Integrative Molecular Profiling of Castration Resistant Prostate Cancer
K Sircar, D Cogdell, J Dhillon, H Huang, L Hu, N Navone, R Katz, A Khanna, TA Bismar, IH Koumakpayi, F Saad, AG Aprikian, FA Monzon, P Troncoso, W Zhang. MD Anderson Cancer Center, Houston, TX; UT Arlington, Arlington, TX; University of Calgary, Calgary, AB, Canada; Universite de Montreal, Montreal, QC, Canada; McGill University, Montreal, QC, Canada; The Methodist Hospital Research Institute, Houston, TX
Background: Castration resistant prostate cancer (CRPC), the lethal phenotype of this disease, has suffered from a lack of molecular understanding due, in part, to a lack of accessible tissues and model systems. Patients are treated with Docetaxel based chemotherapy with minimal survival benefit. In order to rationally select potential therapeutic targets, we have performed integrative molecular profiling of CRPC.
Design: The tumor genome was assessed by high resolution array comparative genomic hybridization (Agilent 244K) on clinical samples and xenografts of locally progressive CRPC (n=20) and a subset of matched hormone sensitive prostate cancer (n=4). Cross platform validation was performed using SNP Genotyping arrays (Affy250KNsp). The CRPC transcriptome was assessed using whole genome gene expression microarray (Agilent 44K). We compared our data with that from existing databases of hormone sensitive prostate cancer to elucidate differential aberrations with disease progression. FISH and IHC were performed on select targets, such as the androgen receptor (AR), on a CRPC tissue array (n=59).
Results: CRPC continues to show common, recurrent copy number alterations such as the prostate specific TMPRSS2:ERG rearrangement, along with a greater incidence of PTEN deletion and AR amplification. AR amplification was also found to be prognostic, with greater disease specific mortality among AR amplified tumors. We have found upregulated copy number and expression of genes that drive testosterone biosynthesis, including FASN (fatty acid synthase), an androgen regulated, metabolic oncogene.
Conclusions: Integrative molecular analysis of CRPC suggests that both intratumoral production of androgen and amplification of AR play major roles in therapy resistance. Targeting FASN would appear to be a potentially rational strategy as FASN is both anti-apoptotic, helping cells to survive chemotherapy induced apoptosis, and involved in testosterone biosynthesis.
Category: Genitourinary (including renal tumors)
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 121, Tuesday Afternoon