Discovery of Novel Drug Targets for Small Cell Prostate Cancer.
Kyung Park, Himisha Beltran, David Rickman, Theresa Y MacDonald, Stephane Terry, Francesca Demichelis, David M Nanus, Mark A Rubin. Weill Cornell Medical College, New York
Background: Small cell carcinoma of the prostate is a rare but an aggressive cancer with poor prognosis. It is believed that small cell carcinoma can arise de novo or from existing adenocarcinoma although no molecular studies have documented this transition. We sought to better understand the molecular transformation of small cell carcinoma and identify novel drug targets.
Design: We used Next Generation RNA sequencing and oligonucleotide arrays to extensively profile small cell prostate tumors, prostate adenocarcinomas, and benign prostate tissue, and validated findings on tumors from a large cohort of patients using immunohistochemistry (IHC) and Fluorescence In Situ Hybridization (FISH).
Results: ERG rearrangement was present in 47% of small cell prostate cancer, but ERG protein expression was absent and corresponded directly with lack of androgen receptor expression. We sequenced 7 small cell prostate tumors, 30 adenocarcinomas, and 5 benign samples. We identified the cell cycle kinases, Aurora kinases A and B, as significantly overexpressed and Aurora A amplified in small cell prostate cancer compared to adenocarcinoma or benign (p<0.001). Evaluation of Aurora kinase expression by IHC of tumors revealed that the majority of small cell cancers (21/28) displayed strong cytoplasmic staining with Aurora A antibody and strong nuclear staining with Aurora B antibody, and IHC was positive in > 50% of tumor cells. In comparison, only 15/118 of adenocarcinoma cases had positive cytoplasmic staining with Aurora A antibody and 34/118 were positive for speckled nuclear and nuclear membrane staining with Aurora B antibody. In these cases, IHC positive cells made up less than 5% of cells. None of the 21 benign samples had Aurora kinase overexpression. FISH evaluation revealed significant copy number gain of Aurora A in 8/28 small cell cancers, 7/118 adenocarcinoma, and none of the benign cases. The small cell prostate cancer cell line and xenografts (NCI-H660), was preferentially sensitive to Aurora kinase inhibition, compared to the prostate adenocarcinoma (VCaP, LnCaP).
Conclusions: There is likely clonal origin of small cell prostate cancer from adenocarcinoma (with ERG fusion positivity seen in both), but ERG expression is limited to adenocarcinoma and driven by AR signaling. Aurora kinase A and B are significantly overexpressed, and Aurora A is amplified, in small cell prostate cancer compared to adenocarcinoma and benign prostate. In vitro and in vivo data confirms that these are novel drug targets for small cell prostate cancer.
Category: Genitourinary (including renal tumors)
Monday, February 28, 2011 1:00 PM
Poster Session II # 152, Monday Afternoon