Combination therapeutic regimens with 1,6-dibromo-1,6-dideoxy-dulcitol

Abstract

To provide methods of treating a subject suffering from a brain tumor.SOLUTION: Methods comprise administering a therapeutically effective amount of a crystalline polymorph of 1,6-dibromo-1,6-dideoxy-dulcitol (DBD), including combination therapies with synergistic second cancer treatments. Also disclosed are methods of screening subjects sensitive to a crystalline DBD polymorph and treating those subjects demonstrating sensitivity.SELECTED DRAWING: None

Description

[Technical field]

[0001] Methods of treating cancer by administering crystalline 1,6-dibromo-1,6-dideoxy-dulcitol (dibromodulcitol or DBD) polymorphs, including DBD, in combination with certain anti-cancer moieties have been shown to have improved safety and efficacy. [Background technology]

[0002] Cancer is the second leading cause of death in the United States after heart disease. Despite recent advances in cancer diagnosis and treatment, most current drug therapies for metastatic disease are palliative and rarely provide long-term cures, although cancer can be cured with surgery and radiation therapy if detected early. Despite new chemotherapeutics entering the market, there is a continuing need for new drugs that are effective as first-line therapy, as second- and third-line therapy, either alone or in combination with existing agents, in the treatment of resistant tumors.

[0003] One example of a chemotherapeutic agent that may be used to treat cancer is 1,6-dibromo-1,6-dideoxy-dulcitol (dibromodulcitol or DBD). The crystal structure of DBD was first published by Simon and Sasvari in Acta. Cryst. (1971) B27, 806-815. Kellner et al. reported that DBD has selectively potent antitumor effects. Kellner et al., "1,6-Dibromo-1,6-Dideoxy-Dulcitol: A New Antitumoral Agent," Nature (1967) 28;213(5074):402-3. However, in these studies, DBD was prepared by treating dulcitol with aqueous hydrobromic acid saturated with gaseous hydrogen bromide at temperatures below 0°C. This process is no longer considered a safe method of producing DBD. Furthermore, it has been reported in the literature that DBD is poorly soluble.

[0004] The present invention addresses this continuing need to improve and develop new cancer treatments with safer and more effective profiles. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Simon and Sasvari, Acta.Cryst.(1971)B27,806-815 [Non-Patent Document 2] Kellner et al., “1,6-Dibromo-1,6-Dideoxy-Dulcitol: A New Antitumoral Agent,” Nature (1967) 28;213(5074):402-3 Summary of the Invention [Means for solving the problem]

[0006] This summary introduces a selection of concepts in a simplified form that are described below in the more detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.

[0007] Described herein is the use of 1,6-dibromo-1,6-dideoxy-dulcitol, including crystalline DBD polymorphs, in combination with certain anti-cancer components to treat cancer. DBD has a molecular weight of 307.98 g / mol, molecular formula CH 12 Br2O4, and has the following structure: [ka] .

[0008] In particular, preferred embodiments include a method of treating a subject suffering from a cancer tumor, said method comprising administering a therapeutically effective amount of a crystalline polymorph of 1,6-dibromo-1,6-dideoxy-dulcitol (DBD). Examples of such cancers that can be treated as described herein include, but are not limited to, adenocarcinoma, sarcoma, skin cancer, melanoma, bladder cancer, brain cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, or lung cancer.

[0009] In a preferred embodiment, the brain cancer is selected from astrocytoma, meningioma, oligodendroglioma, mixed glioma and ependymoma, hi a further preferred embodiment, the brain tumor is glioblastoma multiforme.

[0010] In a more preferred embodiment, the subject is a human.

[0011] In a further preferred embodiment, the method further comprises administering a second cancer treatment selected from temozolomide, radiation, ABT-888, bortezomib, imatinib, panobinostat, or BIBR-1532. In such an embodiment, the crystalline polymorph of DBD acts synergistically with the second cancer treatment. In a further embodiment, the method of claim 6 is characterized in that the radiation therapy is provided by a gantry-based system, a robotic radiosurgery system, a subcutaneous implant, or a radiation delivery system comprising a radioisotope.

