Companion diagnostic for CDK4 inhibitors
The present invention relates to the use of one or more biomarkers to evaluate the likelihood that a CDK4 inhibitor would produce an anti-cancer effect in a subject. It is based, at least in part, on the discovery that cancer treatment with a CDK4 inhibitor is more effective where treated cancer cells undergo cellular senescence rather than a transient cell cycle arrest, where cellular senescence is associated with decreased MDM2 protein level. Accordingly, in non-limiting embodiments, the present invention provides for methods, compositions, and kits for a companion diagnostic for CDK4 inhibitors, and in particular, to the use of MDM2 expression as a biomarker for the likelihood that a cancer can be successfully treated by CDK4 inhibition.
1. A method for treating a subject having a cancer selected from the group consisting of liposarcoma, breast cancer, glioma and glioblastoma, comprising obtaining a sample of the cancer before treatment of the subject with a CDK4 inhibitor selected from the group consisting of an ATP-competitive inhibitor of CDK4, pyridopyrimidine compounds, pyrrolopyrimidine compounds, indolocarbazole compounds, Palbociclib Isethionate, LEE011, LY2835219, PD0332991, Flavopiridol Hydrochloride, an antisense oligonucleotide that inhibits the expression or activity of CDK4, a shRNA molecule that inhibits the expression or activity of CDK4, a siRNA molecule that inhibits the expression or activity of CDK4 and combinations thereof, and determining, in one or more cancer cells from the sample, the effect of treatment with the CDK4 inhibitor on the expression level of a MDM2 biomarker, where if the MDM2 biomarker expression level is decreased following treatment with the CDK4 inhibitor, then initiating treatment of the subject with a therapeutically effective amount of the CDK4 inhibitor.
2. The method of claim 1 , where the cancer is a liposarcoma.
3. The method of claim 1 , where the cancer is a glioma or glioblastoma.
4. The method of claim 1 , where the cancer is a breast cancer.
5. A method for treating a subject having a cancer selected from the group consisting of liposarcoma, breast cancer, glioma and glioblastoma, comprising, obtaining a sample of the cancer after treatment with a CDK4 inhibitor selected from the group consisting of an ATP-competitive inhibitor of CDK4, pyridopyrimidine compounds, pyrrolopyrimidine compounds, indolocarbazole compounds Palbociclib Isethionate, LEE011, LY2835219, PD0332991, Flavopiridol Hydrochloride, an antisense oligonucleotide that inhibits the expression or activity of CDK4, a shRNA molecule that inhibits the expression or activity of CDK4, a siRNA molecule that inhibits the expression or activity of CDK4 and combinations thereof, and determining, in the sample, the expression level of a MDM2 biomarker, where if the MDM2 biomarker expression level, when compared to a reference standard level, is decreased following treatment with a CDK4 inhibitor, then continuing or resuming treatment of the subject with a therapeutically effective amount of a CDK4 inhibitor.
6. The method of claim 5 , where the reference standard level is the level of the MDM2 biomarker in a sample of the cancer prior to treatment with a CDK4 inhibitor.
7. The method of claim 5 , where the reference standard level is the level of the MDM2 biomarker in a parallel culture of the subject's cancer cells.
8. The method of claim 5 , where the cancer is a liposarcoma.
9. The method of claim 5 , where the cancer is a glioma or glioblastoma.
10. The method of claim 5 , where the cancer is a breast cancer.