Compounds, compositions and methods for cancer patient stratification and cancer treatment
The present invention features improved Compounds, especially (I) methods of identifying patients having Cancer using biomarkers (e.g., PDE3A, SLFN12 and/or CREB3L1) that correlate with drug sensitivity and consequently treating a stratified patient population with an agent of the invention (e.g., Compounds 1-6 disclosed herein).
1. A method of killing or reducing survival of a cancer cell selected as responsive to a phosphodiesterase 3A (PDE3A) modulator, the method comprising contacting the cell with a PDE3A modulator selected from compounds having the structure:
wherein the cell was selected as responsive when the cell has an increased level of a PDE3A and Schlafen 12 (SLFN12) polypeptide or polynucleotide, relative to a reference, thereby reducing the survival of the cancer cell.
2. A method of reducing cancer cell proliferation in a subject pre-selected as having a cancer that is responsive to a PDE3A modulator, the method comprising administering to said subject a PDE3A modulator selected from compounds having the structure:
wherein the subject is pre-selected by detecting an increased level of a PDE3A and Schlafen 12 (SLFN12) polypeptide or polynucleotide, relative to a reference, thereby reducing cancer cell proliferation in said subject.
3. The method of claim 1 , wherein said PDE3A modulator has the structure:
4. A method of treating a hyperproliferative disease comprising administering to a subject in need thereof a compound having the structure
or a pharmaceutically acceptable salt thereof,
wherein the hyperproliferative disease is associated with an increased level of a PDE3A and Schlafen 12 (SLFN12) polypeptide or polynucleotide relative to a reference.
5. The method according to claim 4 , wherein said hyperproliferative disease is a cancer.
6. The method according to claim 4 , wherein said subject has been diagnosed with a cancer responsive to a PDE3A modulator.
7. The method according to claim 4 , wherein said cancer is a bone, breast, cervical, colon, endometrium, gastrointestinal stromal tumor (GIST), head and neck, hematopoetic, kidney, leiomyosarcoma, liver, lung, lymphoid, melanoma, ovarian, pancreas, prostate, soft-tissue sarcoma, thyroid cancer, urinary tract cancer.
8. The method according to claim 1 , wherein the cell is selected as responsive when the cell has a lack of decrease in the level of expression of CREB3L1 polypeptide or polynucleotide relative to a reference.