Compositions and methods for cancer expressing PDE3A or SLFN12
The present invention features improved methods of identifying patients having cancer (e.g., melanoma, adenocarcinoma, lung, cervical, liver or breast cancer) using biomarkers (e.g., PDE3A, SLFN12) that correlate with drug sensitivity and consequently treating a stratified patient population with an agent of the invention (e.g., DNMDP, zardaverine, and anagrelide).
1. A method of reducing cancer cell proliferation, killing, or reducing the survival of a cancer cell selected as responsive to a phosphodiesterase 3A (PDE3A) modulator, the method comprising
contacting the cell with a PDE3A modulator that induces interaction between PDE3A and Schlafen 12 (SLFN12) proteins in the cell, wherein the cell was selected as having an increase in the level of a PDE3A and a SLFN12 polypeptide or polynucleotide relative to a reference, thereby reducing cancer cell proliferation, killing, or reducing the survival of the cancer cell,
wherein the PDE3A modulator is 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP), or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the level of PDE3A or SLFN12 was detected by a method selected from the group consisting of immunoblotting, mass spectrometry, and immunoprecipitation.
3. The method of claim 1 , wherein the level of PDE3A or SLFN12 polynucleotide is detected by a method selected from the group consisting of quantitative PCR, Northern Blot, microarray, mass spectrometry, and in situ hybridization.
4. The method of claim 1 , wherein the cancer cell is a melanoma, endometrium, lung, hematopoietic/lymphoid, ovarian, cervical, soft-tissue sarcoma, leiomyosarcoma, urinary tract, pancreas, thyroid, kidney, glioblastoma, or breast cancer cell.
5. The method of claim 1 , wherein the cancer cell is not a B-cell proliferative type cancer.
6. The method of claim 1 , wherein the cancer cell is not multiple myeloma.
7. The method of claim 1 , wherein the PDE3A modulator reduces an activity of PDE3A.
8. The method of claim 1 , wherein the PDE3A modulator is administered orally.
9. The method of claim 1 , wherein the PDE3A modulator is administered by intravenous injection.
10. The method of claim 1 , wherein the cancer is a melanoma, endometrium, lung, hematopoietic/lymphoid, ovarian, cervical, soft-tissue sarcoma, leiomyosarcoma, urinary tract, pancreas, thyroid, kidney, glioblastoma, or breast cancer.