Composition comprising combination of rapamycin and metformin and use thereof for treating neoplastic diseases

1. A method of treating a neoplastic disease or disorder comprising administering an effective amount of a composition comprising a combination of rapamycin and metformin to a subject, wherein the molar ratio of rapamycin to metformin is in the range of about 20:1 to about 1:1.

2. The method of claim 1 , wherein the molar ratio of rapamycin to metformin is in the range of about 15:1 to about 3:1.

3. The method of claim 1 , wherein the molar ratio of rapamycin to metformin is in the range of about 10:1 to about 4:1.

4. The method of claim 1 , wherein the molar ratio of rapamycin to metformin is about 5:1 to about 3:1.

5. The method of claim 1 , wherein the molar ratio of rapamycin to metformin is about 5:1 to about 4:1.

6. The method of claim 1 , wherein the neoplastic disease or disorder is selected from a post-transplant malignancy, a genetically-driven neoplasia associated with mTORC1 hyperactivation, and a viral associated malignancy.

7. The method of claim 6 , wherein the neoplastic disease or disorder is a post-transplant malignancy selected from the group consisting of skin cancer, Kaposi's sarcoma, hepatocellular carcinoma, and renal cell carcinoma.

8. The method of claim 6 , wherein the neoplastic disease or disorder is a genetically-driven neoplasia associated with mTORC1 hyperactivation selected from the group consisting of familial adenomatous polyposis (FAP), colon cancer, vascular neoplasms and anomalies, PTEN Hamartoma Tumor Syndrome (PHTS), PIK3CA mutations, mTORC1 gain-of function mutations, hypereosinophilic syndrome, renal cell carcinoma, Peutz-Jeghers Syndrome, Erdheim-Chester Disease, Chronic Myelogenous Leukemia, tuberous sclerosis complex (TSC), lymphangioleiornyomatosis (LAM), and Neuroendocrine tumors (NETs).

9. The method of claim 6 , wherein the neoplastic disease or disorder is a viral associated malignancy selected from the group consisting of human herpes virus-8 (HHV-8) associated malignancies, hepatocellular carcinoma, lymphoproliferative syndromes, and breast cancer.

10. The method of claim 1 , wherein the composition is formulated for oral administration.

11. The method of claim 1 , wherein the composition is formulated for topical administration.

12. The method of claim 1 , wherein the composition is formulated for parenteral administration.

13. The method of claim 11 , wherein the composition comprises a nanoparticle encapsulating at least the rapamycin, the metformin, or the combination of rapamycin and metformin.

14. A method of treating a neoplastic disease or disorder mediated by mTORC1 activation comprising administering an effective amount of a composition comprising a combination of rapamycin and metformin to a subject, wherein the molar ratio of rapamycin to metformin is in the range of about 20:1 to about 1:1.

15. The method of claim 14 , wherein the molar ratio of rapamycin to metformin is in the range of about 10:1 to about 4:1.

16. The method of claim 15 , wherein the composition comprises a nanoparticle encapsulating at least the rapamycin, the metformin, or the combination of rapamycin and metformin.

17. The method of claim 14 , wherein the neoplastic disease or disorder is selected from a post-transplant malignancy, a genetically-driven neoplasia associated with mTORC1 hyperactivation, and a viral associated malignancy.

18. The method of claim 17 , wherein the neoplastic disease or disorder tuberous sclerosis complex (TSC).

19. The method of claim 17 , wherein the neoplastic disease or disorder is lymphangioleiomyomatosis (LAM) occurring either sporadically or as part of TSC.

20. The method of claim 14 , wherein the neoplastic disease or disorder is a gastrointestinal neoplasm.