Identification of PDE3 modulator responsive cancers
The present disclosure features methods for identifying pateints having a hyperproliferative disease, disorder, or condition responsive to phosphodiesterase 3 (PDE3) and schlafen family member 12 (SLFN12) complex formation. The hyperproliferative disease, disorder, or condition may be cancer in a patient including glioblastoma, melanoma, ovarian cancer, cervical cancer, sarcoma, or hematopoietic cancers, such as acute myeloid leukemia. Those responsive diseases, disorders, or conditions may be identified using the biomarker AIP and/or TRRAP in combination with those biomarkers pertinent to phosphodieseterase 3 and schlafen family member 12 complexes which may be formed by PDE3 modulation with certain active compounds. Expression of combinations of these biomarkers have been shown to correlate with active compound (e.g., PDE3 modulator, PDE3A modulator, PDE3B modulator) sensitivity.
1. A method of killing or reducing the survival of a cell selected as responsive to PDE3A-SLFN12 complex formation or PDE3B-SLFN12 complex formation comprising contacting said cell with a PDE3 modulator, wherein said cell is selected as responsive to said PDE3 modulator when said cell:
(i) expresses AIP and/or TRRAP polypeptides or polynucleotides,
(ii) has increased expression of PDE3A and/or PDE3B polypeptides or polynucleotides relative to a reference, and
(iii) has increased expression of SLFN12 polypeptides or polynucleotides relative to the reference.
2. The method according to claim 1 , wherein said cell is selected as responsive to said PDE3 modulator when said cell:
(i) expresses AIP and TRRAP polypeptides or polynucleotides,
(ii) has increased expression of PDE3A and/or PDE3B polypeptides or polynucleotides relative to a reference, and
(iii) has increased expression of SLFN12 polypeptides or polynucleotides relative to the reference.
3. The method according to claim 1 , wherein said cell is selected as responsive to said PDE3 modulator when said cell:
(i) expresses AIP and TRRAP polypeptides or polynucleotides,
(ii) has increased expression of PDE3A polypeptides or polynucleotides relative to a reference, and
(iii) has increased expression of SLFN12 polypeptides or polynucleotides relative to the reference.
4. The method according to claim 1 , wherein said cell is selected as responsive to said PDE3 modulator when said cell:
(i) expresses AIP and TRRAP polypeptides or polynucleotides,
(ii) has increased expression of PDE3B polypeptides or polynucleotides relative to a reference, and
(iii) has increased expression of SLFN12 polypeptides or polynucleotides relative to the reference.
5. The method of claim 1 , wherein the PDE3 modulator is 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one (DNMDP) or (6S)-5-[4′-fluoro-2-(trifluoromethyl) biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (Compound X).
6. The method of claim 1 , wherein said PDE3 modulator is administered orally or by intravenous injection.
7. A method for the treatment of a hyperproliferative disease, disorder, or condition in a subject comprising administering to said subject a PDE3 modulator, wherein said subject is identified as having a hyperproliferative disease, disorder, or condition that is responsive to the PDE3 modulator by obtaining one or more cells of the hyperproliferative disease, disorder, or condition from the subject and detecting:
(i) the expression of aryl hydrocarbon receptor interacting protein (AIP) polypeptides or polynucleotides and/or transformation/transcription domain associated protein (TRRAP) polypeptides or polynucleotides in the cell;
(ii) the expression of phosphodiesterase 3A (PDE3A) polypeptides or polynucleotides or the expression of phosphodiesterase 3B (PDE3B) polypeptides or polynucleotides in the cell relative to a reference, and
(iii) the expression of Schlafen family member 12 (SLFN12) polypeptides or polynucleotides in the cell relative to the reference;
wherein said hyperproliferative disease, disorder, or condition is characterized as responsive to said complex formation if:
(i) AIP and/or TRRAP are expressed in the cell,
(ii) the expression of PDE3A and/or PDE3B is increased relative to the reference, and
(iii) the expression of SLFN12 is increased relative to the reference.
8. The method of claim 7 , wherein said hyperproliferative disease, disorder, or condition is a myeloproliferative disease.
9. The method of claim 7 , wherein said cell is a cancer cell.
10. The method of claim 9 , wherein said cancer cell is a melanoma-, endometrium-, lung-, hematopoetic-/lymphoid-, ovarian-, cervical-, soft-tissue-sarcoma-, urinary tract, pancreas-, thyroid-, kidney-, glioma-, glioblastoma-, or breast-cancer cell.
11. The method of claim 9 , wherein said cancer cell is a melanoma-, glioma-, glioblastoma-, ovarian-, sarcoma-, acute myeloid leukemia-, or lung adenocarcinoma cell.
12. The method of claim 7 , wherein said cell is collected from a tissue sample, a blood sample, or a plasma sample from the subject.
13. The method of claim 7 , wherein the PDE3 modulator is 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3 (2H)-one (DNMDP) or (6S)-5-[4′-fluoro-2-(trifluoromethyl) biphenyl-4-yl]-6-methyl-3,6-dihydro-2H-1,3,4-oxadiazin-2-one (Compound X).