Use of PCLX-001 or PCLX-002 as a radiosensitizer

Abstract

Described herein is the use of PCLX-001, PCLX-002, or a pharmaceutically acceptable salt thereof, as a radiosensitizer for cancer cells in a subject in need of radiation therapy. The radiosensitizer is administered to a subject undergoing radiation therapy for cancer, particularly a brain cancer such as astrocytoma, glioma, embryonal tumor, non-malignant brain tumor, pediatric brain tumor, or metastatic tumor. The radiosensitizer is administered at a dosage that achieves a blood, target organ, or tumor drug concentration in the range of about 50 nM to about 150 nM.

Description

[Technical Field]

[0001] The present disclosure generally relates to the use of PCLX-001 or PCLX-002 as a radiosensitizer. [Background technology]

[0002] Approximately half of cancer patients are treated with radiation therapy, either alone or in combination with other types of cancer treatment. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2010 / 026365 [Non-patent literature]

[0004] [Non-Patent Document 1] Freshney, RI, 2010. Culture of animal cells: a manual of basic techniques and specialized applications. John Wiley & Sons [Non-patent document 2] Hall, EJ, Giaccia, AJ, 2012. Radiobiology for the radiologist. Lippincott Williams & Wilkins. [Non-patent document 3] Pardridge, WM, 2005. The blood-brain barrier: bottleneck in brain drug development. NeuroRx, 2(1), pp. 3-14. Summary of the Invention [Problem to be solved by the invention]

[0005] There remains a need for radiosensitizers in the treatment of subjects with cancer. [Means for solving the problem]

[0006] In one aspect, a method of radiosensitizing cancer cells in a subject in need of radiation therapy is provided, comprising administering to the subject a compound or PCLX-001, or a pharmaceutically acceptable salt thereof.

[0007] In one aspect, a method of radiosensitizing cancer cells in a subject in need of radiation therapy is provided, comprising administering to the subject a compound of PCLX-001, or a pharmaceutically acceptable salt thereof.

[0008] In one example, the radiation therapy is external radiation therapy, internal radiation therapy, or systemic radiation therapy.

[0009] In one example, the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; small intestine cancer; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

[0010] In one example, the subject is a human.

[0011] In one aspect, a method of treating a subject having, suspected of having, or at risk of developing cancer is provided, comprising administering a radiosensitizer that is PCLX-001 and administering radiation therapy.

[0012] In one example, the radiation therapy is external radiation therapy, internal radiation therapy, or systemic radiation therapy.

[0013] In one example, the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; small intestine cancer; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

[0014] In one example, the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

[0015] In one example, the astrocytoma is an anaplastic astrocytoma, a diffuse astrocytoma, a pilocytic astrocytoma, or a glioblastoma.

[0016] In one example, the glioma is a diffuse midline glioma, an oligodendroglioma, an ependymoma, or a visual pathway glioma.

[0017] In one example, the embryonal tumor is an atypical teratoid / rhaboid (AT / RT) or a medulloblastoma.

[0018] In one example, the non-malignant brain tumor is an acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

[0019] In one example, the pediatric brain tumor is an atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

[0020] In one example, the method further includes administering one or more drugs for treating brain cancer, including methotrexate, vinca alkaloids, carmustine, cisplatin, carboplatin, nitrosoureas, hydroxyurea, cyclophosphamide, etoposide, procarbazine, irinotecan, lomustine, vincristine, and / or conjugates of temozolomide.

[0021] In one example, the subject is a human.

[0022] As described herein, the following embodiments are also provided:

[0023] 1. Use of PCLX-001, or a pharmaceutically acceptable salt thereof, to radiosensitize cancer cells in a subject in need of radiation therapy.

[0024] 2. Use of PCLX-001, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for radiosensitizing cancer cells in a subject in need of radiation therapy.

[0025] 3. The use according to embodiment 1 or 2, wherein said radiotherapy is external radiotherapy, internal radiotherapy or systemic radiotherapy.

[0026] 4. The use of any one of embodiments 1 to 3, wherein the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; cancer of the small intestine; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

[0027] 5. The use of embodiment 4, wherein the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

[0028] 6. The use of embodiment 5, wherein the astrocytoma is anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, or glioblastoma.

[0029] 7. The use of embodiment 5, wherein the glioma is a diffuse midline glioma, oligodendroglioma, ependymoma, or visual pathway glioma.

[0030] 8. The use of embodiment 5, wherein the embryonal tumor is an atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

[0031] 9. The use of embodiment 5, wherein the non-malignant brain tumor is an acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

[0032] 10. The use of embodiment 5, wherein the pediatric brain tumor is an atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

[0033] 11. The use according to any one of the preceding embodiments, wherein the subject is a human.

[0034] 12. The use according to any one of the preceding embodiments, wherein the compound PCLX-001 or a pharmaceutically acceptable salt thereof is in a dosage range of about 50 nM to about 150 nM.

[0035] 13. Use of a radiosensitizer that is PCLX-001, and use of radiation therapy, to treat a subject who has cancer, is suspected of having cancer, or is at risk of developing cancer.

[0036] 14. Use of a radiosensitizer that is PCLX-001 in the manufacture of a medicament for treating a subject with cancer, a subject suspected of having cancer, or a subject at risk of developing cancer, and use of radiation therapy.

[0037] 15. The use according to embodiment 13 or 14, wherein said radiotherapy is external radiotherapy, internal radiotherapy or systemic radiotherapy.

[0038] 16. The use of any one of embodiments 13 to 15, wherein the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; cancer of the small intestine; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

[0039] 17. The use of embodiment 16, wherein the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

[0040] 18. The use according to embodiment 17, wherein the astrocytoma is anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, or glioblastoma.

[0041] 19. The use according to embodiment 17, wherein the glioma is a diffuse midline glioma, an oligodendroglioma, an ependymoma, or a visual pathway glioma.

[0042] 20. The use of embodiment 17, wherein the embryonal tumor is an atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

[0043] 21. The use of embodiment 17, wherein the non-malignant brain tumor is an acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

[0044] 22. The use of embodiment 17, wherein the pediatric brain tumor is atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

[0045] 23. The use of any one of embodiments 13 to 22, further comprising use of one or more drugs for treating brain cancer, including methotrexate, vinca alkaloids, carmustine, cisplatin, carboplatin, nitrosoureas, hydroxyurea, cyclophosphamide, etoposide, procarbazine, irinotecan, lomustine, vincristine, and / or conjugates of temozolomide.

[0046] 24. The use of any one of embodiments 13 to 22, further comprising the use of one or more drugs in the manufacture of a medicament for treating brain cancer, including methotrexate, vinca alkaloids, carmustine, cisplatin, carboplatin, nitrosourea, hydroxyurea, cyclophosphamide, etoposide, procarbazine, irinotecan, lomustine, vincristine, and / or conjugates of temozolomide.

[0047] 25. The use according to any one of embodiments 13 to 24, wherein the subject is a human.

[0048] 26. The use according to any one of embodiments 13 to 23, comprising use of a radiosensitizer at a dosage that achieves a blood or target organ or tumor drug concentration in the range of about 50 nM to about 150 nM.

[0049] 27. The use of any one of embodiments 13 to 26, comprising the use of a radiosensitizer at time A and the use of radiation therapy at time B to achieve a target dosage range of blood or target organ or tumor drug concentrations of about 50 nM to about 150 nM at the site of cancer or potential cancer.

[0050] 28. The use of embodiment 27, wherein when administering a radiosensitizer at time A includes orally administering the radiosensitizer, time B is about 2 hours to about 4 hours after time A.

[0051] 29. The use of embodiment 27, wherein when administering a radiosensitizer at time A comprises initiating radiosensitizer therapy, time B is about 72 hours after time A.

[0052] 30. The use of any one of embodiments 1 to 29, wherein the step of administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier.

[0053] 31. The use of embodiment 30, wherein the use of PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier and acts as a radiosensitizer against primary brain tumors.

[0054] 32. The use of embodiment 30 or 31, wherein the use of PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier approximately 4 hours after administration and acts as a radiosensitizer against primary brain tumors.

[0055] 33. The use of any one of embodiments 30 to 32, wherein the use of PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier and acts as a radiosensitizer against secondary brain tumors.

[0056] 34. The use of any one of embodiments 30 to 33, wherein the use of PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier approximately 4 hours after administration and acts as a radiosensitizer against secondary brain tumors.

[0057] 35. The use according to any one of embodiments 13 to 34, wherein if the patient is using a proton pump inhibitor, the patient discontinues use of the proton pump inhibitor prior to the radiosensitizer and radiotherapy treatment.

[0058] 36. A method of radiosensitizing cancer cells in a subject in need of radiation therapy, comprising administering to the subject the compound PCLX-001, or a pharmaceutically acceptable salt thereof.

[0059] 37. The method of embodiment 36, wherein said radiation therapy is external radiation therapy, internal radiation therapy, or systemic radiation therapy.

[0060] 38. The method of embodiment 36 or 37, wherein the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; small intestine cancer; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

[0061] 39. The method of embodiment 38, wherein the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

[0062] 40. The method of embodiment 39, wherein the astrocytoma is anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, or glioblastoma.

[0063] 41. The method of embodiment 39, wherein the glioma is a diffuse midline glioma, an oligodendroglioma, an ependymoma, or a visual pathway glioma.

[0064] 42. The method of embodiment 39, wherein the embryonal tumor is an atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

[0065] 43. The method of embodiment 39, wherein the non-malignant brain tumor is an acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

[0066] 44. The method of embodiment 39, wherein the pediatric brain tumor is an atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

[0067] 45. The method of any one of embodiments 36 to 44, wherein the subject is a human.

[0068] 46. ​​The method according to any one of embodiments 36 to 45, comprising administering the compound PCLX-001 in a dosage range of about 50 nM to about 150 nM.

[0069] 47. A method for treating a subject having, suspected of having, or at risk of developing cancer, comprising administering a radiosensitizer that is PCLX-001 and performing radiation therapy.

[0070] 48. The method of embodiment 47, wherein the radiation therapy is external radiation therapy, internal radiation therapy, or systemic radiation therapy.

[0071] 49. The method of embodiment 47 or 48, wherein the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; small intestine cancer; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

[0072] 50. The method of embodiment 49, wherein the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

[0073] 51. The method of embodiment 50, wherein the astrocytoma is anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, or glioblastoma.

[0074] 52. The method of embodiment 50, wherein the glioma is a diffuse midline glioma, an oligodendroglioma, an ependymoma, or a visual pathway glioma.

[0075] 53. The method of embodiment 50, wherein the embryonal tumor is an atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

[0076] 54. The method of embodiment 50, wherein the non-malignant brain tumor is an acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

[0077] 55. The method of embodiment 50, wherein the pediatric brain tumor is an atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

[0078] 56. The method of any one of embodiments 48 to 55, further comprising administering one or more drugs for treating brain cancer, including methotrexate, vinca alkaloids, carmustine, cisplatin, carboplatin, nitrosoureas, hydroxyurea, cyclophosphamide, etoposide, procarbazine, irinotecan, lomustine, vincristine, and / or conjugates of temozolomide.

[0079] 57. The method of any one of embodiments 48 to 56, wherein the subject is a human.

[0080] 58. The method according to any one of embodiments 48 to 57, comprising administering the radiosensitizer at a dosage that achieves a blood or target organ or tumor drug concentration in the range of about 50 nM to about 150 nM.