[0012] In other preferred embodiments, the method further comprises: (A) obtaining or having obtained glioma cells from a subject, (b) testing or having tested glioma cells in vitro for sensitivity to a crystalline polymorph of the DBD, and (c) administering the crystalline polymorph of the DBD to the subject exhibiting sensitivity in step (b). By carrying out this method, drugs may be identified for combination with a crystalline polymorph of the DBD that have improved activity and enhanced efficacy at potentially reduced doses, resulting in improved safety and reduced side effects.

[0013] Embodiments are illustrated by way of example, and not limitation, in the figures of the accompanying drawings in which like reference symbols indicate similar elements and in which: [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 is a histogram from T98 cell cultures showing the percentage of viable cells after 5 and 8 days of crystalline DBD polymorph treatment compared to untreated cells, which are considered 100% viability. [Diagram 2] FIG. 2 is a histogram from U373 cell cultures showing the percentage of viable cells after 5 and 8 days of crystalline DBD polymorph treatment compared to untreated cells, which are considered to be 100% viability. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] While certain embodiments of the present invention are shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments described herein may be used in the practice of the present invention, depending on the circumstances. It is intended that the following claims define the scope of the present invention, and that methods and structures within the scope of these claims, and their equivalents, are covered thereby.

[0016] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, instructions, books, manuals, and articles, are expressly incorporated herein by reference in their entirety for any purpose.

[0017] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art, such as peptide chemistry, cell culture, chemistry and biochemistry.Standard techniques are used for molecular biology, genetics and biochemistry methods (see Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., 2001, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Ausubel et al., Short Protocols in Molecular Biology (1999) 4th ed., John Wiley & Sons, Inc.), which are incorporated herein by reference.

[0018] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to a "chemotherapeutic agent" includes two or more such chemotherapeutic agents or a mixture of a plurality of such chemotherapeutic agents.

[0019] As used herein, the term "comprise" or variations thereof, such as "comprises" or "comprising," should be interpreted to indicate the inclusion of any recited integer (e.g., feature, element, property, property, method / process step, or limitation) or group of integers (e.g., multiple features, elements, properties, properties, method / process steps, or limitations) but not the exclusion of any other integer or group of integers. Thus, as used herein, the term "comprising" is inclusive and does not exclude additional unrecited integers or method / process steps.

[0020] In any of the embodiments of the compositions and methods provided herein, "comprising" may be replaced with "consisting essentially of" or "consisting of." The phrase "consisting essentially of" is used herein to require a particular integer (or integers) or steps, as well as those that do not substantially affect the features or functions of the claimed invention. As used herein, the term "consisting" is used to indicate the presence of only the recited integer (e.g., feature, element, property, property, method / process step, or limitation) or group of integers (e.g., feature, element, property, property, method / process step, or limitation).

[0021] As used herein, "DBD" refers to 1,6-dibromo-1,6-dideoxy-dulcitol, the crystal structure of which is reported in the literature in Acta. Cryst. (1971) B27, 806-815.

[0022] The term "crystalline DBD polymorph" or "crystalline polymorph" or "crystalline polymorph of DBD" refers to the crystalline forms of 1,6-dibromo-1,6-dideoxy-dulcitol described in WO 2016 / 205299 and U.S. 2018 / 0362427, which are incorporated by reference in their entireties.

[0023] The term "subject" as used herein in reference to an individual suffering from cancer includes mammals and non-mammals. In a preferred embodiment, the subject is a human.

[0024] The term "effective amount", "therapeutically effective amount" or "pharmaceutical effective amount" as used herein refers to an amount of at least one agent or compound being administered that is sufficient to treat cancer. The result is reduction and / or alleviation of the signs, symptoms, or causes of such disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is necessary to bring about a clinically significant reduction in the disease. An appropriate "effective" amount in any individual case is determined using techniques such as dose escalation studies. Moreover, an "effective amount", "therapeutically effective amount" or "pharmaceutical effective amount" means a compound, material, composition, and / or dosage form that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of a subject (e.g., a human) without undue toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0025] In the present invention, a "tumor" or "cancer" is defined as a heterogeneous collection of cells that collectively form a mass of tissue in a subject due to the abnormal growth of malignant cancer cells. Thus, a "tumor" includes both normal or "non-cancerous" cells and "cancer" or "cancerous" cells.

