Abstract C11: Using GCP to improve initial response to androgen deprivation in prostate cancer

Recurrent prostate cancer (PCa) is treated with androgen deprivation therapy (ADT, chemical castration), but patients on this treatment frequently relapse, indicative of the advent of castration resistant prostate cancer (CRPC). Due to the multifocal nature of the disease, any one treatment may not affect all pathways altered in CRPC; therefore, we set out to delay CRPC by increasing the apoptotic rate during ADT. We previously published that Filamin A (FlnA) is localized to the nucleus in androgen-dependent cells, whereas its expression is lost from the nucleus in CRPC. Restoration of FlnA nuclear expression induced apoptosis in the absence of androgens. We now show that genistein combined polysaccharide (GCP), a combination of isoflavones, can induce FlnA translocation to the nucleus. GCP and its main component genistein previously failed to prevent progression in pre-prostatectomy patients with low-grade PCa. However, our new data, both in vitro and in an animal model, show that GCP impedes relapse following castration, and induces apoptosis in PCa cells undergoing ADT, by promoting FlnA cleavage and nuclear translocation. Investigation of the mechanism of GCP's effects on FlnA showed that ADT phosphorylates FlnA and prevents its cleavage, whereas GCP inhibits FlnA phosphorylation, thereby promoting its cleavage and nuclear translocation. Additional data show that nuclear localization of FlnA induces apoptosis during ADT by preventing androgen receptor (AR) stabilization and by suppression of the ErbB3/PI3K/Akt axis. Taken together, our results identify GCP as a putative therapeutic module to prolong the effectiveness of ADT in patients with metastatic prostate cancer. Citation Format: Benjamin A. Mooso, Maria Mudryj, Ralph W. deVere White, Paramita M. Ghosh, Rosalinda M. Savoy, Jean P. Cheung, Ruth L. Vinall, Clifford G. Tepper, Yu Wang, Salma Siddiqui, Roble G. Bedolla, Margarita Mikhailova. Using GCP to improve initial response to androgen deprivation in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C11.