[0081] 59. The method of any one of embodiments 48 to 58, comprising administering a radiosensitizer at time A and administering radiation therapy at time B to achieve a target dosage range of blood or target organ or tumor drug concentration of about 50 nM to about 150 nM at the cancer site or potential cancer site.

[0082] 60. The method of embodiment 59, wherein when administering a radiosensitizer at time A includes orally administering the radiosensitizer, time B is about 2 hours to about 4 hours after time A.

[0083] 61. The method of embodiment 59, wherein when administering a radiosensitizer at time A includes initiating radiosensitizer therapy, time B is about 72 hours after time A.

[0084] 62. The method of any one of embodiments 36 to 61, wherein administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier.

[0085] 63. The method of embodiment 62, wherein the step of administering PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier and acts as a radiosensitizer against primary brain tumors.

[0086] 64. The method of embodiment 62 or 63, wherein the step of administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier approximately 4 hours after administration and acting as a radiosensitizer against primary brain tumors.

[0087] 65. The method of any one of embodiments 62 to 64, wherein the step of administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier and acting as a radiosensitizer against secondary brain tumors.

[0088] 66. The method of any one of embodiments 26 to 65, wherein the step of administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier approximately 4 hours after administration and acting as a radiosensitizer against secondary brain tumors.

[0089] 67. The method according to any one of embodiments 47 to 66, wherein if the patient is using a proton pump inhibitor, the patient discontinues use of the proton pump inhibitor prior to the radiosensitizer and radiation therapy treatment.

[0090] Embodiments of the present disclosure will now be described, by way of example only, with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0091] [Figure 1] FIG. 1 shows the structure of PCLX-001. [Figure 2] FIG. 1 shows the structure of PCLX-002. [Figure 3]Figure 1 shows a graph depicting cell viability and survival of the U251 glioblastoma cell line in response to radiation therapy, as well as an Alamar Blue-based colorimetric assay measuring the gradient of PCLX-001 drug concentration. Drug was administered 72 hours prior to radiation, and viability was assayed 72 hours after radiation. DETAILED DESCRIPTION OF THE INVENTION

[0092] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0093] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0094] As used herein, the term "comprising" is understood to mean that the following list is not exhaustive and may or may not include any other additional suitable items, such as one or more further features, components and / or ingredients, as appropriate.

[0095] As described in more detail below, in some aspects, compounds, compositions, methods and / or kits are described for increasing the sensitivity of cells and / or tumors to ionizing radiation.

[0096] As discussed in more detail below, PCLX-001 (also known as DDD86481) and its uses are described.

[0097] The structure of PCLX-001 is as follows (see Figure 1):

[0098] [ka]

[0099] The structure of DDD85646 (PCLX-002) is as follows (see Figure 2):

[0100] [ka]

[0101] PCLX-001 (also known as DDD86481) and PCLX-002 (also known as DDD85646) are described in WO 2010 / 026365.

[0102] In one aspect, radiosensitizers and / or compositions comprising radiosensitizers are provided.

[0103] In a specific example, the radiosensitizer can be PCLX-001 (also known as DDD86481).

[0104] In a specific example, the radiosensitizer can be PCLX-002 (also known as DDD85646).

[0105] Examples of known radiosensitizers include, but are not limited to, nitrosoureas such as carmustine (BCNU) or lomustine (CCNU), platinum-based drugs, and anthracyclines such as doxorubicin, and topoisomerase inhibitors such as etoposide.

[0106] The term "radiosensitizer," as used herein, refers to an agent, molecule, compound, or composition that increases the sensitivity of neoplastic cells, cancer cells, and / or tumors to the effects of radiation. The "sensitivity" of neoplastic cells, cancer cells, and / or tumors to radiation is the susceptibility of the neoplastic cells, cancer cells, and / or tumors to the inhibitory effects of radiation on the growth and / or viability of the cells or tumors.

[0107] In particular embodiments, radiosensitizers are compounds and / or compositions that can increase the sensitivity of cells and / or tumors to radiation.

[0108] In some instances, "radiosensitization" refers to making a cell more sensitive to radiation. Radiosensitizing a cell prior to radiation treatment can increase its sensitivity to radiation compared to cells that have not been radiosensitized prior to radiation treatment.

[0109] In some cases, radiosensitizers can increase the effectiveness of radiation therapy, reduce the side effects of radiation therapy, or improve the overall response to treatment.

[0110] In some aspects, there is provided the use of radiosensitizers and radiation therapy in treating subjects with cancer, suspected of having cancer, or at risk of developing cancer.

[0111] Examples of radiation therapy include, but are not limited to, chest radiation, radiation to bone metastases, radiation to lymph node metastases, radiation to adrenal metastases, radiation to liver metastases, radiation to primary brain tumors, radiation to primary brain cancers, radiation to cancers metastasizing to the brain, and the like.

[0112] In one example, there may be provided the use of PCLX-001 (also known as DDD86481) and radiation therapy in treating a subject with cancer, a subject suspected of having cancer, or a subject at risk of developing cancer.

[0113] In one example, there is provided the use of PCLX-002 (also known as DDD85646) and radiation therapy in treating a subject with cancer, a subject suspected of having cancer, or a subject at risk of developing cancer.

[0114] The term "subject," as used herein, refers to an animal and may include, for example, domestic animals, such as cats, dogs, etc., livestock (e.g., cows, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mice, rabbits, rats, guinea pigs, etc.), mammals, non-human mammals, primates, non-human primates, rodents, birds, reptiles, amphibians, fish, and any other animals.

[0115] In a specific example, the subject is a human.

[0116] As used herein, the term "treatment" or "treating" refers to obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, diminishment of the extent of the disease, stabilized (i.e., not worsening) disease, prevention of disease spread, delay or slowing of disease progression, improvement or palliation of the disease state, diminished recurrence of disease, and remission (whether partial or total). "Treating" and "treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. As used herein, "treating" and "treatment" also include prophylactic treatment.

[0117] The terms "prevent" or "prevention" refer to prophylactic or preventative measures that prevent and / or slow the onset of a targeted condition or disorder, such as cancer. Thus, those in need of prevention include those at risk of developing the disorder or those susceptible to developing the disorder. In certain embodiments, the disease or disorder is successfully prevented, either temporarily or permanently, by the methods provided herein, when the patient develops, e.g., results in less frequent or less severe symptoms associated with the disease or disorder, or a later onset of symptoms associated with the disease or disorder, than in a patient not subjected to the methods of the invention.

[0118] In some cases, treatment results in preventing or delaying the onset of symptoms of a disease or ameliorating symptoms, or achieving a desired biological outcome in a subject.

[0119] As used herein, the term "diagnosis" refers to the identification of a molecular and / or pathological state, disease or condition, for example, the identification of cancer.

[0120] As used herein, the term "ameliorate" refers to the diminishment, reduction, or elimination of a condition, disease, disorder, or phenotype, including an abnormality or symptom.

[0121] The term "cancer," as used herein, refers to a variety of conditions resulting from the abnormal, uncontrolled growth of cells. Cells that can give rise to cancer, termed "cancer cells," have characteristic properties such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and / or certain typical morphological features. Cancer cells can be in the form of a tumor, but such cells can also exist alone in a subject or can be non-tumorigenic cancer cells.

[0122] Cancer can be detected in any of several ways, including, but not limited to, detecting the presence of one or more tumors (e.g., by clinical or radiological methods), examining cells within a tumor or from another biological sample (e.g., from a tissue biopsy), measuring blood markers indicative of cancer, and detecting genotypes indicative of cancer. However, a negative result from one or more of the above detection methods does not necessarily indicate the absence of cancer; for example, a patient who exhibits a complete response to cancer treatment may still have cancer, as evidenced by a subsequent recurrence.

[0123] It is generally understood that determining disease severity requires identifying certain disease characteristics, such as whether the cancer is pre-metastatic or metastatic, the stage and / or grade of the cancer, etc.

[0124] Staging is a process used to describe how advanced a cancer is in a subject. Staging can be important for determining prognosis, planning treatment, and evaluating the results of such treatment. Although different cancer staging systems may need to be used for different types of cancer, most staging systems generally involve describing how far the cancer has spread anatomically and attempt to place subjects with similar prognosis and treatment into the same staging group.

[0125] Examples of common staging systems used for many solid tumors and some leukemias and lymphomas are the Overall Stage Grouping system and the TMN system. Overall staging systems use Roman numerals I through IV to indicate four stages of cancer. Generally, stage I refers to cancer that has not spread to any lymph nodes and is detectable only in the area of ​​the primary tumor. Stage II and stage III cancers generally are locally advanced and / or have spread to regional lymph nodes. For example, stage II refers to cancer that is locally advanced and has spread only to the nearest lymph nodes. In stage III, cancer is locally advanced and has generally spread to lymph nodes close to the site of the primary tumor. Cancer that has metastasized from the primary tumor to distant parts of the body, such as the liver, bone, brain, or another site, is called stage IV and is the most advanced stage. Thus, stage I cancers are generally small, localized cancers that are treatable, while stage IV cancers usually represent inoperable or metastatic cancers. As with other staging systems, the prognosis for a given stage and treatment often depends on the type of cancer. For some cancers, classification into four prognostic groups is insufficient, and the overall staging system is further divided into subgroups. In contrast, some cancers may have fewer than four stages.

[0126] Cancer that recurs after all visible tumor has been eradicated is generally referred to as recurrent disease, with local recurrence occurring at the site of the primary tumor and distant recurrence representing distant metastasis.

[0127] Variations on the staging system can depend on the type of cancer. Furthermore, for a particular type of cancer, the staging system for an individual cancer can be revised with new information, and the resulting stage can subsequently alter the prognosis and treatment of a particular cancer.

[0128] The "grade" of a cancer can be used to describe how similar a tumor is to normal tissue of the same type. Based on the microscopic appearance of a tumor, pathologists identify the grade of the tumor based on parameters such as cell morphology, cell organization, and other markers of differentiation. As a general rule, the grade of a tumor corresponds to its rate of growth or invasiveness, and tumors are typically classified as minimally invasive (Grade I) to most invasive (Grade IV).

[0129] Therefore, the higher the grade, the more aggressive and fast-growing the cancer. Information about tumor grade is useful for planning treatment and predicting prognosis.

[0130] In one example, the cancer is brain cancer.

[0131] In some instances, the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

[0132] Examples of astrocytomas include, but are not limited to, anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, or glioblastoma.

[0133] Examples of gliomas include, but are not limited to, diffuse midline glioma, oligodendroglioma, ependymoma, or visual pathway glioma.

[0134] Examples of embryonal tumors include, but are not limited to, atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

[0135] Examples of non-malignant brain tumors include, but are not limited to, acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

[0136] Examples of pediatric brain tumors include, but are not limited to, atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

[0137] Examples of other brain tumors and related conditions include, but are not limited to, brain cysts, dysembryoplastic neuroepithelial tumors (DNETs), germ cell tumors, subependymoma, neurofibromatosis type I, pineal tumors, chordoma, ganglioneuroblastoma, neurofibromatosis type 2, or tuberous sclerosis complex (TSC).

[0138] The brain cancer can be a primary or secondary brain cancer.

[0139] In one example, a "primary brain cancer" is an intracranial cancer of central nervous system cells.

