Asparagine Synthetase Is a Target in Castration Resistant Prostate Cancer.
Kanishka Sircar, Heng Huang, David Cogdell, Jasreman Dhillon, Vassiliki Tzelepi, Nora Navone, Tarek Bismar, Herve Koumakpayi, Fred Saad, Armen Aprikian, Patricia Troncoso, Wei Zhang. UT MD Anderson Cancer Center, Houston, TX; UT Arlington, TX; University of Calgary, AB, Canada; University of Montreal, QC, Canada; McGill University, Montreal, QC, Canada
Background: Recent developments in the treatment of the lethal, castration resistant phenotype of prostate cancer (CRPC) have largely focused on abrogating the androgen signaling axis. Novel targets that work by a different mechanism are also needed for this therapy resistant phase of disease. Gene expression studies, with an inherent high false discovery rate, have been further hindered by the paucity of frozen CRPC samples. We sought to narrow the list of candidate genes to those that are biologically meaningful and potential drivers by integrating DNA copy number with mRNA expression and to validate our results at the proteomic level.
Design: Clinical samples and xenografts of locally advanced CRPC tissues from 27 patients were interrogated using high throughput molecular profiling platforms: DNA copy number was assessed by high resolution aCGH (Agilent 244K); the transcriptome was studied using whole genome gene expression microarray (Agilent 44K). We compared our expression data to existing GEO datasets of CRPC. Validation of the proteins of interest was performed using reverse phase protein lysate arrays (RPPA) on frozen samples from 25 patients and immunohistochemistry on tissue arrays from 120 unique CRPC patients.
Results: Our integrative analysis of overexpressed (n=711) and amplified (n=2171) genes in CRPC showed only 32 genes with both increased copy number and mRNA overexpression, including (predictably) the androgen receptor. The asparagine synthetase (ASNS) gene was prioritized for further study as it survived both our integrative genomic analysis and was overexpressed in other CRPC datasets. Validation at the protein level by both RPPA and IHC methods showed ASNS to be significantly overexpressed in CRPC (p<0.05) of both adenocarcinoma and small cell carcinoma histologies. Further, we identified parent/mouse xenograft models of CRPC that possess and lack ASNS overexpression, respectively.
Conclusions: We have identified and validated asparagine synthetase as a novel target in both glandular and small cell CRPC. Future functional studies using asparagine depletion strategies may be performed using our identified xenograft model system.
Category: Genitourinary (including renal tumors)
Tuesday, March 1, 2011 2:15 PM
Platform Session: Section A, Tuesday Afternoon