[0026] As used herein, "and / or" should be construed as a specific disclosure of each of the two specified features or components, whether or not the other is present. For example, "A and / or B" should be construed as a specific disclosure of each (i) A, (ii) B, and (iii) A and B, as if each were listed individually.

[0027] As used herein, the term "about" is used to refer to an amount that is approximately, nearly, roughly, or nearly equal to the stated amount, or an amount equal to, for example, the state amount plus / minus about 5%, about 4%, about 3%, about 2%, or about 1%.

[0028] It should be understood that the present application discloses all combinations of any of the above aspects and embodiments with each other, unless the context requires otherwise.Similarly, the present application discloses all combinations of preferred and / or optional features alone or with any of the other aspects, unless the context requires otherwise. EXAMPLES

[0029] The invention will now be further described with reference to the following examples, which are merely illustrative and it will be understood that modifications of detail may be made within the scope of the invention.

[0030] In the examples below, the following abbreviations are used: Definitions and Abbreviations ·A2,5 ABT-888 concentration 2,5 μM ·A10 ABT-888 concentration 10μM B1 Bortezomib concentration 1nM B2,5 Bortezomib concentration 2,5nM ·B5 BIBR1532 concentration 5 μM ·B10 BIBR1532 concentration 10μM ·CTG CellTiter-Glo (viability assay) DBD Dibromodulositol DMSO Dimethyl sulfoxide (solvent for drugs, used as control) ·GBM glioblastoma multiforme ·GBM(rec) Recurrent glioblastoma multiforme Glioma serum-free stem-like cell cultures (GSC's) IC50 Half-maximal inhibitory concentration I4 Imatinib concentration 4μM I15 Imatinib concentration 15μM MGMT O6-methylguanine methyltransferase NT untreated control cell cultures P5 Panobinostat concentration 5nM P20 Panobinostat concentration 20nM RLU Relative Light Unit ·RTX radiation therapy TMZ (temozolomide) ·T50 TMZ concentration 50μM ·T100 TMZ concentration 100μM 1 / 2 IC50 Half the concentration of IC50 3Gy (3 gray radiation) 6Gy (6 Gray radiation)

[0031] overview The crystalline DBD polymorphs were studied in an in vitro system using two human glioma cell lines in an attempt to identify the ability of the DBD to reduce cell viability and to identify synergistic effects with other compounds. The following study examples 1-3 were performed. The following results are presented. a. Demonstration of suitable in vitro concentration ranges of polymorphic DBD drugs that can be used in other cellular studies (Example 1); b. Determination of IC50 (half maximal inhibitory concentration) values ​​on days 5 and 8 of over 20 patient-derived cell-free cultures (Example 2); and c. Determining whether the effects of DBD (1 / 2 the IC50 dose, and the IC50 dose) are enhanced by combination with TMX (temozolomide), radiation therapy, or other targeted therapies in a panel of 20 primary serum-free cell cultures (Example 3).

[0032] Example 1: Determination of the appropriate concentration range of DBD for crystalline DBD polymorphs using two glioma cell lines Since the concentration range of the crystalline DBD polymorph that demonstrates efficacy in serum-free patient-derived glioma cell cultures is not yet known, a wide range of concentrations was tested on two glioma cell lines. The lines were seeded in triplicate in 96-well plates at a dilution of 500 cells / well. ATP-based Cell Titer-Glo® (CTG) assays were performed on days 5 and 8 to monitor cell proliferation and the efficiency of the DBD in reducing cell viability. Figures 1 and 2 show the histogram results for the two glioma cell lines used, T98 and U373.

[0033] Specifically, the histograms were normalized by percentage, where untreated cells have 100% viability. The two lowest concentrations, 0.1 μM and 0.3 μM, had no effect. Moreover, almost all cells treated with a DBD dose of 300 μM are non-viable. However, a concentration range of 1-100 μM was chosen and then tested on 20 serum-free cell cultures derived from patients.

[0034] Example 2: Determination of DBD IC50 values ​​for crystalline DBD polymorphs in a panel of 20 primary serum-free cell cultures from patients To evaluate the effect of crystalline DBD polymorphisms on the proliferation of patient-derived GSCs (glioma serum-free stem cell-like cultures), a dose-response assay was performed on 20 cultures.

[0035] To determine the IC50 of the crystalline DBD polymorphs, concentrations between 1 μM and 100 μM were applied. A dose-dependent decrease in viability was found, and IC50 values ​​could be calculated using linear regression analysis. An overview of all IC50 values ​​(μM) of DBD for 20 cell cultures, from both day 5 and day 8 analyses, is shown in Table 1. Specifically, looking at Table 1, a wide variety of IC50 values ​​are seen in this panel of patient-derived GSCs. Furthermore, no correlation is found between MGMT promoter methylation status and the amount of IC50 values. (MGMT methylation status may be prognostic and in some studies has significantly improved survival in patients with unresectable glioblastoma multiforme who received concomitant radiation therapy and temozolomide.)

[0036] However, over time, between days 5 and 8, cells become more sensitive to the drug and lower IC50 values ​​are observed. See, for example, GS102peri, where the IC50 at day 5 is 41.77 but at day 8 the IC50 drops to 11.94. This is surprising, since known mechanisms of decreased responsiveness of tumor cells to certain chemotherapeutic agents include (1) decreased cellular uptake or increased efflux of the drug from the cell, (2) increased inactivation of the drug within the cell, (3) enhanced repair of DNA damage caused by alkylating agents, and (4) the absence of cellular mechanisms that result in cytotoxicity in response to DNA damage. It is therefore surprising to observe increased sensitivity of cancer cells to cell killing upon treatment of the DBD polymorphism in combination with one of the described chemotherapeutic agents. [Table 1]

[0037] Example 2: Determining whether the effect of DBD polymorphisms (1 / 2 and IC50 doses) is enhanced in combination with TMZ (temozolomide, a chemotherapy alkylating agent used in the treatment of gliomas), RTX (radiotherapy), or any other compound in a panel of 20 primary serum-free cell cultures The crystalline DBD polymorphic treatment was combined with chemotherapy, radiation therapy and targeted inhibitors to determine whether the crystalline DBD polymorphic form could enhance the efficacy of conventional treatments, enhance efficacy when combined with newer "targeted" therapies, or increase the sensitivity of (a subset of) the cultures to this treatment.

[0038] Therefore, cultures were treated with: a. Crystalline DBD polymorphs at IC50 and 1 / 2 IC50 doses (determined on day 5); and b. Temozolomide, radiotherapy, ABT-888 (PARP (poly ADP-ribose polymerase) inhibitor), bortezomib (proteasome inhibitor), imatinib (Bcr-Abl, PDGF and c-KIT receptor tyrosine kinase inhibitor), panobinostat (pan-HDAC (histone deacetylase inhibitor) or BIBR1532 (telomerase inhibitor) at two different concentrations.

[0039] Table 2 (day 5) and Table 3 (day 8) show the enhancement factors (viability of the most effective monotherapy divided by the viability in combination with temozolomide or radiation therapy) for all 20 cell cultures used for all treatment combinations. In some cases, an effect of crystalline DBD polymorph treatment (reduced cell viability) was seen compared to monotherapy temozolomide, radiation, ABT-888, bortezomib, imatinib, panobinostat or BIBR1532.

[0040] A "heat map" (heat map = display of data in a tabular form where data values ​​are displayed as different colors) makes the data easier to visualize, with "darker grey" in the table cells representing larger integer values. The "darker" the data cell, the more effective the combination of both therapies is compared to the most effective monotherapy. As shown in Tables 2 and 3, both imatinib and panobinostat have the highest overall enhancement factors. [Table 2] [Table 3]

[0041] Summary and Conclusion Chemical moieties, including therapeutic agents, may be synthesized to obtain different crystal structures. Often these different "polymorphs" can have different physicochemical properties depending on their crystal structure.

[0042] Due to the changes in physicochemical properties, polymorphs may also have different therapeutic profiles and may alter the safety and efficacy of the delivered compound during therapeutic use in humans. This may affect the use of polymorphs with other adjuvants or combination drugs and therapies. This is particularly important in combination therapies for oncological conditions.

[0043] The methods and results presented identified an in vitro therapeutic dose range in patient-derived glioma cell cultures and demonstrated that these effects were not influenced by MGMT status when treated with the crystalline DBD polymorph, as described in WO 2016 / 205299 and US 2018 / 0362427.

[0044] Furthermore, with regard to other combination therapies, treatment with the DBD polymorphism enhanced the cytotoxic effect when combined with another alkylating agent, temozolomide (50%) and radiation therapy (30%).

[0045] When combined with newer targeted therapies (see below), the combination of DBD polymorphisms with the newer targeted therapies showed enhanced efficacy in in vitro patient-derived cell studies. Specifically, a selection of targeted drugs was tested in combination with the DBD in a panel of 20 patient-derived cell cultures. The selection encompassed the most important pathways in the initiation and ongoing growth of malignant human glioblastoma, including: a. bcr / abl, c-kit and pdgfR tyrosine kinases b. HDAC C telomerase inhibition D. Proteasome inhibition e.DNA repair (PARP) inhibition

[0046] These results (high enhancement factors in most cases) were achieved using the tyrosine kinase inhibitor imatinib in combination with HDAC inhibition (panobinostat) and inhibition of the Ras / MapK, Src / Pax / Fak / Rac, PI / PI3K / AKT / BCL-2 and JAK / STAT pathways (downstream effects of the Bcr-Abl pathway).

[0047] Example 3: Incorporation of the disclosures of International Publication No. WO 2016 / 205299 (U.S. Patent No. 20180362327) As described in paragraphs [007-010] of WO 2016 / 205299 (US 20180362327), the DBD polymorph has a molecular weight of 307.98 g / mol and the molecular formula CH 12 It has Br2O4.

[0048] In one aspect, the crystalline polymorph of 1,6-dibromo-1,6-dideoxy-dulcitol described herein is characterized by peaks in 2θ±0.1° at 19.59° (100,00), 24.380° (79,52), 31.260° (8,32), 34.500° (25,56), 34.810° (22,83), and 39.260° (23,63). In further embodiments, such crystalline polymorphs are further characterized by at least two peaks at 2θ±0.1° selected from 19.59°(100,00) and 24.380°(79,52) and 31.260°(8,32) and 34.500°(25,56) and 34.810°(22,83) and 39.260°(23,63). In further embodiments, such crystalline polymorphs are further characterized by at least three peaks at 2θ±0.1° selected from 19.59°(100,00) and 24.380°(79,52) and 31.260°(8,32) and 34.500°(25,56) and 34.810°(22,83) and 39.260(23,63). In further embodiments, such crystalline polymorphs are further characterized by at least four peaks in 2θ±0.1° selected from 19.59°(100,00) and 24.380°(79,52) and 31.260°(8,32) and 34.500°(25,56) and 34.810°(22,83) and 39.260°(23,63). In further embodiments, such crystalline polymorphs are further characterized by at least five peaks in 2θ±0.1° selected from 19.59°(100,00) and 24.380°(79,52) and 31.260°(8,32) and 34.500°(25,56) and 34.810°(22,83) and 39.260°(23,63).

[0049] In yet further embodiments, the crystalline polymorph exhibits an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern shown in Figure 1 of WO 2016 / 205299 (US 20180362327). In further embodiments, the crystalline polymorph exhibits an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern shown in Figure 2 of WO 2016 / 205299 (US 20180362327). In yet further embodiments, the crystalline polymorph exhibits an X-ray powder diffraction pattern substantially similar to the X-ray powder diffraction pattern set forth in Table 1 of WO 2016 / 205299 (US 20180362327). In yet further embodiments, the crystalline polymorph exhibits a beta angle of 96° compared to a beta angle of 98° reported in the literature.