[0140] "Secondary brain cancer" is a cancer located in the central nervous system comprising cells that have metastasized from other areas of the body, including, but not limited to, solid tumor cancer, breast cancer, lung cancer, colorectal cancer, endometrial cancer, ovarian cancer, testicular cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, adrenal cortical cancer, non-Hodgkin's lymphoma, multiple myeloma, leukemia, Kaposi's sarcoma, Ewing's sarcoma, soft tissue sarcoma, nephroblastoma, glioblastoma multiforme, prostate cancer, liver cancer, bone cancer, chondrosarcoma, kidney cancer, bladder cancer, and gastric cancer.

[0141] In some instances, the brain cancer is primary brain cancer. In some instances, the brain cancer is metastatic brain cancer.

[0142] In some cases, in the case of lymphoma, stage I refers to lymphoma in only one group of lymph nodes. Stage II refers to two or more groups of lymph nodes being affected, but either all above or below the diaphragm, all in the chest, or all in the abdomen. Stage III refers to two or more groups of lymph nodes being affected in both the chest and the abdomen. Stage IV refers to lymphoma present in at least one organ (e.g., bone marrow, liver, or lung) as well as in the lymph nodes. Additional designations can be added to the aforementioned stages. For example, "A" generally means that the patient is not experiencing any troublesome symptoms. "B" means that the patient is experiencing B symptoms (e.g., fever, night sweats, weight loss). X means that the patient has bulky disease (e.g., a large tumor over 10 cm in size). E means that the patient has extranodal disease (e.g., disease outside the lymph nodes).

[0143] In some cases, radiosensitizers can be used in the treatment of breast cancer, head and neck cancer, prostate cancer, pancreatic cancer, or lymphoma.

[0144] In some cases, radiosensitizers may be used to treat anaplastic large cell lymphoma, acute myeloid leukemia, blastic phase chronic myeloid leukemia, Burkitt's lymphoma, plasma cell myeloma, intestinal adenocarcinoma, intestinal squamous cell carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, mixed adenosquamous carcinoma of the lung, small cell lung carcinoma, lung, esophageal squamous cell carcinoma, bone, ductal carcinoma, lobular carcinoma of the breast, diffuse gastric adenocarcinoma, medullary thyroid carcinoma, transitional cell carcinoma of the urinary tract, ovarian myeloma, and ovarian myeloma. It can be used in the treatment of clear cell carcinoma, transitional cell carcinoma (ureter and bladder cancer), neuroendocrine carcinoma, chronic myeloid leukemia (CML), lymphoma-CLL, breast carcinoma, colorectal adenocarcinoma, pancreatic adenocarcinoma, ovarian carcinoma, non-small cell lung carcinoma, osteosarcoma, melanoma, gastric adenocarcinoma, endometrial adenocarcinoma, cholangiocarcinoma (bile duct cancer), gallbladder cancer, liver cancer, esophageal squamous cell carcinoma, or primary brain cancer and primary brain tumors.

[0145] In some cases, radiosensitizers can be used in the treatment of brain cancer, including astrocytoma, glioma, ganglioneuroma, ganglioglioma, ependymoma, meningioma, primary CNS lymphoma, neuroblastoma, embryonal tumor, non-malignant brain tumor, pediatric brain tumor, or metastatic tumor.

[0146] In some cases, radiosensitizers can be used in the treatment of anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, xanthoastrocytoma, or glioblastoma.

[0147] In some cases, radiosensitizers can be used in the treatment of diffuse midline glioma, oligodendroglioma, ependymoma, or visual pathway glioma.

[0148] In some cases, radiosensitizers can be used in the treatment of atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

[0149] In some cases, radiosensitizers can be used in the treatment of acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

[0150] In some cases, radiosensitizers can be used in the treatment of atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

[0151] In some cases, radiosensitizers can be used in the treatment of brain cysts, dysembryoplastic neuroepithelial tumors (DNETs), germ cell tumors, subependymoma, neurofibromatosis type I, pineal tumors, chordoma, ganglioneuroblastoma, neurofibromatosis type 2, or tuberous sclerosis complex (TSC).

[0152] In some cases, radiosensitizers can be used in the treatment of primary or secondary brain cancers.

[0153] In some cases, radiosensitizers can be used in the treatment of intracranial cancers of central nervous system cells.

[0154] In some cases, radiosensitizers can be used in the treatment of cancers located in the central nervous system, including cells metastasized from other areas of the body, including, but not limited to, solid tumor cancer, breast cancer, lung cancer, colorectal cancer, endometrial cancer, ovarian cancer, testicular cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, adrenal cortical cancer, non-Hodgkin's lymphoma, multiple myeloma, leukemia, Kaposi's sarcoma, Ewing's sarcoma, soft tissue sarcoma, nephroblastoma, glioblastoma multiforme, prostate cancer, liver cancer, bone cancer, chondrosarcoma, kidney cancer, bladder cancer, and gastric cancer.

[0155] In some cases, the radiosensitizer can be used in the treatment of primary brain cancer. In some cases, the brain cancer is metastatic brain cancer.

[0156] In another embodiment, a method is provided wherein the subject is a child, adolescent, adult, or elderly. In another embodiment, the subject is male or female. In another embodiment, the subject is human.

[0157] The term "lymphoma" generally refers to malignant neoplasms of the lymphatic system, including cancers of the lymphatic system. The two main types of lymphoma are Hodgkin's disease (HD or HL) and non-Hodgkin's lymphoma (NHL). Abnormal cells may enlarge lymph nodes, form solid tumors in the body, or, more rarely, appear as collections circulating in the blood, similar to leukemia. Hodgkin's disease lymphomas include nodular lymphocyte-predominant Hodgkin's lymphoma; classical Hodgkin's lymphoma; nodular sclerosing Hodgkin's lymphoma; lymphocyte-rich classical Hodgkin's lymphoma; mixed cytology Hodgkin's lymphoma; and lymphopenic Hodgkin's lymphoma. Non-Hodgkin's lymphomas include small lymphocytic NHL, follicular NHL, mantle cell NHL, mucosa-associated lymphoid tissue (MALT) NHL, diffuse large B-cell NHL, mediastinal large B-cell NHL, precursor T-lymphoblastic NHL, cutaneous T-cell NHL, T-cell and natural killer cell NHL, mature (peripheral) T-cell NHL, Burkitt lymphoma, mycosis fungoides, Sézary syndrome, precursor B-lymphoblastic lymphoma, and Includes B-cell small lymphocytic lymphoma; lymphocytic plasmacytic lymphoma; splenic marginal zone B-cell lymphoma; nodal marginal zone lymphoma; plasma cell myeloma / plasmacytoma; intravascular large B-cell NHL; primary effusion lymphoma; blastic natural killer cell lymphoma; enteropathic T-cell lymphoma; hepatosplenic gamma-delta T-cell lymphoma; subcutaneous panniculitis-like T-cell lymphoma; angioimmunoblastic T-cell lymphoma; and primary systemic anaplastic large T / null-cell lymphoma.

[0158] In some instances, the compounds and / or compositions described herein (e.g., PCLX-001 or PCLX-002) can be used as radiosensitizers to treat various stages and grades of cancer development and progression.

[0159] In some examples, PCLX-001 or PCLX-002 can be used as a radiosensitizer in the treatment of early stage cancers, including early neoplasias which may be small, slow-growing, localized and / or non-invasive, with the intent of curing the disease or causing cancer regression, as well as in the treatment of intermediate stage cancers and the treatment of late stage cancers, including advanced and / or metastatic and / or invasive and / or recurrent neoplasias, e.g., to slow disease progression, reduce metastasis, or prolong patient survival.

[0160] Similarly, PCLX-001 or PCLX-002 can be used as a radiosensitizer in the treatment of low-grade, intermediate-grade and / or high-grade cancers.

[0161] In some instances, it is contemplated that PCLX-001 or PCLX-002 may be used as a radiosensitizer in the treatment of recurrent, metastatic, locally advanced, and invasive cancers, including indolent, locally recurrent, distantly recurrent, and / or refractory cancers (i.e., cancers that are not responding to treatment).

[0162] As used herein, the term "inhibit" or "inhibitor" refers to any method or technique that inhibits the synthesis, level, activity, or function of a protein, as well as methods that inhibit the induction or stimulation of the synthesis, level, activity, or function of a protein of interest. In some instances, the term also refers to any metabolic or regulatory pathway that can modulate the synthesis, level, activity, or function of a protein of interest. The term includes binding and complex formation with other molecules. Thus, the term "inhibitor" refers to a drug or compound, the application of which results in the inhibition of a protein function or a protein pathway function. However, the term does not indicate that any of these functions need to be inhibited simultaneously.

[0163] As used herein, "radiation therapy" refers to the use of high-energy radiation to treat a subject, including, but not limited to, external radiation therapy and internal radiation therapy, which may also be referred to as brachytherapy.

[0164] In some instances, external radiation therapy involves directing a beam of ionizing radiation, either directly or indirectly, at the site of the tumor or cancer. The beam of radiation, photons, cobalt, or particle therapy can be focused at the site of the tumor or cancer. It is understood that exposure of normal, healthy tissue is nearly unavoidable when using this therapy.

[0165] External radiation therapy can be used to treat many types of cancer, including, but not limited to, cancer of the bladder, brain, breast, neck, pharynx, lung, prostate, and vagina. Intraoperative radiation therapy (IORT) is a form of external radiation administered during surgery and can be used to treat localized cancers that cannot be completely removed or that have a high risk of recurrence in nearby tissues, including, but not limited to, the treatment of thyroid and colorectal cancer, gynecological cancer, small intestine cancer, and pancreatic cancer. Prophylactic cranial irradiation (PCI) is another type of external radiation administered to the brain when there is a high risk of the primary cancer (e.g., small cell lung cancer) spreading to the brain.

[0166] Energy sources for external radiation therapy include, but are not limited to, direct or indirect ionizing radiation, such as: x-rays, gamma rays, and particle beams, or combinations thereof.

[0167] Internal radiation therapy, also sometimes referred to as brachytherapy, involves implanting radiation-emitting sources such as beads, wires, pellets, capsules, etc., inside the body at or near the tumor site. The energy source for internal radiation therapy can be a radioisotope, including iodine (iodine-125 or iodine-131), strontium-89, phosphorus, palladium, cesium, indium, phosphate, or cobalt, and combinations thereof. Such implants can be removed or inactivated within the body following treatment. Types of internal radiation therapy include, but are not limited to, interstitial brachytherapy and intracavitary brachytherapy (high-dose, low-dose, and pulsed-dose). Internal radiation therapy may also involve a biological carrier of the radioisotope, for example, in conjunction with radioimmunotherapy, in which a tumor-specific antibody bound to a radioactive substance is administered to the patient. The antibody binds to the tumor antigen, thereby effectively delivering a dose of radiation to the relevant tissue.

[0168] In a specific example, the radiation is gamma radiation. In one example, the ionizing radiation is x-rays produced in a linear accelerator (Linac).

[0169] In other examples, radiation therapies that can be used in combination with CER therapy include external beam radiation therapy (e.g., conventional external beam radiation therapy, stereotactic radiation, three-dimensional conformal radiation therapy, intensity-modulated radiation therapy, intensity-modulated arc therapy, particle therapy, proton therapy, and Auger therapy), brachytherapy, systemic radioisotope therapy, intraoperative radiation therapy, or any combination thereof.

[0170] Methods for administering radiation therapy are well known to those skilled in the art.

[0171] The described radiosensitizer compounds or compositions can be formulated and used for any route of administration, such as, for example, intranasal administration; oral administration; inhalation administration; subcutaneous administration; transdermal administration; intra-arterial administration with or without occlusion; intracranial administration; intraventricular administration; intravenous administration; buccal administration; intraperitoneal administration; intraocular administration; intramuscular administration; administration by implant; and central venous administration.

