Method of treatment of p53 WT tumors
The present invention relates to methods of treating p53 wild type (WT) tumors. In particular, the invention provides novel therapies for p53 WT tumors based on the combination of Mouse Double Minute 2 (MDM2) inhibitors, e.g. HDM201, together with Casein Kinase 1 alpha (CK1α) degrading agents and/or an MDM4 inhibitors, e.g. lenalidomide. The combination may be used in the treatment of solid as well as hematologic p53 WT tumors, e.g. Merkel cell carcinoma (MCC) or myelodysplastic syndrome (MDS).
1. A pharmaceutical composition comprising (a) a mouse double minute 2 (MDM2) inhibitor which is HDM201 ((S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one) or nutlin-3 and (b) i) a Casein Kinase 1 alpha (CKlα) degrading agent which is lenalidomide and/or ii) a mouse double minute 4 (MDM4) inhibitor which is SC-24-UR-99 (4-(3-amino-1-(4-chloro-5-methyl-6-(methylamino)pyridin-3-yl)-5-fluoro-1H-indazol-6-yl)naphthalen-1-ol).
2. The composition of claim 1 , wherein (a) is HDM201.
3. The composition of claim 1 , wherein (a) is nutlin-3.
4. The composition of claim 1 , wherein (a) is HDM201 and (b) is lenalidomide.
5. The composition of claim 1 , wherein (a) is HDM201 and (b) is SC-24-UR99.
6. The composition of claim 1 , wherein (a) is HDM201 and (b) is lenalidomide and SC-24-UR99.
7. A method of treating a p53 wild type (WT) tumor in a subject, comprising administering to the subject (a) an MDM2 inhibitor which is HDM201 or nutlin-3 and (b) i) a CKlα degrading agent which is lenalidomide and/or ii) an MDM4 inhibitor which is SC-24-UR-99.
8. The method of claim 7 , wherein (a) is HDM201.
9. The method of claim 7 , wherein (a) is nutlin-3.
10. The method of claim 7 , wherein (a) is HDM201 and (b) is lenalidomide.
11. The method of claim 7 , wherein (a) is HDM201 and (b) is SC-24-UR99.
12. The method of claim 7 , wherein (a) is HDM201 and (b) is lenalidomide and SC-24-UR99.
13. The method of claim 7 , wherein the p53 WT tumor is a solid tumor.
14. The method of claim 13 , wherein the solid tumor is selected from the group consisting of sarcomas, liposarcoma, soft tissue sarcoma, lymphomas, non-Hodgkin's lymphoma (NHL), Mantle cell lymphoma (MCL), melanomas, skin melanoma, uveal melanoma, blastomas, neuroblastoma, colon tumor, colorectal tumor, kidney tumor, liver tumor, skin cancer, and Merkel cell carcinoma (MCC).
15. The method of claim 14 , wherein the solid tumor is a Merkel cell carcinoma (MCC).
16. The method of claim 14 , wherein the Merkel cell carcinoma (MCC) is a Merkel cell polyomavirus (MCV)-positive MCC.
17. The method of claim 7 , wherein the p53 WT tumor is a hematological tumor or a hematologic malignancy.
18. The method of claim 17 , wherein the hematological tumor is selected from the group consisting of acute myeloid leukemia (AML), multiple myeloma (MM), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL).
19. The method of claim 17 , wherein the hematological tumor is multiple myeloma (MM) or myelodysplastic syndrome (MDS).
20. The method of claim 19 , wherein the hematological tumor is myelodysplastic syndrome (MDS).
21. The method of claim 7 , wherein (a) is HDM201, wherein (b) is lenalidomide, and wherein the p53 WT tumor is MCV-positive MCC.
22. The method of claim 7 , wherein (a) is HDM201, wherein (b) is lenalidomide, and wherein the p53 WT tumor is MDS.
23. The method of claim 7 , further comprising one or more further anti-cancer agent(s).