TY - JOUR
T1 - A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer
AU - Lunardi, Andrea
AU - Ala, Ugo
AU - Epping, Mirjam T.
AU - Salmena, Leonardo
AU - Clohessy, John G.
AU - Webster, Kaitlyn A.
AU - Wang, Guocan
AU - Mazzucchelli, Roberta
AU - Bianconi, Maristella
AU - Stack, Edward C.
AU - Lis, Rosina
AU - Patnaik, Akash
AU - Cantley, Lewis C.
AU - Bubley, Glenn
AU - Cordon-Cardo, Carlos
AU - Gerald, William L.
AU - Montironi, Rodolfo
AU - Signoretti, Sabina
AU - Loda, Massimo
AU - Nardella, Caterina
AU - Pandolfi, Pier Paolo
N1 - Funding Information:
We would like to thank current members of the Pandolfi laboratory for critical discussion and T. Garvey for insightful editing. We are grateful to the Preclinical Murine Pharmacogenetics Facility at Beth Israel Deaconess Medical Center and the Dana-Farber/Harvard Cancer Center for expert support in all aspects related to the work in mice. The Dana-Farber/Harvard Cancer Center is supported in part by a National Cancer Institute Cancer Center Support grant (US National Institutes of Health (NIH) 5 P30 CA06516). We also thank C. Abate-Shen (Columbia University) for kindly providing the antibody to Probasin and the Small-Animal Imaging Facility at Beth Israel Deaconess Medical Center for the MRI work. Additionally, we are grateful to G. Fedele and X. Wu from the Loda laboratory and the Center for Molecular Oncologic Pathology at Dana-Farber/Brigham and Women’s for their technical support in the generation, staining and analysis of the TMA. U.A. has been supported by a fellowship from the Italian Association for Cancer Research (AIRC) under grant IG-9408. A.L. has been supported in part by a fellowship from the Istituto Toscano Tumori (ITT, Italy). This work has been supported through the Mouse Models of Human Cancer Consortium/National Cancer Institute grant (RC2 CA147940-01) and the A. David Mazzone Research Awards Program, Project Development Award to P.P.P.
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
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U2 - 10.1038/ng.2650
DO - 10.1038/ng.2650
M3 - Article
C2 - 23727860
AN - SCOPUS:84879671701
SN - 1061-4036
VL - 45
SP - 747
EP - 755
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -