Use of dianhydrogalactitol and analogs or derivatives thereof in combination with platinum-containing antineoplastic agents to treat non-small-cell carcinoma of the lung and brain metastases
The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of non-small-cell lung carcinoma (NSCLC) and ovarian cancer, as well as other types of malignancy, including brain metastases of NSCLC. Dianhydrogalactitol acts as an alkylating agent on DNA that creates N 7 methylation. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide, cisplatin, and tyrosine kinase inhibitors; the drug acts independently of the MGMT repair mechanism. Dianhydrogalactitol can be used together with other anti-neoplastic agents and can possess additive or super-additive effects.
1. A method of treating a patient with non-small cell lung cancer (NSCLC) resistant to a platinum-based anti-neoplastic agent consisting of the steps of:
(a) administering a therapeutically effective quantity of dianhydrogalactitol to the patient to treat the NSCLC; and
(b) administering a therapeutically effective quantity of the platinum-based anti-neoplastic agent to the patient to treat the NSCLC.
2. A method of treating a patient with non-small cell lung cancer (NSCLC) resistant to a platinum-based anti-neoplastic agent consisting of the steps of:
(a) administering a therapeutically effective quantity of dianhydrogalactitol to the patient to treat the NSCLC;
(b) administering a therapeutically effective quantity of the platinum-based anti-neoplastic agent to the patient to treat the NSCLC, and
(c) resecting the NSCLC surgically subsequent to the administration of the dianhydrogalactitol and the platinum-based anti-neoplastic agent.
3. A method of treating a patient with non-small cell lung cancer (NSCLC) resistant to a platinum-based anti-neoplastic agent consisting of the steps of:
(a) administering a therapeutically effective quantity of dianhydrogalactitol to the patient to treat the NSCLC;
(b) administering a therapeutically effective quantity of the platinum-based anti-neoplastic agent to the patient to treat the NSCLC, and
(c) resecting the NSCLC surgically prior to the administration of the dianhydrogalactitol and the platinum-based anti-neoplastic agent.
4. The method of claim 1 wherein the patient has brain metastases.
5. The method of claim 1 wherein the dianhydrogalactitol and the platinum-based anti-neoplastic agent are administered in a single pharmaceutical composition, wherein the pharmaceutical composition comprises: (i) dianhydrogalactitol; (ii) the platinum-based anti-neoplastic agent; and (iii) at least one pharmaceutically acceptable carrier.
6. The method of claim 1 wherein the dianhydrogalactitol and the platinum-based anti-neoplastic agent are administered in two pharmaceutical compositions: (i) a first pharmaceutical composition comprising dianhydrogalactitol and at least one pharmaceutically acceptable carrier; and (ii) a second pharmaceutical composition comprising the platinum-based anti-neoplastic agent and at least one pharmaceutically acceptable carrier.
7. The method of claim 1 wherein the patient has a wild-type p53 genotype.
8. The method of claim 1 wherein the patient has a mutated p53 genotype.
9. The method of claim 1 wherein the patient has a wild-type EGFR genotype.
10. The method of claim 1 wherein the patient has at least one mutation in a gene encoding a protein that is a target of at least one tyrosine kinase inhibitor (TKI).
11. The method of claim 1 wherein the patient is characterized by the presence of at least one gene in either a wild-type or mutated state encoding a product that confers resistance to the therapeutic effects of at least one tyrosine kinase inhibitor (TKI).
12. The method of claim 11 wherein the gene in either a wild-type or mutated state encoding a product that confers resistance to the therapeutic effects of at least one TKI is AHI-1.
13. The method of claim 12 wherein the AHI-1 gene is mutated as the result of a proviral insertion.
14. The method of claim 1 wherein the patient is characterized by a mutation in the kinase domain of ABL1 protein that is part of a BCR-ABL fusion protein that is a target of TKIs.
15. The method of claim 1 wherein the patient is characterized by a germline DNA deletion polymorphism conferring resistance to tyrosine kinase inhibitors (TKIs).
16. The method of claim 15 wherein the germline DNA deletion polymorphism is a germline DNA deletion polymorphism of 2903 bp located in the BIM gene.
17. The method of claim 16 wherein the germline DNA deletion polymorphism causes a splicing variation that leads to expression of an isoform of BIM protein that lacks a BH3 domain and thus inhibits the induction of apoptosis.
18. The method of claim 1 wherein the platinum-based anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lobaplatin, heptaplatin, and lipoplatin.
19. The method of claim 18 wherein the platinum-based anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin.
20. The method of claim 19 wherein the platinum-based anti-neoplastic agent is cisplatin.
21. The method of claim 1 wherein the cytotoxic activity of dianhydrogalactitol and the platinum-based anti-neoplastic agent is higher than the cytotoxic activity of the dianhydrogalactitol administered at the same dosage as a single anti-neoplastic agent.
22. The method of claim 21 wherein the platinum-based anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin.
23. The method of claim 22 wherein the platinum-based anti-neoplastic agent is cisplatin.
24. A method for treating a patient with non-small cell lung cancer (NSCLC) resistant to a platinum-based anti-neoplastic agent, wherein the patient has a mutated p53 gene consisting of the steps of:
(a) determining the existence of a mutated p53 gene in the patient, wherein the mutated p53 gene affects the resistance of the NSCLC to at least one platinum-based anti-neoplastic agent;
(b) administering a therapeutically effective quantity of dianhydrogalactitol to the patient to treat the NSCLC, wherein the therapeutically effective quantity of dianhydrogalactitol is determined from results on cell lines with a mutated p53 gene; and
(c) administering a therapeutically effective quantity of the platinum-based anti-neoplastic agent to the patient to treat the NSCLC, wherein the therapeutically effective quantity of the platinum-based anti-neoplastic agent is determined from results on cell lines with a mutated p53 gene.
25. The method of claim 24 , wherein the existence of the mutated p53 gene in the patient is determined by a method selected from the group consisting of gene sequencing, restriction fragment length polymorphism, and determining whether p53 in a cell sample from the patient binds to a pGL3 vector.
26. The method of claim 24 , wherein the method further comprises the step of administering a therapeutically effective quantity of a p53 mimetic to the patient to treat the NSCLC.
27. The method of claim 24 wherein the platinum-based anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lobaplatin, heptaplatin, and lipoplatin.
28. The method of claim 27 wherein the platinum-based anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin.
29. The method of claim 28 wherein the platinum-based anti-neoplastic agent is cisplatin.
30. The method of claim 24 wherein the cytotoxic activity of dianhydrogalactitol and the platinum-based anti-neoplastic agent is higher than the cytotoxic activity of the dianhydrogalactitol administered at the same dosage as a single anti-neoplastic agent.
31. The method of claim 30 wherein the platinum-based anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin.
32. The method of claim 31 wherein the platinum-based anti-neoplastic agent is cisplatin.
33. The method of claim 1 , wherein the combination of the therapeutically effective quantity of dianhydrogalactitol and the therapeutically effective quantity of the platinum-based anti-neoplastic agent act synergistically to treat the patient with NSCLC resistant to the platinum-based anti-neoplastic agent.