Abstract IA06: Co-Targeting cell cycle and androgen signaling to personalize therapy for hormone dependent prostate cancer

Prostate cancer (PC) is an androgen driven and dependent disease and androgen deprivation therapy (ADT) is the standard for patients with metastatic hormone sensitive disease. Despite a high response rate, most patients will progress to castration resistance. The expanding molecular knowledge highlights the biologic heterogeneity and adaptive capacity of PC, and provides the rationale for a preemptive multi-targeted therapeutic strategy. Compelling support for the latter strategy is provided by recent data from two randomized trials demonstrating an unprecedented impact on survival with the addition of docetaxel to ADT.Androgens drive proliferation of PC cells via upregulation of cyclin D which complexes with the cyclin-dependent protein kinases 4/6 (CDK4/6) resulting in phosphorylation of retinoblastoma (Rb) tumor suppressor protein and G1/S progression. Alterations in this pathway contribute to progression to castration-resistance. Palbociclib is a novel specific CDK4/ 6 inhibitor which was recently approved in combination with letrozole for postmenopausal women with ER +, HER2 negative advanced breast cancer. In preclinical prostate cancer models, palbociclib inhibited proliferation and promoted G1 arrest in an Rb and Cyclin D dependent manner. Current data indicate that wild-type Rb expression is present in in 95% vs 75% of patients with newly diagnosed vs metastatic castration resistant PC respectively. We estimate that 80-90% of early metastatic hormone-sensitive PC wil...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Targeting CDK/cyclins: Hormone Dependent Cancers and Beyond: Oral Presentations - Invited Abstracts Source Type: research