CDK8/19 inhibitors for therapy of advanced prostate cancer

DESCRIPTION provided by applicant All existing forms of androgen deprivation therapy ADT the backbone of systemic prostate cancer PCa treatment involve inhibition of either ligand production or ligand binding to the androgen receptor AR However most of the patients with advanced PCa eventually progress into castration refractory prostate cancer for which there are no current cures The principal cause of ADT failure is the selection for the forms of AR that no longer require androgen but remain active in regulating transcription of androgen responsive genes and confer resistance to anti androgens or testosterone synthesis inhibitors Furthermore the inhibition of AR not only suppresses AR activated cancer supporting genes but also induces other genes supporting cell proliferation which are normally repressed by AR Thus there is a need for therapies that i block AR induced transcription but do not interfere with the inhibition of transcription by AR and ii act downstream of AR and should therefore be effective against its androgen independent forms We have now identified two closely related transcription regulating kinases CDK as novel modulators of AR signaling that satisfy the above criteria CDK inhibition suppresses AR induced gene expression and cell proliferation in androgen dependent and androgen independent PCa models and inhibits other transcription factors implicated in PCa such as MYC and NFkB We have developed a first in class selective CDK inhibitor drug candidate Senexin B which is non toxic bioavailable both parenterally and orally and active in various cancer models in vivo We now propose to investigate the suitability of this compound for the treatment of advanced PCa For this purpose we will verify the tumor suppressive effects of the CDK inhibitor Senexin B observed in preliminary studies in a partially androgen independent PCa model that expresses the full length form of AR determine if oral administration of Senexin B can be used in this model instead of the parenteral The efficacy of Senexin B will be compared in intact and castrated mice as an indication if CDK inhibition may be advantageously used in combination with ADT We will also determine the efficacy of Senexin B in a fully androgen independent xenograft model that expresses a splice variant of AR commonly found in human tumors In addition we will test the efficacy of Senexin B in a syngeneic murine PCa transplant model proliferation of which is driven by MYC oncogene Phase II of this project will comprise detailed analysis of the effects of Senexin B in different PCa models comparison of the efficacy of Senexin B alone and in combinations with ADT and chemotherapy and IND enabling preclinical studies required to start clinical trials of the first in class CDK inhibitor for he treatment of advanced PCa PUBLIC HEALTH RELEVANCE Androgen deprivation therapy is the backbone of systemic prostate cancer treatment but most of the patients with advanced prostate cancer eventually develop an androgen independent form of the disease for which there are no current cures We have now identified two closely related enzymes CDK and CDK as playing a key role in both androgen dependent and androgen independent prostate cancers and developed the first in class selective CDK inhibitor We now propose to explore in animal models the utility of this inhibitor for the therapy of advanced prostate cancer