[0050] In a related aspect, the crystalline polymorph of 1,6-dibromo-1,6-dideoxy-dulcitol described herein is characterized by an endothermic onset of about 184.4° C. and a peak of about 191° C. as determined by differential scanning calorimetry. In a further embodiment, the crystalline polymorph is characterized by a differential scanning calorimetry pattern substantially the same as the differential scanning calorimetry pattern shown in Figure 3 and / or Figure 4 of WO 2016 / 205299 (US 20180362327). References 1.Chang,AY,et al.,Induction chemotherapy of dibromodulcitol,Adriamycin,vincristine,tamoxifen,and Halotestin with methotrexate in metastatic breast cancer:an Eastern Cooperative Oncology Group Study(E1181).Am J Clin Oncol,1998.21(1):p.99-104 2.Csetenyi,J.,et al.,The distribution of [3H]-dibromodulcitol in the central nervous system of patients with brain tumour.Eur J Cancer Clin Oncol,1983.19(10):p.1389-92 3.Berghauser Pont,L.M.,et al.,The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells.Genes Cancer,2014.5(11-12):p.445-59 4.Lee,J.,et al.,Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines.Cancer Cell,2006.9(5):p.391-403 5.Fael Al-Mayhani,T.M.,et al.,An efficient method for derivation and propagation of glioblastoma cell lines that conserves the molecular profile of their original tumours.J Neurosci Methods,2009.176(2):p.192-9 6. Nikanjam, M., S. Liu, and R. Kurzrock, Dosing targeted and cytotoxic two-drug combinations:Lessons learned from analysis of 24,326 patients reported 2010 through 2013.Int J Cancer,2016.139(9):p.2135-41 The present invention also includes the following embodiments. [1] A method of treating a subject suffering from cancer, comprising administering a therapeutically effective amount of a crystalline polymorph of 1,6-dibromo-1,6-dideoxy-dulcitol (DBD). [2] The method according to [1], wherein the cancer is selected from adenocarcinoma, sarcoma, skin cancer, melanoma, bladder cancer, brain cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, or lung cancer. [3] The method according to [2], wherein the brain cancer is selected from astrocytoma, meningioma, oligodendroglioma, mixed glioma and ependymoma. [4] The method according to [3], wherein the brain tumor is glioblastoma multiforme. [5] The method according to any one of [1] to [4], wherein the subject is a human. [6] The method of any one of [1] to [5], further comprising administering a second cancer treatment selected from temozolomide, radiation, ABT-888, bortezomib, imatinib, panobinostat, or BIBR-1532. [7] The method of claim 6, wherein the radiation therapy is provided by a radiation delivery system including a gantry-based system, a robotic radiosurgery system, a subcutaneous implant, or a radioisotope. [8] The method of [6], wherein the crystalline polymorph of the DBD acts synergistically with the second cancer treatment. [9] a. obtaining or having been obtained from said subject glioma cells; b. testing, or having been tested, said glioma cells in vitro for sensitivity to crystalline polymorphism of said DBD; and c. The method according to any one of [1] to [8], further comprising administering the DBD crystalline polymorph to the subject who showed sensitivity in step (b).

[10] A composition for use in treating a patient having cancer, comprising administering a therapeutically effective amount of a crystalline polymorph of said DBD.

Claims

1. A method of treating a subject suffering from cancer comprising administering a therapeutically effective amount of a crystalline polymorph of 1,6-dibromo-1,6-dideoxy-dulcitol (DBD).

2. 10. The method of claim 1, wherein the cancer is selected from adenocarcinoma, sarcoma, skin cancer, melanoma, bladder cancer, brain cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, or lung cancer.

3. 3. The method of claim 2, wherein the brain cancer is selected from astrocytoma, meningioma, oligodendroglioma, mixed glioma, and ependymoma.

4. The method of claim 3 , wherein the brain tumor is glioblastoma multiforme.

5. The method of any one of claims 1 to 4, wherein the subject is a human.

6. 6. The method of any one of claims 1 to 5, further comprising administering a second cancer treatment selected from temozolomide, radiation, ABT-888, bortezomib, imatinib, panobinostat, or BIBR-1532.

7. 7. The method of claim 6, wherein the radiation therapy is provided by a radiation delivery system including a gantry-based system, a robotic radiosurgery system, a subcutaneous implant, or a radioisotope.

8. 7. The method of claim 6, wherein the crystalline polymorph of DBD acts synergistically with the second cancer treatment.

9. a. obtaining or having been obtained from said subject glioma cells; b. testing, or having been tested, said glioma cells in vitro for sensitivity to crystalline polymorphism of said DBD; and c) The method of any one of claims 1 to 8, further comprising administering said DBD crystalline polymorph to said subject who exhibits susceptibility in step (b).

10. A composition for use in treating a patient having cancer, comprising administering a therapeutically effective amount of said crystalline polymorph of DBD.

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