Tailored combinatorial epigenetic therapies for P53 gain-of-function tumors
The present invention provides compositions and methods for treating and preventing cancer. The invention comprises an inhibitor of epigenetic regulators, including MLL1, MLL2, MOZ, menin, WDR5, or a combination thereof. In one embodiment, the invention provides a personalized method of treating a cancer as dependent upon its epigenetic signature.
1. A method of treating cancer caused by a p53 gain of function (GOF) mutation selected from the group consisting of R248Q, R248W, R249S, and R273H in a subject comprising administering to the subject an effective amount of a composition comprising at least one compound selected from the group consisting of MI-2-2 or a derivative or analogue thereof, OICR-9429 or a derivative or analogue thereof, or —N,N′-bis(4-aminophenyl)-N,N′-dimethylethylenediamine (ISC-30) or a derivative or analogue thereof:
2. The method of claim 1 , wherein the compound inhibits the interaction between an MLL and menin.
3. The method of claim 2 , wherein the compound is N,N′-bis(4-aminophenyl)-N,N′-dimethylethylenediamine (ISC-30)
4. The method of claim 2 , wherein the compound is MI-2-2, or an analog or derivative thereof.
5. The method of claim 1 , wherein the compound inhibits the interaction between an MLL and WDR5.
6. The method of claim 5 , wherein the compound is OICR-9429, or a derivative or analogue thereof.
7. The method of claim 1 , wherein the cancer is selected from the group consisting of carcinomas, sarcomas, lymphomas, leukemia, blastomas, germ cell cancers, breast cancer, lung cancer, pancreatic cancer, stomach cancer, bone cancer, ovarian cancer, prostate cancer, bladder cancer, cervical cancer, colon cancer, skin cancer, gliomas, esophageal cancer, oral cancer, gallbladder cancer, liver cancer, testicular cancer, uterine cancer, thyroid cancer, throat cancer, Li-Fraumeni Syndrome and a combination thereof.
8. A personalized method of treating cancer in a subject comprising detecting a p53 gain of function (GOF) mutation selected from the group consisting of R248Q, R248W, R249S, and R273H, in a tumor cell of the subject, and administering to the subject an effective amount of a composition comprising at least one compound selected from the group consisting of MI-2-2 or a derivative or analogue thereof, OICR-9429 or a derivative or analogue thereof, or —N,N′-bis(4-aminophenyl)-N,N′-dimethylethylenediamine (ISC-30) or a derivative or analogue thereof:
9. The method of claim 8 , wherein the compound inhibits the interaction between an MLL and menin.
10. The method of claim 9 , wherein the compound is N,N′-bi s(4-aminophenyl)-N,N′-dimethylethylenediamine (ISC-30)
11. The method of claim 9 , wherein the compound is MI-2-2 or a derivative or analogue thereof.
12. The method of claim 8 , wherein the compound inhibits the interaction between an MLL and WDR5.
13. The method of claim 12 , wherein the compound is OICR-9429, or a derivative or analogue thereof.
14. The method of claim 8 , wherein the cancer is selected from the group consisting of carcinomas, sarcomas, lymphomas, leukemia, blastomas, germ cell cancers, breast cancer, lung cancer, pancreatic cancer, stomach cancer, bone cancer, ovarian cancer, prostate cancer, bladder cancer, cervical cancer, colon cancer, skin cancer, gliomas, esophageal cancer, oral cancer, gallbladder cancer, liver cancer, testicular cancer, uterine cancer, thyroid cancer, throat cancer, Li-Fraumeni Syndrome and combinations thereof.