[0172] In some cases, intracranial administration of the radiosensitizer to a selected target tissue is provided, including injection of an aqueous solution of the radiosensitizer and implantation of a controlled release system, e.g., targeted delivery of the radiosensitizer incorporating a polymer implant at the selected target site. The use of a controlled release implant reduces the need for repeated injections. Intracranial implants are known.

[0173] In some cases, the subject may be given multiple doses or courses of therapy with respect to radiation therapy, a radiosensitizer compound, or a composition comprising a radiosensitizer compound, or both.

[0174] In some examples, the patient may be exposed to at least one course of radiation therapy within, at least, or at most 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 minutes, or 1, 2, 3, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 42, 48, 54, 86, 84, 96, 96, 102, 108, 114, 120, 126, 130, 136, 142 hours, or 1, 2, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or more, or a combination thereof, of the time that the patient is administered the radiosensitizer compound or a composition comprising a radiosensitizer compound.

[0175] In some examples, a pharmaceutically effective amount of PCLX-001 is used. In some examples, a therapeutically effective amount of PCLX-001 is used.

[0176] As used herein, the term "pharmaceutically effective amount" or "effective amount" refers to an amount of a drug or pharmaceutical agent, such as PCLX-001, that elicits a biological or medical response in a tissue, system, animal, or human as determined by a researcher or clinician. This amount may be a "therapeutically effective amount." These terms refer to an amount of a compound and / or composition described herein that, upon administration in single or multiple doses, treats a subject with a disease or condition. An effective amount can be readily determined by a diagnostician of ordinary skill in the art through the use of known techniques and observations made under analogous circumstances. In determining an effective amount, dosage, several factors will be considered by the diagnostician, including, but not limited to, the subject's species; its size, age, and general health; the particular condition, disorder, or disease involved; the extent or involvement or severity of the condition, disorder, or disease; the individual subject's response; the particular compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosing regimen; the use of concomitant medications; and other relevant circumstances.

[0177] Thus, the term "therapeutically effective amount," as used herein, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired result. An effective amount may vary depending on factors such as the disease state, age, sex, and / or weight of the subject. The amount of a given compound or composition corresponding to such an amount will vary depending on various factors, such as the given drug or compound, pharmaceutical formulation, route of administration, identity of the subject being treated, etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0178] As used herein, the term "pharmaceutically acceptable" includes compounds, substances, compositions, and / or dosage forms (e.g., unit dosages) that are suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable risk / benefit ratio. Each carrier, excipient, etc., is also "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0179] The term "excipient" means a pharmacologically inactive ingredient such as a diluent, lubricant, surfactant, carrier, etc. Excipients that are useful in preparing pharmaceutical compositions are generally safe, non-toxic, and acceptable for human pharmaceutical use. A reference to an excipient includes both one excipient and two or more excipients.

[0180] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, including, but not limited to, phosphate buffered saline solution, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents, any solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintegrants (e.g., potato starch or sodium starch glycolate), stabilizers, and preservatives.

[0181] Pharmaceutical compositions may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsified hard or soft capsules, or syrups or elixirs. Compositions intended for oral administration can be prepared by methods known in the art for the manufacture of pharmaceutical compositions and may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide pharmaceutically elegant and palatable preparations. Tablets contain die-formed active ingredients mixed with suitable non-toxic pharmaceutically acceptable additives, including inert fillers such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as cornstarch or alginic acid; binding agents such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a long period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

[0182] Pharmaceutical compositions for oral use may also be presented as hard gelatin capsules (wherein the active ingredient is mixed with an inert solid excipient, for example, calcium carbonate, calcium phosphate, or kaolin) or as soft gelatin capsules (wherein the active ingredient is mixed with an aqueous or oily medium, such as peanut oil, liquid paraffin, or olive oil).

[0183] Aqueous suspensions contain the active compound in admixture with suitable excipients, including, for example, suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as natural phosphatides, for example, lecithin, or condensates of alkylene oxides with fatty acids, for example, polyoxyethyene stearate, or condensates of ethylene oxide with long-chain aliphatic alcohols, for example, hepta-decaethyleneoxycetanol, or condensates of ethylene oxide with fatty acids and partial esters derived from hexitols, for example, polyoxyethylene sorbitol monooleate, or condensates of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin.

[0184] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and / or flavoring agents, such as those described above, can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0185] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional additives, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0186] Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or it may be a mixture of these oils.

[0187] Suitable emulsifiers may be natural gums such as gum acacia or gum tragacanth; natural phosphatides such as soybean, lecithin; or esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the above partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweeteners and flavoring agents.

[0188] Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and / or flavoring and coloring agents.

[0189] The pharmaceutical compositions may be in the form of a sterile injectable aqueous suspension. This suspension can be formulated by known techniques using suitable dispersing or wetting agents and suspending agents, such as those mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable excipient or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be employed include, but are not limited to, water, Ringer's solution, lactated Ringer's solution, and isotonic sodium chloride solution. Other examples include sterile fixed oils conventionally used as solvents or suspending media, and various bland fixed oils, including, for example, synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable solutions.

[0190] The compounds and compositions can be administered to a subject by any convenient route of administration, including, but not limited to, oral (e.g., by ingestion); topical (including, e.g., transdermal, intranasal, ocular, buccal, and sublingual); intrapulmonary (e.g., by inhalation or insufflation therapy, e.g., using an aerosol, e.g., through the mouth or nose); rectal; vaginal; parenteral, e.g., by injection, including subcutaneous, intratumoral, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intrathecal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; depot implant / e.g., subcutaneous or intramuscular, whether systemic / peripheral or at the site of desired action.

[0191] As used herein, the term "contacting" refers to a process by which, for example, a compound may be delivered to a cell. Compounds can be administered in several ways, including, but not limited to, direct introduction into a cell (i.e., intracellularly) and / or extracellular introduction into a cavity, interstitial space, or into the circulation of an organism.

[0192] Thus, in some instances, the contacting occurs in vivo. In other instances, the contacting can occur in vitro.

[0193] "Cell" refers to an individual cell or a cell culture. In one example, the cell is obtained or derived from a subject. Cell cultures and suitable culture media are known.

[0194] Formulations suitable for oral administration (e.g., by ingestion) may be presented as discrete units such as capsules, cachets, or tablets (each containing a predetermined amount of the active compound); powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water or water-in-oil liquid emulsions; boluses; electuaries; or pastes.

[0195] Formulations suitable for parenteral administration (e.g., by injection, including cutaneous, subcutaneous, intramuscular, intravenous, and intradermal) include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions that may contain antioxidants, buffers, preservatives, stabilizers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents, as well as liposomes or other microparticulate systems designed to target compounds to blood components or one or more organs. Examples of suitable isotonic vehicles for use in such formulations include sodium chloride injection, Ringer's solution, or lactated Ringer's injection.

[0196] The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. The formulations may be in the form of liposomes or other microparticulate systems designed to target the active compound to blood components or one or more organs.

[0197] The compounds and / or compositions described herein can be administered either simultaneously (or substantially simultaneously) or sequentially depending on the condition being treated, and can be administered in combination with other treatments, which can be administered either simultaneously (or substantially simultaneously) or sequentially.

[0198] As used herein, "treatment or dosing regimen" refers to a combination of dosages, frequency of administration, or duration of treatment, with or without a second drug.

[0199] The compounds or compositions can be administered alone or in combination with other treatments, either simultaneously or sequentially depending on the condition being treated.

[0200] When treating a subject, a therapeutically effective amount can be administered to the subject.

[0201] In some cases, a therapeutic formulation comprising a compound or composition, as described herein, can be prepared by mixing the compound or composition having the desired purity with any physiologically acceptable carriers, additives, or stabilizers in the form of an aqueous solution, lyophilized, or other dried formulation. Acceptable carriers, additives, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citrate, histidine, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (fewer than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; These include chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as Tween™, Pluronics™, or polyethylene glycol (PEG).

[0202] Therapeutic formulations may also optionally contain more than one active compound for the particular indication being treated, typically those with complementary activities that do not adversely affect each other. Such molecules are suitably present in combination in amounts that are effective for the intended purpose.

[0203] For example, known treatments depend on the subject being treated, the type of disease, and its stage.

[0204] Existing treatment modalities for various cancers are known to those skilled in the art.

[0205] Therefore, known treatments for cancer can be used in conjunction with PCLX-001.

[0206] Common drugs used to treat primary and secondary brain cancers include, but are not limited to, methotrexate, vinca alkaloids, carmustine, cisplatin, carboplatin, nitrosoureas, hydroxyurea, cyclophosphamide, etoposide, procarbazine, irinotecan, lomustine, vincristine, bevacizumab, vorasidenib, ivosidenib, tucatinib, capecitabine, trastuzumab, and / or conjugates of temozolomide.

[0207] When a subject is treated with dexamethasone, the subject may develop an ulcer. Thus, in some cases, a subject treated with dexamethasone may also be treated with a proton pump inhibitor.

[0208] As used herein, the term "proton pump inhibitor" refers to a class of compounds that reduce or downregulate the production of stomach acid. Typically, PPIs function by inhibiting the hydrogen / potassium adenosine triphosphatase (H / K ATPase) enzyme system in the stomach.

[0209] Protein pump inhibitors include, but are not limited to, omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, and ilaprazole.

[0210] In some cases, PPIs can reduce the absorption of PCLX-001 by decreasing gastric acidity.

[0211] Common drug combinations used to treat lymphoma include CHOP (i.e., cyclophosphamide, doxorubicin, vincristine, and prednisone), GAP-BOP (i.e., cyclophosphamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone), m-BACOD (i.e., methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, and leucovorin), ProMACE-MOPP (i.e., standard MOPP). PP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, leucovorin), ProMACE-CytaBOM (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, and leucovorin), and MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin, and leucovorin). For relapsed aggressive non-Hodgkin's lymphoma, the following chemotherapeutic drug combinations can be used with the compounds and compositions described herein: IMVP-16 (i.e., ifosfamide, methotrexate, and etoposide), MIME (i.e., methyl-gag, ifosfamide, methotrexate, and etoposide), DHAP (i.e., dexamethasone, -16 high-dose cytarabine, and cisplatin), ESHAP (i.e., etoposide, methylprednisone, high-dose cytarabine, and cisplatin), CEFF(B) (i.e., cyclophosphamide, etoposide, procarbazine, prednisone, and bleomyxacin), and CAMP (i.e., lomustine, mitoxantrone, cytarabine, and prednisone).

[0212] Salvage chemotherapy treatments used for certain lymphomas, such as relapsed resistant Hodgkin's disease, include VABCD (i.e., vinblastine, doxorubicin, dacarbazine, lomustine, and bleomycin), ABDIC (i.e., doxorubicin, bleomycin, dacarbazine, lomustine, and prednisone), CBVD (i.e., lomustine, bleomycin, vinblastine, dexamethasone), PCVP (i.e., vinblastine, procarbazine, cyclophosphamide, and prednisone), CEP (i.e., lomustine, etoposide, and prednimustine), EVA (i.e., etoposide, vinblastine, and doxorubicin), MOPLACE (i.e., cyclophosphamide, etoposide, prednisone, methotrexate, cytarabine, and vinblastine), and cyclophosphamide, etoposide, prednisone, methotrexate, cytarabine, and vinblastine. MTX-CHOP (i.e., methotrexate and CHOP), CEM (i.e., lomustine, etoposide, and methotrexate), CEVD (i.e., lomustine, etoposide, vindesine, and dexamethasone), CAVP (i.e., lomustine, melphalan, etoposide, and prednisone), EVAP (i.e., etoposide, vinblastine, cytarabine, and cisplatin), and EPOCH (i.e., etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone).

