| Title | A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer. |
| Publication Type | Journal Article |
| Year of Publication | 2013 |
| Authors | Lunardi A, Ala U, Epping MT, Salmena L, Clohessy JG, Webster KA, Wang G, Mazzucchelli R, Bianconi M, Stack EC, Lis R, Patnaik A, Cantley LC, Bubley G, Cordon-Cardo C, Gerald WL, Montironi R, Signoretti S, Loda M, Nardella C, Pandolfi PPaolo |
| Journal | Nat Genet |
| Volume | 45 |
| Issue | 7 |
| Pagination | 747-55 |
| Date Published | 2013 Jul |
| ISSN | 1546-1718 |
| Keywords | Androgen Antagonists, Androgens, Animals, Antineoplastic Agents, Cell Line, Tumor, Drug Evaluation, Preclinical, Humans, Male, Mice, Mice, Transgenic, Models, Biological, Orchiectomy, Phenylthiohydantoin, Prostatic Neoplasms, PTEN Phosphohydrolase, Signal Transduction, Therapies, Investigational, Translational Medical Research, Treatment Failure |
| Abstract | Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten loss-driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed with deletion of either Trp53 or Zbtb7a together with Pten, leading to the development of castration-resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1, XIAP and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments. |
| DOI | 10.1038/ng.2650 |
| Alternate Journal | Nat Genet |
| PubMed ID | 23727860 |
| Grant List | 5 P30 CA06516 / CA / NCI NIH HHS / United States RC2 CA147940-01 / CA / NCI NIH HHS / United States |
Related Faculty:
Massimo Loda, M.D.