541 A” means the compound of the formula:SR-8541 A is described in WO 2021 / 158829 Al, in Example 5 (compound 015-HC1; 4-(6,7- dimeth oxy quinazolin-4-yl)-l,4-diazepane-l -sulfonamide hydrochloride salt).

[0056] The term “Pluvicto™” means lutetium Lu 177 vipivotide tetraxetan.

[0057] The compounds of the invention encompass pharmaceutically acceptable salts of the compounds.

[0058] The term “pharmaceutically acceptable salts” is meant to include salts of active compounds which are prepared with relatively nontoxic acids. Acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic; propionic; isobutyric; maleic; malonic; benzoic; succinic; suberic; fumaric; mandelic; phthalic; benzenesulfonic; toluenesulfonic, including / ?-tol uenesul fonic. m-toluenesul Ionic, and o-toluenesulfonic; citric; tartaric; methanesulfonic; and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al. J. Pharm. Sci. 66: 1-19 (1977)).

[0059] The terms, “polymorphs” and “polymorphic forms” and related terms herein refer to crystal forms of a molecule. Different polymorphs may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates and / or vibrational spectra as a result of the arrangement or conformation of the molecules in the crystal lattice. The differences in physical properties exhibited by polymorphs affectpharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in bioavailability). Polymorphs of a molecule can be obtained by a number of methods, as known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion and sublimation.COMBINATIONS OF ENPP1 INHIBITORS AND RADIOTHERAPY OR RADIOLIGANDS

[0060] The invention provides a combinational therapy that comprises: a) an ENPP1 inhibitor, for example SR-8541A; and b) a radiation therapy or a radioligand, for example, Pluvicto™.

[0061] In one embodiment, the invention provides a method for treating cancer in a subject comprising administering an effective amount of an ENPP1 inhibitor or a pharmaceutically acceptable salt thereof and a radiation therapy or a radioligand.

[0062] In a preferred embodiment, said ENPP1 inhibitor is SR-8541 A (4-(6,7- dimeth oxy quinazolin-4-yl)-l,4-diazepane-l -sulfonamide hydrochloride salt).

[0063] In one embodiment, said ENPP1 inhibitor comprises one more inhibitors selected from RBS2418, SR-8541A, TXN10128. ZX-8177, AVA-NP-695, AG-3132, STF-1623 / CM- 3163, ISM5939, GBD09259, LCB33-089, POM-1, VIR3, Ex54, QPS2, SK4A, and LCB33- 117.

[0064] In said ENPP1 inhibitor comprises one more ENPP1 inhibitors selected from all ENPP1 inhibitors disclosed in WO 2019 / 051269 Al, WO 2020 / 160333 Al, WO 2021 / 133915 Al, WO 2021 / 158829 Al, WO 2021 / 257614 Al, US 2019 / 0201423 Al, US 2021 / 0121484 Al, US 11,591,313 B2, and US 2023 / 0190927 Al, the contents of which are hereby incorporated by reference in their entirety.

[0065] The invention encompasses all ENPP1 inhibitors to be used in combination with a radiation therapy or a radioligand, even if a specific ENPP1 inhibitor is not explicitly listed inthe application. As long as a compound acts to inhibit ENPP1, it can be used for the purposes of the present invention.

[0066] In another preferred embodiment, the radioligand is selected from the group consisting of Pluvicto™ (lutetium Lu 177 vipivotide tetraxetan), zevalin, actimab-A, iomab- ACT, iomab-B, lutetium-177-DOTAGA-PEG-IAC. tozaride, SS0110, BAY-2701439,177Lu- rhPSMA-10.1, CTT-1403, lopofosine, SAR-BBN, SAR-bisPSMA, SARTATE, FAP-2286, CONV-Ol-a,177LU-PSMA-I&T, FPI-2059, FPI-1434, FPI-1966, [177LU] ludotadipep,161Tb- PSMA-I&T, ITM-31, ITM-11, JNJ-69086420, 1-131-1095, azedra, PSMA ETC / BAY- 2315497.177LU-DOTA-EB-TATE, betalutin, AAA817, AAA603, lutathera, PPMX-T002, 186RNL. PNT2003, CAM-H2. AlphaMedix, RYZ101, Sn-117m-DTPA. TLX592. TLX66, TLX250, TLX591, TLX101,124I-omburtamab, GD2-SADA,131I-omburtamab, and pharmaceutically acceptable salts thereof.

[0067] In one embodiment, radiation therapy is beam radiation therapy, also known as external beam radiation therapy (EBRT).

[0068] In another embodiment, radiation therapy is liquid radiation therapy, also known as systemic radiation therapy or radioisotope therapy, wherein the radioactive liquid is administered through a vein, by mouth, or as an injection.

[0069] In a preferred embodiment, the cancer is selected from the group consisting of breast cancer, lung cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, bladder cancer, colorectal cancer, endometrial carcinoma, kidney cancer, thyroid cancer, basal cell carcinoma, biliary tract cancer, bone cancer, brain and CNS cancer, choriocarcinoma, connective tissue cancer, esophageal cancer, eye cancer, cancer of the head and neck, gastric cancer, intra-epitheli al neoplasm, larynx cancer, lymphoma, melanoma, myeloma, neuroblastoma, oral cavity cancer, retinoblastoma, rhabdomyosarcoma, rectal cancer, cancer of the respiratory system, sarcoma, skin cancer, stomach cancer, testicular cancer, uterine cancer, and cancer of the urinary system.

[0070] The invention also provides pharmaceutical compositions comprising the combinations of the invention. In one embodiment, the combination pharmaceutical agent is itself a pharmaceutical composition.

[0071] In one embodiment, an ENPP1 inhibitor and a radioligand are formulated as a single composition.

[0072] In one embodiment, SR-8541A and lutetium Lu 177 vipivotide tetraxetan are formulated as a single composition.

[0073] In another embodiment, an ENPP1 inhibitor and a radioligand are formulated as separate compositions.

[0074] The invention also provides methods for the treatment of solid cancers comprising administering to a patient in need thereof a therapeutically effective amount of the combination pharmaceutical agents of the invention.

[0075] The invention also provides methods for the treatment of solid cancers, wherein ENPP1 inhibitors (for example, SR-8541 A) are administered prior to, or concurrently with administration of radioligands (for example, lutetium Lu 177 vipivotide tetraxetan).

[0076] In a preferred embodiment, solid cancers are selected from the group consisting of prostate cancer, lung cancer, breast cancer, glioma, squamous cell carcinoma, melanoma, renal cancer, colorectal cancer, ovarian cancer, pancreatic cancer, sarcoma, and stomach cancer.

[0077] In one embodiment, the invention provides a kit for treating cancer in a subject comprising: an ENPP1 inhibitor and instructions for administering an ENPP1 inhibitor in combination with a radiation therapy or a radioligand.

[0078] Non-limiting examples of ENPP1 compounds that can be used in the compositions and methods of the invention include compounds described in WO 2021 / 158829 (the disclosure of which is hereby incorporated by reference in its entirety):

[0079] The presently described and claimed combination pharmaceutical agents can be used for the treatment of various solid cancers, including, but not limited to, lung cancer, breast cancer, glioma, squamous cell carcinoma, prostate cancer, melanoma, renal cancer, colorectal cancer, ovarian cancer, pancreatic cancer, sarcoma, and stomach cancer.PHARMACEUTICAL COMPOSITIONS

[0080] Compositions of the present invention may be prepared as a single unit dose or as a plurality of single unit doses. As used herein, a “unit dose” means a discrete amount of the composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a patient or a fraction thereof.

[0081] It is thus contemplated that in some embodiments of the invention, an ENPP1 inhibitor and a radioligand can be present as part sof the same formulation.

[0082] In certain aspects, the disclosed pharmaceutical compositions comprise the ENPP1 inhibitors (including pharmaceutically acceptable salt(s) thereof) as one active ingredient, a pharmaceutically acceptable carrier, a radioligand, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral,rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0083] As used herein, the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non -toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium, manganese (-ic and -ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N - dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0084] As used herein, the term “pharmaceutically acceptable non-toxic acids”, includes inorganic acids, organic acids, and salts prepared therefrom, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

[0085] The pharmaceutical carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the combinations of ENPP1 inhibitors and radioligands can also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy.

[0086] Thus, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier, an ENNP1 inhibitor compound or a pharmaceutically acceptable salt of the ENPP1 inhibitor, and a radioligand. The combinations of the invention can also be included in pharmaceutical compositions in combination with additional therapeutically active compounds.

[0087] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0088] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0089] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder,lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0090] The pharmaceutical compositions of the present invention comprise an ENPP1 inhibitor as one active ingredient, a radioligand (or a radiotherapy) as the other active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0091] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0092] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0093] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the ENPP1 inhibitor, and a certain amount of a radioligand, to produce a cream or ointment having a desired consistency.

[0094] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.

[0095] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions can also be prepared in powder or liquid concentrate form.

[0096] In the treatment conditions which require inhibition or negative modulation of ENPP1 protein activity' an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day and can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg / kg per day; more preferably 0.5 to 100 mg / kg per day. A suitable dosage level can be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0. 1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg / kg per day. For oral administration, the compositions are preferably provided in the from of tablets containing 1.0 to 1000 miligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20. 25, 50, 75, 100, 150, 200, 250, 300, 400, 500. 600, 750, 800. 900 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage of the patient to be treated. The compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response.

[0097] It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors. Such factors include the age, body weight, general health, sex, and diet of the patient. Other factors include the time and route of administration,rate of excretion, drug combination, and the type and severity of the particular disease undergoing therapy.

[0098] The present invention is further directed to a method for the manufacture of a medicament for inhibiting or negatively modulating ENPP1 protein activity' (e.g., treatment of a disorder of uncontrolled cellular proliferation, or one or more neurodegenerative disorders associated with ENPP1 dysfunction) in mammals (e.g., humans) comprising combining an ENPP1 inhibitor and a radioligand, with a pharmaceutically acceptable carrier or diluent. Thus, in one aspect, the invention relates to a method for manufacturing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.METHODS FOR THE TREATMENT OF SOLID CANCERS

[0099] The invention also provides methods for the treatment of cancers comprising administering to a patient in need thereof a therapeutically effective amount of the combinations of the invention.

[0100] The combinations disclosed herein are useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders wherein the patient or subject would benefit from inhibition or negative modulation of ENPP1. In one aspect, provided is a method of treating or preventing a disorder in a subject comprising the step of administering to the subject a combination of an ENPP1 inhibitor and a radiotherapy or a radioligand in a dosage and amount effective to treat the disorder in the subject.

[0101] In one aspect, provided is a method for treating a disorder of uncontrolled cellular proliferation, comprising administering to a subject in need thereof at least one ENPP1 inhibitor, and at least one radioligand or a radiotherapy, in a dosage and amount effective to treat the disorder in the subject.

[0102] The invention is directed at the use of described chemical compositions to treat diseases or disorders in patients (preferably human) wherein ENPP1 inhibition would be predicted to have a therapeutic effect, such as disorders of uncontrolled cellular proliferation (e.g. cancers) and neurodegenerative disorders such as Alzheimer’s disease, Huntington’sdisease, and Parkinson’s disease, diseases caused by bacteria and / or viruses (including DNA and RNA viruses), by administering one or more disclosed compounds or products.

[0103] The combinations of the invention can also be used for immunotherapy. In one embodiment, the combinations of the invention treat disorders of uncontrolled cellular proliferation, and / or diseases caused by bacteria and / or viruses through immunotherapy, meaning that the compounds elicit immunotherapeutic response which results in the treatment of these diseases.

[0104] The combinations disclosed herein are useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders of uncontrolled cellular proliferation.

[0105] The radiotherapy or a radioligand can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with an ENPP1 inhibitor. When an ENPP1 inhibitor is used contemporaneously with one or more radioligands or radiotherapy, a pharmaceutical composition in unit dosage form containing both active agents can be used. However, the combination therapy can also be administered on overlapping schedules.

[0106] Examples of disorders treatable with the provided compounds include a disorder of uncontrolled cellular proliferation. In a yet further aspect, the disorder of uncontrolled cellular proliferation is cancer. In a yet further aspect, the cancer is a leukemia. In an even further aspect, the cancer is a sarcoma. In a still further aspect, the cancer is a solid tumor. In a yet further aspect, the cancer is a lymphoma.

[0107] It is understood that cancer refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. The cancer may be multi-drug resistant (MDR) or drug-sensitive. Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include breast cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, e.g., hepatic carcinoma, bladder cancer, colorectal cancer, endometrial carcinoma, kidney cancer, and thyroid cancer.

[0108] In various aspects, further examples of cancers are basal cell carcinoma, biliary tract cancer; bone cancer; brain and CNS cancer; choriocarcinoma; connective tissue cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer; intra-epithelial neoplasm; larynx cancer; lymphoma including Hodgkin’s and Non-Hodgkin’s lymphoma; melanoma; myeloma; neuroblastoma; oral cavity7cancer (e.g., lip, tongue, mouth, and pharynx); retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; sarcoma; skin cancer; stomach cancer; testicular cancer; uterine cancer; cancer of the urinary system, as well as other carcinomas and sarcomas

[0109] In a further aspect, the cancer is a hematological cancer. In a still further aspect, the hematological cancer is selected from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy7cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), Hodgkin lymphoma, Non-Hodgkin lymphoma, multiple myeloma, solitary myeloma, localized myeloma, and extramedullary myeloma. In a still further aspect, the cancer is selected from chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell non-Hodgkin lymphoma, and large B-cell lymphoma.

[0110] In a further aspect, the cancer is a cancer of the brain. In a still further aspect, the cancer of the brain is selected from a glioma, medulloblastoma, primitive neuroectodermal tumor (PNET), acoustic neuroma, glioma, meningioma, pituitary adenoma, schwannoma, CNS lymphoma, primitive neuroectodermal tumor, craniopharyngioma, chordoma, medulloblastoma, cerebral neuroblastoma, central neurocytoma, pineocytoma, pineoblastoma. atypical teratoid rhabdoid tumor, chondrosarcoma, chondroma, choroid plexus carcinoma, choroid plexus papilloma, craniopharyngioma, dysembryoplastic neuroepithelial tumor, gangliocytoma, germinoma, hemangioblastoma, hemangiopercytoma, and metastatic brain tumor. In a yet further aspect, the glioma is selected from ependymoma, astrocytoma, oligodendroglioma, and oligoastrocytoma. In an even further aspect, the glioma is selected from juvenile pilocytic astrocytoma, subependymal giant cell astrocytoma, ganglioglioma, subependymoma, pleomorphic xanthoastrocytom, anaplastic astrocytoma, glioblastoma multiforme, brain stem glioma, oligodendroglioma, ependymoma, oligoastrocytoma, cerebellar astrocytoma, desmoplastic infantile astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, mixed glioma, optic glioma, gliomatosis cerebri,multifocal gliomatous tumor, multicentric glioblastoma multiforme tumor, paraganglioma, and ganglioglioma.

[0111] In one aspect, the cancer can be a cancer selected from cancers of the blood, brain, genitourinary tract, gastrointestinal tract, colon, rectum, breast, kidney, lymphatic system, stomach, lung, pancreas, and skin. In a further aspect, the cancer is selected from prostate cancer, glioblastoma multiforme, endometrial cancer, breast cancer, and colon cancer. In a further aspect, the cancer is selected from a cancer of the breast, ovary, prostate, head, neck, and kidney. In a still further aspect, the cancer is selected from cancers of the blood, brain, genitourinary tract, gastrointestinal tract, colon, rectum, breast, livery, kidney, lymphatic system, stomach, lung, pancreas, and skin. In a yet further aspect, the cancer is selected from a cancer of the lung and liver. In an even further aspect, the cancer is selected from a cancer of the breast, ovary , testes and prostate. In a still further aspect, the cancer is a cancer of the breast. In a yet further aspect, the cancer is a cancer of the ovary. In an even further aspect, the cancer is a cancer of the prostate. In a still further aspect, the cancer is a cancer of the testes.

[0112] In various aspects, disorders associated with an ENPP1 dysfunction include neurodegenerative disorders. In a further aspect, the neurodegenerative disease is selected from Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

[0113] The combinations are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The combinations are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.

[0114] It was unexpected and surprising that a combination of an ENPP1 inhibitor and a radiotherapy showed synergistic results.EXAMPLESEXAMPLE 1A Pilot Animal Study Of A Combination Or A Radioligand Therapy (RLT) And ENPP1 Inhibitor For The Treatment Of Prostate Cancer.Experimental methods:

[0115] Mice bearing subcutaneous RM1-PGLS tumors were used to study effect of a combination of an RLT therapy and ENPP1 inhibitor (n=20, 4 / group).

[0116] Animals were administered RM1-PGLS subcutaneous injection. About 2 weeks after the injection, verification of target expression using PET / CT or SPECT / CT was conducted, and mice with negative PET / SPECT were excluded. Then, the mice were divided into four groups as follows:

[0117] The NT group was not administered any cancer treatment therapy.

[0118] The ENPPli group was administered 0.2 mg / kg SR-8541A BID for 14 days, starting on Day -1.

[0119] The RLT group was administered 60 MBq177Lu-PSMA on Day 0.

[0120] The combination ENPPli. / RLT group was administered both .2 mg / kg SR-8541 ABID for 14 days, starting on Day -1 and 60 MBq177Lu-PSMA on Day 0.Results:

[0121] The results are shown in Figures 1A-1F.

[0122] Fig. 1 A is a graph showing tumor grow th inhibition (TGI) in various treatment groups (not treated (NT), ENPPli, radioligand therapy (RLT), RLT+ENPPli) in prostate cancer models.

[0123] Fig. IB is a graph of tumor volume vs time for the NT group.

[0124] Fig. 1C is a graph of tumor volume vs time for the ENPPli group.

[0125] Fig. ID is a graph of tumor volume vs time for the RLT group.

[0126] Fig. IE is a graph of tumor volume vs time for the combination of ENPPli andRLT group.

[0127] Fig. IF is a time to progression (TTP) graph of the NT, ENPPli, RLT, and the combination of RLT and ENPPli groups.

[0128] The results demonstrate that a combination of Pluvicto™ and SR-8541A resulted in a strong synergistic effect compared to administering these agents alone.EXAMPLE 2Administering SR-8541A and Radiation Therapy Resulted in Abscopal Tumor responseExperimental methods:

[0129] The experiment was conducted as follows. 6 groups consisting of 10 female C57BL / 6 mice per group were subcutaneously injected in the right hind flank with 5 x 106 MC38 cells. Two additional groups were implanted bilaterally to allow for evaluation of abscopal effect. Tumor growth was monitored by caliber measurements three times per week. Body weights of animals were measured three times per week and dosing holidays, if needed, were added for animals to recover body weight. Groups were treated with vehicle or SR- 8541 A (25 or 50 mg / kg) IP twice daily for the first 5 days, followed by every’ other day for the remainder of the study. 10 Gy radiation was given once on day 18. For the bilateral abscopal groups, 10 Gy radiation was given to the right tumor only on day 19 and mice were treated with 50 mg / kg SR-8541 A IP as described above. The endpoint of the experiment w as when the tumors reached 2000 mm3 or at the end of the study on Day 31 .Results:

[0130] Abscopal effect occurs when radiation treatment not only shrinks the targeted tumor, but also leads to the shrinkage of untreated tumors elsewhere in the body. Although the precise biological mechanisms responsible for the abscopal effect are still being investigated, the immune system is thought to play an important role.

[0131] Figs. 2A-2B are graphs of a normalized tumor volume vs time in the vehicle, radiation only, SR-8541 A only, and the combination of radiation and SR-8541 A groups, where Fig 2A represents the 25 mg / kg dose of SR-8541 A and Fig. 2B represents the 50 mg / kg dose of SR-8541 A.

[0132] Fig. 2C shows abscopal effect of administering a combination of radiation and SR-8541 A treatment. SR-8541 A was administered to the right flank while the left flank was dosed with 10 Gy radiation. The abscopal effect was observed.

[0133] Thus, a combination of SR-8541A with focal radiation showed strong effect both in the primary and abscopal tumors.EXAMPLE 3Murine Colon Carcinoma (MC38) Efficacy StudyExperimental methods:

[0134] The experiment was conducted as follows. The animals were divided into four groups: vehicle (no treatment); radiation only (10 Gy); SR-8541A (50 mg / kg) IP BID; and a combination of radiation and SR-8541 A (50 mg / kg) IP BID. The expression of ARG1 (M2 marker) and INOS (Ml marker) was measured.Results:

[0135] Fig. 3 A shows results of a MC38 efficacy study, where ARG1 expression, M2 marker, was measured for radiation only, SR-8541 A only, and the combination of radiation and SR-8541 A groups.

[0136] Fig. 3B shows results of a MC38 efficacy study, where INOS expression. Ml marker, was measured for radiation only, SR-8541 A only, and the combination of radiation and SR-8541 A groups.

[0137] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary’ skill in the art in light of the teachings of the specification that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A method for treating cancer in a subj ect comprising administering an effective amount of an ENPP1 inhibitor or a pharmaceutically acceptable salt thereof and a radiation therapy or a radioligand.

2. The method of claim 1, wherein the ENPP1 inhibitor is selected from the group consisting of3. The method of claim 1, wherein the ENPP1 inhibitor is SR-8541A (4-(6,7- dimethoxyquinazolin-4-yl)-l,4-diazepane-l-sulfonamide hydrochloride salt).

4. The method of claim 1, wherein the ENPP1 inhibitor comprises one more inhibitors selected from RBS2418, SR-8541A, TXN10128, ZX-8177, AVA-NP-695, AG-3132, STF- 1623 / CM-3163, ISM5939. GBD09259, LCB33-089, POM-1, VIR3, Ex54, QPS2, SK4A, and LCB33-117.

5. The method of claim 1, wherein the radioligand is selected from the group consisting of Pluvicto™ (lutetium Lu 177 vipivotide tetraxetan), zevalin, actimab-A, iomab-ACT, iomab-B. lutetium- 177-DOTAGA-PEG-IAC, tozaride, SSO11O, BAY-2701439,177Lu- rhPSMA-10.1, CTT-1403, iopofosine, SAR-BBN, SAR-bisPSMA, SARTATE, FAP-2286, CONV-Ol-a,177LU-PSMA-I&T, FPI-2059, FPI-1434, FPI-1966, [177LU] ludotadipep,161Tb- PSMA-I&T, ITM-31, ITM-11, JNJ-69086420, 1-131-1095, azedra, PSMA TTC / BAY-2315497,177LU-DOTA-EB-TATE, betalutin, AAA817, AAA603, lutathera, PPMX-T002, 186RNL. PNT2003, CAM-H2. AlphaMedix, RYZ101, Sn-117m-DTPA. TLX592. TLX66, TLX250, TLX591, TLX101,124I-omburtamab, GD2-SADA,131I-omburtamab, and pharmaceutically acceptable salts thereof.

6. The method of claim 1, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, bladder cancer, colorectal cancer, endometrial carcinoma, kidney cancer, thyroid cancer, basal cell carcinoma, biliary tract cancer, bone cancer, brain and CNS cancer, choriocarcinoma, connective tissue cancer, esophageal cancer, eye cancer, cancer of the head and neck, gastric cancer, intra-epitheli al neoplasm, larynx cancer, lymphoma, melanoma, myeloma, neuroblastoma, oral cavity cancer, retinoblastoma, rhabdomyosarcoma, rectal cancer, cancer of the respiratory system, sarcoma, skin cancer, stomach cancer, testicular cancer, uterine cancer, and cancer of the urinary system.

7. The method of claim 1, wherein the ENPP1 inhibitor is SR-8541A and wherein the radioligand is Pluvicto™ (lutetium Lu 177 vipivotide tetraxetan).

8. The method of claim 7, wherein the cancer is prostate cancer.

9. The method of claim 1, wherein the ENPP1 inhibitor and the radiation therapy or the radioligand are administered simultaneously.

10. The method of claim 1, wherein the ENPP1 inhibitor and the radiation therapy or the radioligand are administered sequentially.

11. A pharmaceutical composition for the treatment of cancer comprising an ENPP 1 inhibitor and a radioligand, wherein the ENPP1 inhibitor and the radioligand are formulated as a single composition.

12. The pharmaceutical composition of claim 11, wherein the ENPP1 inhibitor is SR- 8541 A.

13. The pharmaceutical composition of claim 11, wherein the radioligand is Pluvicto™.

14. A kit for treating cancer in a subject comprising: an ENPP1 inhibitor and instructions for administering an ENPP 1 inhibitor in combination with a radiation therapy or a radioligand.

15. The kit of claim 14, wherein the ENPP1 inhibitor is SR8541A.

16. The kit of claim 14, wherein the radioligand is Pluvicto™.

Images