[0213] Treatments for breast cancer include treatment with paclitaxel, docetaxel, nanoparticle albumin-bound paclitaxel, capecitabine, doxorubicin, eribulin, vinorelbine, trastuzumab, tucatinib, carboplatin, cisplatin; endocrine therapy including tamoxifen, anastrozole, letrozole, exemestane, fulvestrant, and cell cycle inhibitors including palbocilib, ribociclib, LEE001, and everolimus; and treatment with immune checkpoint inhibitors including nivolumab and pembrolizumab, either individually or in combination.

[0214] Treatment for small cell lung cancer includes treatment with carboplatin, cisplatin, etoposide, irinotecan, atezolizumab, and pembrolizumab, either individually or in combination.

[0215] Treatment of non-small cell lung cancer includes treatment with carboplatin, paclitaxel, docetaxel, gefitinib, erlotinib, afatinib, bevacizumab, ramucirumab, osimertinib, necitumumab, crizotinib, ceritinib, alectinib, and immune checkpoint inhibitors, including nivolumab, pembrolizumab, either individually or in combination.

[0216] Treatments for bladder cancer include treatment with methotrexate, vinblastine, doxorubicin, cisplatin; carboplatin and paclitaxel; docetaxel, gemcitabine and cisplatin, either individually or in combination.

[0217] One of ordinary skill in the art can determine the appropriate dosage for a particular subject by following the label instructions. Preparation and dosing schedules for commercially available second therapeutic compounds and other compounds to be combined with or co-administered with the compounds or compositions described herein can be used according to the manufacturer's instructions or can be determined empirically by one of ordinary skill in the art.

[0218] Factors that may be considered when determining an appropriate dosage include the severity of the disease state, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, the particular components of the combination, reaction sensitivities, and tolerance / response to the therapy.

[0219] As described herein, the following embodiments are also provided:

[0220] 1. Use of PCLX-001, or a pharmaceutically acceptable salt thereof, to radiosensitize cancer cells in a subject in need of radiation therapy.

[0221] 2. Use of PCLX-001, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for radiosensitizing cancer cells in a subject in need of radiation therapy.

[0222] 3. The use according to embodiment 1 or 2, wherein said radiotherapy is external radiotherapy, internal radiotherapy or systemic radiotherapy.

[0223] 4. The use of any one of embodiments 1 to 3, wherein the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; cancer of the small intestine; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

[0224] 5. The use of embodiment 4, wherein the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

[0225] 6. The use of embodiment 5, wherein the astrocytoma is anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, or glioblastoma.

[0226] 7. The use of embodiment 5, wherein the glioma is a diffuse midline glioma, oligodendroglioma, ependymoma, or visual pathway glioma.

[0227] 8. The use of embodiment 5, wherein the embryonal tumor is an atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

[0228] 9. The use of embodiment 5, wherein the non-malignant brain tumor is an acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

[0229] 10. The use of embodiment 5, wherein the pediatric brain tumor is an atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

[0230] 11. The use according to any one of the preceding embodiments, wherein the subject is a human.

[0231] 12. The use according to any one of embodiments 1 to 11, wherein the compound PCLX-001 or a pharmaceutically acceptable salt thereof is in a dosage range of about 50 nM to about 150 nM.

[0232] 13. Use of a radiosensitizer that is PCLX-001, and use of radiation therapy, to treat a subject who has cancer, is suspected of having cancer, or is at risk of developing cancer.

[0233] 14. Use of a radiosensitizer that is PCLX-001 in the manufacture of a medicament for treating a subject with cancer, a subject suspected of having cancer, or a subject at risk of developing cancer, and use of radiation therapy.

[0234] 15. The use according to embodiment 13 or 14, wherein said radiotherapy is external radiotherapy, internal radiotherapy or systemic radiotherapy.

[0235] 16. The use of any one of embodiments 13 to 15, wherein the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; cancer of the small intestine; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

[0236] 17. The use of embodiment 16, wherein the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

[0237] 18. The use according to embodiment 17, wherein the astrocytoma is anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, or glioblastoma.

[0238] 19. The use according to embodiment 17, wherein the glioma is a diffuse midline glioma, an oligodendroglioma, an ependymoma, or a visual pathway glioma.

[0239] 20. The use of embodiment 17, wherein the embryonal tumor is an atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

[0240] 21. The use of embodiment 17, wherein the non-malignant brain tumor is an acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

[0241] 22. The use of embodiment 17, wherein the pediatric brain tumor is atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

[0242] 23. The use of any one of embodiments 13 to 22, further comprising the use of one or more drugs for treating brain cancer, including methotrexate, vinca alkaloids, carmustine, cisplatin, carboplatin, nitrosoureas, hydroxyurea, cyclophosphamide, etoposide, procarbazine, irinotecan, lomustine, vincristine, and / or conjugates of temozolomide.

[0243] 24. The use of any one of embodiments 13 to 22, further comprising the use of one or more drugs in the manufacture of a medicament for treating brain cancer, including methotrexate, vinca alkaloids, carmustine, cisplatin, carboplatin, nitrosourea, hydroxyurea, cyclophosphamide, etoposide, procarbazine, irinotecan, lomustine, vincristine, and / or conjugates of temozolomide.

[0244] 25. The use according to any one of embodiments 13 to 24, wherein the subject is a human.

[0245] 26. The use according to any one of embodiments 13 to 23, comprising use of a radiosensitizer at a dosage that achieves a blood or target organ or tumor drug concentration in the range of about 50 nM to about 150 nM.

[0246] 27. The use of any one of embodiments 13 to 26, comprising the use of a radiosensitizer at time A and the use of radiation therapy at time B to achieve a target dosage range of blood or target organ or tumor drug concentrations of about 50 nM to about 150 nM at the site of cancer or potential cancer.

[0247] 28. The use of embodiment 27, wherein when administering a radiosensitizer at time A includes orally administering the radiosensitizer, time B is about 2 hours to about 4 hours after time A.

[0248] 29. The use of embodiment 27, wherein when administering a radiosensitizer at time A comprises initiating radiosensitizer therapy, time B is about 72 hours after time A.

[0249] 30. The use of any one of embodiments 1 to 29, wherein the step of administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier.

[0250] 31. The use of embodiment 30, wherein the use of PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier and acts as a radiosensitizer against primary brain tumors.

[0251] 32. The use of embodiment 30 or 31, wherein the use of PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier approximately 4 hours after administration and acts as a radiosensitizer against primary brain tumors.

[0252] 33. The use of any one of embodiments 30 to 32, wherein the use of PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier and acts as a radiosensitizer against secondary brain tumors.

[0253] 34. The use of any one of embodiments 30 to 33, wherein the use of PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier approximately 4 hours after administration and acts as a radiosensitizer against secondary brain tumors.

[0254] 35. The use according to any one of embodiments 13 to 34, wherein if the patient is using a proton pump inhibitor, the patient discontinues use of the proton pump inhibitor prior to the radiosensitizer and radiotherapy treatment.

[0255] 36. A method of radiosensitizing cancer cells in a subject in need of radiation therapy, comprising administering to the subject the compound PCLX-001, or a pharmaceutically acceptable salt thereof.

[0256] 37. The method of embodiment 36, wherein said radiation therapy is external radiation therapy, internal radiation therapy, or systemic radiation therapy.

[0257] 38. The method of embodiment 36 or 37, wherein the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; small intestine cancer; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

[0258] 39. The method of embodiment 38, wherein the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

[0259] 40. The method of embodiment 39, wherein the astrocytoma is anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, or glioblastoma.

[0260] 41. The method of embodiment 39, wherein the glioma is a diffuse midline glioma, an oligodendroglioma, an ependymoma, or a visual pathway glioma.

[0261] 42. The method of embodiment 39, wherein the embryonal tumor is an atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

[0262] 43. The method of embodiment 39, wherein the non-malignant brain tumor is an acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

[0263] 44. The method of embodiment 39, wherein the pediatric brain tumor is an atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

[0264] 45. The method of any one of embodiments 36 to 44, wherein the subject is a human.

[0265] 46. ​​The method according to any one of embodiments 36 to 45, comprising administering the compound PCLX-001 in a dosage range of about 50 nM to about 150 nM.

[0266] 47. A method for treating a subject having, suspected of having, or at risk of developing cancer, comprising administering a radiosensitizer that is PCLX-001 and performing radiation therapy.

[0267] 48. The method of embodiment 47, wherein the radiation therapy is external radiation therapy, internal radiation therapy, or systemic radiation therapy.

[0268] 49. The method of embodiment 47 or 48, wherein the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; small intestine cancer; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

[0269] 50. The method of embodiment 49, wherein the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

[0270] 51. The method of embodiment 50, wherein the astrocytoma is anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, or glioblastoma.

[0271] 52. The method of embodiment 50, wherein the glioma is a diffuse midline glioma, an oligodendroglioma, an ependymoma, or a visual pathway glioma.

[0272] 53. The method of embodiment 50, wherein the embryonal tumor is an atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

[0273] 54. The method of embodiment 50, wherein the non-malignant brain tumor is an acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

[0274] 55. The method of embodiment 50, wherein the pediatric brain tumor is an atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

[0275] 56. The method of any one of embodiments 48 to 55, further comprising administering one or more drugs for treating brain cancer, including methotrexate, vinca alkaloids, carmustine, cisplatin, carboplatin, nitrosoureas, hydroxyurea, cyclophosphamide, etoposide, procarbazine, irinotecan, lomustine, vincristine, and / or conjugates of temozolomide.

[0276] 57. The method of any one of embodiments 48 to 56, wherein the subject is a human.

[0277] 58. The method according to any one of embodiments 48 to 57, comprising administering the radiosensitizer at a dosage that achieves a blood or target organ or tumor drug concentration in the range of about 50 nM to about 150 nM.

[0278] 59. The method of any one of embodiments 48 to 58, comprising administering a radiosensitizer at time A and administering radiation therapy at time B to achieve a target dosage range of blood or target organ or tumor drug concentration of about 50 nM to about 150 nM at the cancer site or potential cancer site.

[0279] 60. The method of embodiment 59, wherein when administering a radiosensitizer at time A includes orally administering the radiosensitizer, time B is about 2 hours to about 4 hours after time A.

[0280] 61. The method of embodiment 59, wherein when administering a radiosensitizer at time A includes initiating radiosensitizer therapy, time B is about 72 hours after time A.

[0281] 62. The method of any one of embodiments 36 to 61, wherein administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier.

[0282] 63. The method of embodiment 62, wherein the step of administering PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier and acts as a radiosensitizer against primary brain tumors.

[0283] 64. The method of embodiment 62 or 63, wherein the step of administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier approximately 4 hours after administration and acting as a radiosensitizer against primary brain tumors.

[0284] 65. The method of any one of embodiments 62 to 64, wherein the step of administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier and acting as a radiosensitizer against secondary brain tumors.

[0285] 66. The method of any one of embodiments 26 to 65, wherein the step of administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier approximately 4 hours after administration and acting as a radiosensitizer against secondary brain tumors.

