Abstract B11: Stromal response to prostate cancer therapeutics

Abstract

Abstract Docetaxel (D) is a clinically used front-line chemotherapeutic agent for castration resistant advanced prostate cancer (Pca). However, its long-term benefits are limited, with most patients eventually progressing because of inherent or acquired drug resistance. The treatment of advanced Pca is a significant challenge and there are no effective treatments that stably suppress the disease. The mechanisms behind the resistance to Docetaxel are not fully understood. It is well accepted that tumor microenvironment is essential for tumor cells survival, cancer progression and metastasis. However, the mechanisms by which tumor cells interact with their surrounding at different stages of cancer development or during chemotherapy are largely unidentified. The central goal is to identify the cellular and biochemical responses of stromal cells in tumor microenvironment with which prostate cancer cells interact. Specifically, the interaction of prostate cancer cells with stromal cells of the prostate or the bone microenvironment in the presence of clinically used cancer therapeutics will be examined. Key regulators of these interactions will also be identified. Such regulators include cytokines, growth factors, proteins, and their receptors. By identifying these regulators and their contribution to tumor drug response, novel therapeutics targeted to the microenvironment can be developed. Therefore, we hypothesize that the response of prostate stromal cells exposed to chemotherapeutic agents could modify drug response or therapeutic outcome of prostate cancer. Cellular proliferation was analyzed by MTT assay. The IC50 of Docetaxel for WPMY-1 (normal stromal), LNCaP (androgen dependent), DU-145 (androgen independent), and HS27A (bone stromal) showed inhibitory effects between 2-10nM. Cell cycle profiles were assessed by flow cytometry. The analysis showed that Docetaxel (2-50nM) induced prominent G2-M arrest in prostate and stromal cells within 24 hours. Gene expression profiling of prostate cancer and stromal cells lines were evaluated. To obtain the expression profiles, we conducted a human cytokines and chemokines array, which consisted of 84 specific genes. Analysis of the prostate cancer and stromal cells treated with Docetaxel revealed differential expression patterns. These results suggest Docetaxel exhibits strong anti-proliferative effects and analysis of the gene array suggest regulation of genes associated with, cell growth, survival, proliferation, metastasis, angiogenesis, and apoptosis. Note: This abstract was not presented at the conference. Citation Format: Dominique Nicole Gales, Khalda Fadlalla, Upender Manne, Clayton Yates, Temesgen Samuel. Stromal response to prostate cancer therapeutics. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B11.