[0286] 67. The method according to any one of embodiments 47 to 66, wherein if the patient is using a proton pump inhibitor, the patient discontinues use of the proton pump inhibitor prior to the radiosensitizer and radiation therapy treatment.

[0287] The methods of the present invention are conveniently practiced by providing the compounds and / or compositions used in such methods in the form of a kit. Such kits preferably contain the compositions. Such kits preferably contain instructions for their use.

[0288] In order to gain a better understanding of the invention described herein, the following examples are set forth. It should be understood that these examples are for illustrative purposes only, and therefore should not be construed as limiting the scope of the invention in any way. [Example]

[0289] Typically, experiments will be performed, including, but not limited to, cell viability testing of various cancer cell lines under irradiation conditions ranging from 2 Gy to 10 Gy, including different drug dosage levels to find the optimal sensitizing effect. Drug dosages are expected to range from 10 nM to 500 nM. Radiation and drug exposures will be performed simultaneously on consecutive days.

[0290] Example 1 Establishment of drug cytotoxicity in multiple cell lines in vitro with dose and scheduling schemes suitable for the use of PCLX-001 as a radiosensitizer. The effect of PCLX-001 on cell survival following exposure is measured in a clonogenic assay.

[0291] Cells are seeded at various densities onto 60 mm tissue culture plates to obtain approximately 100-1000 colonies per plate and returned to the incubator overnight to allow cells to attach. Cells are incubated with or without PCLX-001 for a period of time. This period can be up to 24 hours, at least 24 hours, or up to 96 hours prior to radiation exposure to allow for a reduction in myristoylated protein levels in cancer cells to match the cellular need for these proteins in repairing radiation-related damage. After incubation with PCLX-001, cells are incubated for an additional period. Colonies are stained with crystal violet after 10-14 days and counted using an automated counting machine.

[0292] Other methods for measuring cytotoxicity are well known to those skilled in the art and can be used, including MTT or MTS assays, Alamar Blue assays, ATP-based assays including bioluminescence assays, sulforhodamine B (SRB) assays, WST assays, clonogenic assays, and ECIS techniques.

[0293] Example 2 In vitro radiation and drug combination testing across multiple cell lines, accessing the optimal timing of drug and radiation administration is determined empirically based on these tests. The effect of PCLX-001 on cell survival following exposure to PCLX-001 and ionizing radiation is measured in a clonogenic assay.

[0294] Cells are seeded at various densities into 60 mm tissue culture plates to obtain approximately 100-1000 colonies per plate and returned to the incubator overnight to allow the cells to attach. For radiosensitization studies, cells are incubated with or without PCLX-001 for a period of time before irradiation and then exposed to increasing doses of gamma radiation. After irradiation, cells are incubated for an additional period of time. Colonies are stained with crystal violet after 10-14 days and counted using an automated counting machine.

[0295] Other methods for measuring cytotoxicity are well known to those skilled in the art and can be used, including MTT or MTS assays, Alamar Blue assays, ATP-based assays including bioluminescence assays, sulforhodamine B (SRB) assays, WST assays, clonogenic assays, and ECIS techniques.

[0296] Example 3 Possible mechanisms of radiosensitization by measuring the most likely candidate pathways of synergy: PARP-1 expression, γH2AX levels, which indicate the conversion of unrepaired single-strand DNA breaks to double-strand DNA breaks, and PI3K lipid kinase activity, which regulates transformation to a more invasive phenotype. In some examples, cells are treated with PCLX-001 and accessed for levels of PARP-1 and / or γH2AX.

[0297] In one example, a radiolabeled PARP-1 inhibitor is used to measure PARP-1 expression and image PARP-1 distribution in vivo using PET.

[0298] In one example, γH2AX protein levels are measured after radiation in the presence and absence of PCLX-001.

[0299] In one example, PI3K activity in the presence and absence of PCLX-001 during radiation therapy is assessed as a marker of cancer cell invasiveness and pathways driving tumorigenesis.

[0300] Example 4 By measuring the apoptotic rate of cell death, we investigate the role of radiosensitization in induced cell death. We can determine whether apoptosis or some other cell death pathway is involved in the effect. Methods for measuring apoptosis are known to those skilled in the art and include, but are not limited to, FACS analysis using Annexin V staining, DNA electrophoresis, propidium iodide (PI) uptake, TUNEL assay, flow cytometry, microscopy, trypan blue, or 7AAD.

[0301] In some cases, cells can be incubated with anti-Fas antibody to stimulate apoptosis through the extrinsic pathway, and 2.5 μM staurosporine (STS) can be used to stimulate apoptosis through the intrinsic pathway. Cycloheximide can be used to inhibit protein translation and further promote cell death.

[0302] In another example, Western blotting or immunofluorescence, for example, probing with specific antibodies that recognize proteins associated with apoptosis, for example, the caspases or Bcl-2 family of proteins.

[0303] Example 5 Replication of in vitro data in vivo, including orthotopic and / or subcutaneous tumor models in mice treated orally or by SQ injection with PCLX-001 in combination with radiotherapy. In one example, mouse orthotopic and / or subcutaneous tumor models are treated orally or by SQ injection with PCLX-001 in combination with radiation therapy.

[0304] Thus, in one example, a method is provided for forming an orthotopic solid tumor in a host, the method comprising orthotopically introducing cells into the host and allowing the introduced cells to form a tumor.

[0305] This example is useful, for example, to generate tumors in animals, which can then be used to determine the efficacy of PCLX-001 as a radiosensitizer.

[0306] As used herein, the term "orthotopic tumor" refers to any tumor that forms in a particular organ in a host in which the cells of the tumor are derived from the same or similar cell type as the cell type of the organ in which the tumor resides. For example, transformed cells from a mammalian epithelial cell line can be introduced into the mammalian tissue of the host.

[0307] As used herein, the term "orthotopic" refers to a site in the host that contains cells of the same or similar cell type as the introduced cells.

[0308] In another example, PCLX-001 in combination with radiation therapy can be evaluated in heterotopic tumor models, or other suitable disease models.

[0309] In another example, PCLX-001 can be evaluated with external radiation therapy to improve tumor response.

[0310] In another example, PCLX-001 can be evaluated in internal radiation therapy to improve tumor response.

[0311] Example 6 Investigating the ability of PCLX-001 to cross the blood-brain barrier in an orthotopic brain tumor model in combination with radiation therapy. As used herein, the term "blood-brain barrier" refers to a selective barrier that actively regulates the exchange of substances, including peptides, between the central nervous system (CNS) and the peripheral circulation.

[0312] In one example, the biodistribution of PCLX-001 within the CNS is assessed by assaying PCLX-001 in the brain of a normal animal model, in drug concentrations in cerebrospinal fluid, brain parenchyma, and serum following drug administration.

[0313] In one example, a normal brain in an animal model is subjected to radiation doses of 2, 4, 6, or 10 Gy, followed by administration of PCLX-001, and biodistribution within the CNS is assessed by assaying PCLX-001 in cerebrospinal fluid, brain parenchyma, and serum drug concentrations.

[0314] In one example, a biodistribution assay is performed using orthotopic tumors implanted in the brain.

[0315] Example 7 Demonstration of PCLX-001 (referred to herein as zelenilstat) radiosensitization in vitro, dose and schedule and target organ optimization reported in human plasma pharmacokinetics and mouse plasma, brain, and cerebrospinal fluid pharmacokinetics. PCLX-001 in combination with radiation therapy Myristoylation is a form of lipid modification of proteins, both co-translationally and post-translationally, involving the addition of a myristoyl group to the N-terminus of the protein. This modification is important for protein-protein interactions, protein stability, and subcellular localization (Reference 1). PCLX-001 (referred to herein as zelenilstat) is a small-molecule N-myristoyltransferase (NMT) inhibitor that selectively kills human cancers, many of which have aberrant N-myristoyltransferase expression through several described mechanisms (References 3, 7, 8, 9) (References 2, 3, 4, 5). While the mechanism of cytotoxic action is pleiotropic, one of its therapeutic effects is the inhibition of src family kinases (SFKs). PCLX-001 monotherapy has shown activity in multiple cancer types (References 3, 4). Most cancer histologies tested with this drug respond to nM drug concentrations in the IC50-IC90 range. PCLX-001 has not previously been studied in combination with radiation therapy. However, there are indications that PCLX-001 may be a good radiosensitizer. PCLX-001 inhibition of NMT1 and NMT2 may result in downstream effects of loss of function mediated through poly(ADP-ribose) polymerase (PARP) cleavage and inhibition of calcium efflux from the endoplasmic reticulum. PARP cleavage in response to radiation-induced DNA damage may result in delayed failure of DNA damage repair, thereby enhancing the efficacy of radiation therapy.

[0316] The use and timing of combination therapies involving drugs and radiation therapy generally require an understanding of plasma pharmacokinetics after administration. Furthermore, drug penetration into target organs is a determining factor in the usefulness of drugs used for radiosensitization. One such target organ is the brain, where many drugs are unable to cross the blood-brain barrier in sufficient concentrations to enable radiosensitization of primary or secondary brain tumors (the latter also known as brain metastases).

[0317] Section I - Demonstration of Radiosensitization Materials and Methods: Cancer cell culture Human cancer cell lines were cultured in appropriate culture media enriched with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin mixture. They were incubated at 37°C in a humidified atmosphere of 5% CO2. Cells were subcultured with 0.25% trypsin-EDTA when they reached 80% confluence [Freshney, RI, 2010. Culture of animal cells: a manual of basic technique and specialized applications. John Wiley & Sons].

[0318] PCLX-001 Treatment PCLX-001 was prepared at several concentrations (serial dilutions from 1000 nM, including a 0 nM control) for use as a radiosensitizing drug in culture medium. Cancer cell cultures were then treated with the aforementioned PCLX-001 concentrations and allowed to settle for 24, 48, 72, and 96 hours to allow for maximum pharmacodynamic effects. Cells were then plated at 5000 cells per well into 96-well plates and allowed to adhere overnight while continuing to incubate with the drug / media cocktail.

[0319] Radiation Applications Upon completion of the PCLX-001 incubation period, a single dose of radiation was administered to the cells using a preclinical irradiator. The radiation dose was determined based on results from a previous optimization study [Hall, EJ, Giaccia, AJ, 2012. Radiobiology for the radiologist. Lippincott Williams & Wilkins.] Radiation doses included 0, 2, and 4 Gy, which represent fractions of the most common clinical radiation doses used.

[0320] Cell viability assessment Seventy-two hours after irradiation, an Alamar Blue assay was performed to determine cell viability. Alamar Blue dye was added to the medium (10% v / v), and the plates were incubated at 37°C for 4 hours. Fluorescence was measured at excitation / emission wavelengths of 560 / 590 nm using a fluorescent plate reader. To quantify cell viability, results were normalized to data from untreated controls [Ahmed, SA et al., 1994].

[0321] Data analysis Data were collected from three or more independent experiments and presented as mean ± standard deviation (SD). One-way ANOVA followed by post-hoc Tukey's test was used for statistical analysis to find significant differences between treatment groups. The cutoff for statistical significance was a p-value of less than 0.05. A representative experiment is shown in Figure 3.

[0322] result Delivery schedule of PCLX-001 and radiation therapy Empirical studies suggest that the target timing window for administering PCLX-001 prior to radiation therapy delivery is approximately 72 hours to achieve substantial maximal efficacy in vitro. This is consistent with the observation that, although PCLX-001 directly inhibits N-myristoylation within minutes of cell exposure, residual N-myristoylated proteins often require 48–96 hours to demonstrate reduced protein levels in Western blots, and the biological effects of PCLX-001 are often only apparent after 48–96 hours (Ref. 3). It is well known that the kinetics of DNA damage repair, particularly double-strand breaks, occurs as early as the first 6 hours after radiation exposure. However, PCLX-001 reveals its downregulation of PARP levels and cleavage after a delayed period, typically 3 days later (Ref. 3). Pre-treating cancer cells for 72 hours likely promotes, if not substantially maximizes, the synergistic properties of drug and radiation therapy, likely via this mechanism.

[0323] Optimal drug dosing for radiosensitization Through empirical testing, it was observed that PCLX-001 exhibited radiosensitizing effects at drug doses ranging from 50 nM to 150 nM. At doses below 25 nM, the dose-enhancement factor for the tested U251 glioblastoma cell line was observed to be less than 1.2 (insufficient). Above 150 nM, the toxicity of the drug itself exceeded the dose-per-fraction effect of typical radiation therapy. This suggests that a balance between drug toxicity and synergistic effects exists between 50 nM and 150 nM.

[0324] Within this range, statistically and clinically significant radiotherapy dose enhancement was observed at 2 Gy per radiotherapy dose, a typical dose seen in clinical treatment (see Figure 3). Statistical significance was established via statistical analysis with a significance threshold of p<0.05. Clinical significance is typically held for radiosensitizers as any drug that enhances the radiation effect by 20% or more. For the U251 glioblastoma cell line, a dose enhancement factor of 1.8-2.0 was estimated based on these results, which represents a significant radiosensitizing effect compared to other radiosensitizers used clinically, which range from 1.2-1.6. See Figure 3.

[0325] Section II - PLCX-001 Plasma Pharmacokinetics Determined in Clinical Trial NCT04836195 as a Basis for Selection of Radiation Timing, Timing of Drug Initiation, Timing of Drugs in Relation to Radiation, and Drug Dosage Selection for Radiosensitization Materials and Methods: Plasma Pharmacokinetic Sampling, Assay, and Analysis A Phase I, multicenter, non-randomized, open-label study of zelenilstat, entitled "Phase I Trial of PCLX-001 in B-cell Non-Hodgkin Lymphoma and Advanced Solid Malignancies" (Reference 6), will be conducted and registered with clinicaltrials.gov as NCT04836195. In this study, PCLX-001 was administered as a daily oral dose every morning to patients with advanced cancer in 28-day cycles until toxicity or disease progression. Peripheral blood samples were collected at six time points: during the first 8 hours of Cycle 1, Day 1, and again on Cycle 1, Day 15, with pretreatment Day 1 levels obtained for each subsequent cycle. Plasma concentrations of PCLX-001 / zelenilstat were quantified using validated ultra-high-performance liquid chromatography with tandem mass spectrometry detection and analyzed using a nonlinear mixed-effects model.

[0326] result The complete plasma pharmacokinetics of PCLX-001 across a wide range of doses from 21 participants in Study NCT04836195 were investigated and are summarized in Table 1 below. In general, following a single oral dose of 20 mg to 210 mg of PCLX-001 / zelenilstat on Cycle 1, Day 1 (C1D1), plasma concentrations of zelenilstat steadily increased, with median T values ​​ranging from 1 to 4 hours across dose cohorts. max After repeated daily dosing, zelenilstat T at C1D15 was observed to reach peak levels with max The median T values ​​were comparable to those obtained for C1D1. max The range of T was slightly wider (1–6 hours) in patients receiving proton pump inhibitors (PPIs), with a maximum T max The peak concentration (C1D1) was observed at approximately 8 hours in these patients. max ), zelenilstat was eliminated from plasma with a mean terminal half-life ranging from 6.7 to 9.5 hours across dose cohorts.

[0327] Systemic exposure to zelenilstat (C maxThe area under the concentration-time curve (AUC) values ​​tended to increase with increasing dose over the dose range of 20 mg to 210 mg. Dose proportionality across this dose range was not supported by statistical analysis due to the limited number of subjects and variability caused by the concomitant use of proton pump inhibitors. The primary patient had limited accumulation (less than two-fold) of zelenilstat following 14 days of repeated dosing, with C max Accumulation ratio (Ar Cmax ) value and AUC 0-24 Accumulation ratio (Ar AUC0-24 The accumulation ratios (Ar) of 3 to 6 times for both were 0.41 to 1.72 and 1.0 to 1.9, respectively. Cmax and Ar AUC0-24 ) based on predose concentrations over multiple cycles. No accumulation was seen beyond day 15. Time to steady state was assessed by visual observation of predose zelenilstat concentrations. Steady state, with some variability, was achieved in most patients between days 8 and 15 of dosing.

[0328] [Table 1]

[0329] Section III - Determination of Brain Penetration and Accumulation of PCLX-001 Through the Blood-Brain Barrier background: The blood-brain barrier (BBB) ​​is a highly selective, semipermeable boundary of endothelial cells that prevents nonselective passage of solutes in circulating blood into the extracellular fluid (CSF) of the central nervous system, while allowing diffusion of essential substances such as glucose and oxygen. The BBB is formed by brain capillary endothelial cells connected by tight junctions, a type of intercellular junction that forms a virtually impermeable barrier to fluids. These cells are surrounded and supported by endfeet of pericytes and astrocytes. The BBB is important for protecting the brain from harmful substances in the blood, maintaining homeostasis, and regulating the transport of essential molecules to the brain. This selectivity is necessary to support effective neuronal function and protects the brain from many common bacterial infections.

[0330] However, the BBB can also block the delivery of therapeutic drugs to the brain, which is a major challenge in the treatment of many neurological disorders such as brain tumors and neurodegenerative diseases. As a result, much research has been conducted to develop methods to bypass or temporarily open the BBB for therapeutic purposes (see Pardridge, WM, 2005. The blood-brain barrier: bottleneck in brain drug development. NeuroRx, 2(1), pp. 3-14).

[0331] Computer modeling and drug exposure / brain penetration and accumulation studies were performed to determine whether PCLX-001 accumulates in brain tissue.

[0332] Materials and Methods: Computer modeling simulation of PCLX-001 penetration into the BBB: Support vector machine (SVM) modeling software (https: / / pubchem.ncbi.nlm.nih.gov) predicted a BBB penetration score of 0.094 for PCLX-001. This exceeds the 0.00 threshold for BBB penetration, with negative values ​​indicating that the compound does not penetrate the BBB and more positive values ​​indicating a higher propensity to penetrate the BBB. Therefore, PCLX-001 is predicted to penetrate the BBB. For comparison, temozolomide, the most commonly used radiosensitizer and anticancer drug for primary brain tumors, was predicted to have a lower BBB penetration score of 0.034, suggesting that PCLX-001 may exhibit better brain penetration than commercially available products in this space.

[0333] Measurement of brain tissue PCLX-001 accumulation Pharmacokinetic parameters and tissue accumulation of PCLX-001 were determined in male C57BL / 6 mice. All procedures were performed in accordance with relevant guidelines and regulations, and ethical approval was obtained from the Institutional Animal Care and Use Committee.

[0334] Animals and Drug Administration: Male C57BL / 6 mice, 8-10 weeks old, were used in this study. Mice were allowed to acclimate for 1 week with free access to food and water prior to the start of the experiment. The drug PCLX-001 was administered at 5 mg / kg body weight either intravenously (IV) via the tail vein or orally (OG) via gavage. For IV and OG administration, the drug was diluted in sterile saline, and for OG, it was suspended in sterile water.

[0335] sampling At designated time points post-dose (0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours), blood samples were collected into heparinized tubes and immediately centrifuged at 4°C to separate the plasma. Mice were then sacrificed by cervical dislocation under anesthesia, and cerebrospinal fluid (CSF) was collected. Brains were rapidly excised, rinsed with cold saline to remove residual blood, blotted dry, weighed, and flash-frozen in liquid nitrogen. All samples were stored at -80°C until analysis.

[0336] Sample analysis: Concentrations of PCLX-001 in plasma, CSF, and brain tissue were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Brain tissue was homogenized prior to analysis, and all samples were processed using appropriate extraction procedures to isolate the drug.

[0337] Pharmacokinetic and tissue drug level analysis: C for both IV and OG administration max (maximum observed drug concentration), T max (C max time to reach 0), AUC (area under the concentration-time curve), T 1 / 2Pharmacokinetic parameters, including elimination half-life, and bioavailability, were determined by non-compartmental analysis using standard pharmacokinetic software. The ratios of brain and CSF drug concentrations to plasma were calculated to assess the ability of PCLX-001 to cross the blood-brain barrier.

[0338] result The following were observed: (I) Single-dose oral administration of PCLX-001 resulted in a relatively short T max (II) PCLX-001 rapidly accumulated in brain tissue, and (III) as shown in Section I, it exhibited radiosensitizing effects at concentrations of approximately 50 nM to 150 nM. Brain concentrations measured over time suggested that peak brain drug concentrations occurred approximately 4 hours after oral administration. The tissue to plasma ratio was found to be 0.02, indicating relatively significant accumulation in brain tissue. Drug retention in the brain may be longer than in plasma, with a half-life of 4.17 hours rather than 1.77 hours in plasma. These data are shown in Tables 2 and 3.

[0339] [Table 2]

[0340] [Table 3]

[0341] Discussion of the findings in Sections I, II, and III The experimental details described above in Sections I-III demonstrate that the use of PCLX-001 as a radiosensitizer can provide insights that, collectively, can inform the design of preclinical and clinical trials and clinical care for cancer patients combining PCLX-001 with radiation therapy to treat cancer.

[0342] The preclinical studies described above demonstrated that PCLX-001 is an effective radiosensitizer in the cultured cancer cells tested. The model cell line used, a human glioblastoma cell line commonly used in such studies, demonstrated strong radiosensitizing effects. The studies suggested that the timing of drug delivery approximately 72 hours before radiation therapy, as an induction regimen, would allow for the necessary downregulation of DNA damage repair proteins followed by daily dosing to maintain inhibition of these proteins. The maximum therapeutic index as a radiosensitizer was estimated to be in the drug dosing range of 50 nM to 150 nM. In the cancer cell lines tested, the addition of PCLX-001 appears to increase the efficacy of radiation therapy by approximately 80%.

[0343] These radiosensitizing effects, combined with the complete pharmacokinetic profile across a wide range of daily oral PCLX-001 doses, lead to several conclusions that inform the design of combination PCLX-001 + radiation regimens in terms of timing of initiation of radiation relative to initiation of daily oral PCLX-001, drug dosing, and scheduling. For example, several components of clinical dosing schedules can be derived from the data, including the following: i) Pretreating patients with oral PCLX-001 prior to radiation, rather than vice versa. ii) Pretreating patients with oral PCLX-001 at 3 to 5 daily doses prior to initiating radiation to achieve steady-state drug levels and pharmacodynamic effects in target tissues. iii) Delivery of radiation therapy at the time of peak plasma concentration of the drug, for example, 2 hours after oral PCLX-001 daily. iv) Discontinuing patients' proton pump inhibitors prior to combining oral PCLX-001 and radiation therapy to have predictable peak concentrations. v) Select a dose of PCLX-001 that achieves a concentration of 50 nM to 100 nM in the target tissue at the time of radiation therapy. vi) Given that the target concentrations described above are lower than those achieved with higher doses of PCLX-001, use of lower doses of PCLX-001 in combination radiation and PCLX-001 therapy to reduce systemic toxicity while preserving radiosensitization. vii) Treating primary or secondary brain tumors with oral PCLX-001 in combination with radiation therapy four hours later.

[0344] The above results provide fundamental insight into how PCLX-001 can be administered in conjunction with radiation to increase the therapeutic index of the combination therapy and improve the benefit-to-risk ratio of such combination therapy.

[0345] To mitigate these implementation challenges, it may be appropriate to treat radiation patients with a non-brain tumor regimen of oral daily PCLX-001 starting three days before the start of a daily dose of external beam radiation therapy and timed to last two hours after each daily dose of PCLX-001, selecting a non-toxic drug dose of 100 mg rather than a higher, more toxic anti-cancer drug dose, as an example.

[0346] In another example, treating a radiation patient with a primary or secondary brain tumor with a regimen of oral daily PCLX-001 starting three days before the start of a daily dose of external beam radiation therapy and timed to last four hours after each daily dose of PCLX-001 may be appropriate to select a non-toxic drug dose of 100 mg rather than a higher, more toxic, anti-cancer drug dose.

[0347] (References)

[0348] [Table 4]

[0349] The embodiments described herein are intended as examples only. Alterations, modifications, and variations may occur to particular embodiments by those skilled in the art. The claims should not be limited to the particular embodiments described herein, but should be construed in a manner consistent with the specification as a whole.

[0350] All publications, patents, and patent applications mentioned in this specification are indicative of the level of those skilled in the art to which this invention pertains and are herein 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.

[0351] The invention having been described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and it is intended that all such modifications which are obvious to those skilled in the art be included within the scope of the following claims.

Claims

1. Use of PCLX-001, or a pharmaceutically acceptable salt thereof, to radiosensitize cancer cells in a subject in need of radiation therapy.

2. 1. Use of PCLX-001, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for radiosensitizing cancer cells in a subject in need of radiation therapy.

3. 3. The use according to claim 1 or 2, wherein the radiotherapy is external radiotherapy, internal radiotherapy or systemic radiotherapy.

4. 4. The use of any one of claims 1 to 3, wherein the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; cancer of the small intestine; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

5. 5. The use according to claim 4, wherein the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

6. 6. The use according to claim 5, wherein the astrocytoma is anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, or glioblastoma.

7. 6. The use according to claim 5, wherein the glioma is a diffuse midline glioma, an oligodendroglioma, an ependymoma, or a visual pathway glioma.

8. 6. The use according to claim 5, wherein the embryonal tumor is an atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

9. 6. The use according to claim 5, wherein the non-malignant brain tumor is acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

10. 6. The use of claim 5, wherein the pediatric brain tumor is atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

11. The use according to any one of claims 1 to 10, wherein the subject is a human.

12. 12. The use according to any one of claims 1 to 11, wherein the compound PCLX-001 or a pharmaceutically acceptable salt thereof is in a dosage range of about 50 nM to about 150 nM.

13. The use of a radiosensitizer that is PCLX-001, and the use of radiation therapy, to treat a subject who has cancer, is suspected of having cancer, or is at risk of developing cancer.

14. Use of a radiosensitizer that is PCLX-001 in the manufacture of a medicament for treating a subject with cancer, a subject suspected of having cancer, or a subject at risk of developing cancer, and use of radiation therapy.

15. 15. The use according to claim 13 or 14, wherein the radiotherapy is external radiotherapy, internal radiotherapy or systemic radiotherapy.

16. 16. The use of any one of claims 13 to 15, wherein the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; cancer of the small intestine; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

17. 17. The use of claim 16, wherein the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

18. 18. The use according to claim 17, wherein the astrocytoma is anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, or glioblastoma.

19. 18. The use of claim 17, wherein the glioma is a diffuse midline glioma, an oligodendroglioma, an ependymoma, or a visual pathway glioma.

20. 18. The use according to claim 17, wherein the embryonal tumor is an atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

21. 18. The use of claim 17, wherein the non-malignant brain tumor is acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

22. 18. The use of claim 17, wherein the pediatric brain tumor is atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

23. 23. The use of any one of claims 13 to 22, further comprising the use of one or more drugs for treating brain cancer, including methotrexate, vinca alkaloids, carmustine, cisplatin, carboplatin, nitrosoureas, hydroxyurea, cyclophosphamide, etoposide, procarbazine, irinotecan, lomustine, vincristine, and / or conjugates of temozolomide.

24. 23. The use of any one of claims 13 to 22, further comprising use of one or more drugs in the manufacture of a medicament for treating brain cancer, including conjugates of methotrexate, vinca alkaloids, carmustine, cisplatin, carboplatin, nitrosourea, hydroxyurea, cyclophosphamide, etoposide, procarbazine, irinotecan, lomustine, vincristine, and / or temozolomide.

25. 25. The use according to any one of claims 13 to 24, wherein the subject is a human.

26. 24. The use of any one of claims 13 to 23, comprising use of a radiosensitizer at a dosage that achieves a blood or target organ or tumor drug concentration in the range of about 50 nM to about 150 nM.

27. 27. The use of any one of claims 13 to 26, comprising the use of a radiosensitizer at time A and the use of radiation therapy at time B to achieve a target dosage range of blood or target organ or tumor drug concentration of about 50 nM to about 150 nM at the site of cancer or potential cancer.

28. 28. The use of claim 27, wherein when administering the radiosensitizer at time A comprises orally administering the radiosensitizer, time B is about 2 hours to about 4 hours after time A.

29. 28. The use of claim 27, wherein when administering a radiosensitizer at time A comprises initiating radiosensitizer therapy, time B is about 72 hours after time A.

30. 30. The use of any one of claims 1 to 29, wherein the step of administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier.

31. 31. The use of claim 30, wherein the use of PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier and acts as a radiosensitizer against primary brain tumors.

32. The use of claim 30 or 31, wherein the use of PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier approximately 4 hours after administration and acts as a radiosensitizer against primary brain tumors.

33. 33. The use of any one of claims 30 to 32, wherein the use of PCLX-001 comprises PCLX-001 crossing the blood-brain barrier and acting as a radiosensitizer against secondary brain tumors.

34. 34. The use of any one of claims 30 to 33, wherein the use of PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier about 4 hours after administration and acts as a radiosensitizer against secondary brain tumors.

35. 35. The use according to any one of claims 13 to 34, wherein if the patient is using a proton pump inhibitor, the patient discontinues the use of the proton pump inhibitor prior to the radiosensitizer and radiotherapy treatment.

36. 1. A method of radiosensitizing cancer cells in a subject in need of radiation therapy, comprising administering to the subject the compound PCLX-001, or a pharmaceutically acceptable salt thereof.

37. 37. The method of claim 36, wherein the radiation therapy is external radiation therapy, internal radiation therapy, or systemic radiation therapy.

38. 38. The method of claim 36 or 37, wherein the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; small intestine cancer; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

39. 39. The method of claim 38, wherein the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

40. 40. The method of claim 39, wherein the astrocytoma is anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, or glioblastoma.

41. 40. The method of claim 39, wherein the glioma is a diffuse midline glioma, an oligodendroglioma, an ependymoma, or a visual pathway glioma.

42. 40. The method of claim 39, wherein the embryonal tumor is an atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

43. 40. The method of claim 39, wherein the non-malignant brain tumor is an acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

44. 40. The method of claim 39, wherein the pediatric brain tumor is atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

45. 45. The method of any one of claims 36 to 44, wherein the subject is a human.

46. 46. ​​The method of any one of claims 36 to 45, comprising administering the compound PCLX-001 in a dosage range of about 50 nM to about 150 nM.

47. A method of treating a subject having, suspected of having, or at risk of developing cancer, comprising administering a radiosensitizer that is PCLX-001 and administering radiation therapy.

48. 48. The method of claim 47, wherein the radiation therapy is external radiation therapy, internal radiation therapy, or systemic radiation therapy.

49. 49. The method of claim 47 or 48, wherein the subject has cancer of the bladder, brain, breast, cervix, pharynx, lung, prostate, vagina, thyroid, pancreas, ovary, breast, uterus, gallbladder, perianal and pelvic region; colorectal cancer; gynecological cancer; small intestine cancer; small cell lung cancer; head and neck cancer; bronchial cancer; oral cancer; rectal cancer; tracheal cancer; or adult non-Hodgkin's lymphoma.

50. 50. The method of claim 49, wherein the brain cancer is an astrocytoma, a glioma, an embryonal tumor, a non-malignant brain tumor, a pediatric brain tumor, or a metastatic tumor.

51. 51. The method of claim 50, wherein the astrocytoma is anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma, or glioblastoma.

52. 51. The method of claim 50, wherein the glioma is a diffuse midline glioma, an oligodendroglioma, an ependymoma, or a visual pathway glioma.

53. 51. The method of claim 50, wherein the embryonal tumor is an atypical teratoid / rhabdoid (AT / RT) or medulloblastoma.

54. 51. The method of claim 50, wherein the non-malignant brain tumor is an acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, or pilocytic astrocytoma.

55. 51. The method of claim 50, wherein the pediatric brain tumor is an atypical teratoid / rhabdoid tumor (AT / RT), diffuse midline glioma, medulloblastoma, pilocytic astrocytoma, craniopharyngioma, ependymoma, or visual pathway glioma.

56. 56. The method of any one of claims 48-55, further comprising administering one or more drugs for treating brain cancer comprising methotrexate, vinca alkaloids, carmustine, cisplatin, carboplatin, nitrosoureas, hydroxyurea, cyclophosphamide, etoposide, procarbazine, irinotecan, lomustine, vincristine, and / or conjugates of temozolomide.

57. 57. The method of any one of claims 48 to 56, wherein the subject is a human.

58. 58. The method of any one of claims 48 to 57, comprising administering the radiosensitizer at a dosage that achieves a blood or target organ or tumor drug concentration in the range of about 50 nM to about 150 nM.

59. 59. The method of any one of claims 48 to 58, comprising administering a radiosensitizer at Time A and administering radiation therapy at Time B to achieve a target dosage range of blood or target organ or tumor drug concentration of about 50 nM to about 150 nM at the site of the cancer or potential cancer.

60. 60. The method of claim 59, wherein when administering the radiosensitizer at time A comprises orally administering the radiosensitizer, time B is about 2 hours to about 4 hours after time A.

61. 60. The method of claim 59, wherein when administering a radiosensitizer at time A comprises initiating radiosensitizer therapy, time B is about 72 hours after time A.

62. 62. The method of any one of claims 36 to 61, wherein administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier.

63. 63. The method of claim 62, wherein the step of administering PCLX-001 comprises PCLX-001 that crosses the blood-brain barrier and acts as a radiosensitizer against primary brain tumors.

64. 64. The method of claim 62 or 63, wherein the step of administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier about 4 hours after administration and acting as a radiosensitizer against primary brain tumors.

65. 65. The method of any one of claims 62 to 64, wherein the step of administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier and acting as a radiosensitizer against secondary brain tumors.

66. 66. The method of any one of claims 26 to 65, wherein the step of administering PCLX-001 comprises PCLX-001 crossing the blood-brain barrier about 4 hours after administration and acting as a radiosensitizer against secondary brain tumors.

67. 67. The method of any one of claims 47 to 66, wherein if the patient is using a proton pump inhibitor, the patient discontinues use of the proton pump inhibitor prior to the radiosensitizer and radiotherapy treatment.

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