A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer
Copyright policy )A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer
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.
- Harvard Medical School United States
- DANA-FARBER CANCER INSTITUTE
- BETH ISRAEL DEACONESS MEDICAL CENTER
- Broad Institute United States
- Department of System Biology Harvard Medical School United States
Male, Therapies, Investigational, Androgen Antagonists; Androgens; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Evaluation, Preclinical; Humans; Male; Mice; Mice, Transgenic; Models, Biological; Orchiectomy; PTEN Phosphohydrolase; Phenylthiohydantoin; Prostatic Neoplasms; Signal Transduction; Translational Medical Research; Treatment Failure; Therapies, Investigational; Genetics, Drug Evaluation, Preclinical, PTEN Phosphohydrolase, 610, 500, Prostatic Neoplasms, Androgen Antagonists, Antineoplastic Agents, Mice, Transgenic, Models, Biological, Article, Translational Research, Biomedical, Mice, Cell Line, Tumor, Benzamides, Nitriles, Phenylthiohydantoin, Androgens, Animals, Humans, Orchiectomy, Signal Transduction
Male, Therapies, Investigational, Androgen Antagonists; Androgens; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Evaluation, Preclinical; Humans; Male; Mice; Mice, Transgenic; Models, Biological; Orchiectomy; PTEN Phosphohydrolase; Phenylthiohydantoin; Prostatic Neoplasms; Signal Transduction; Translational Medical Research; Treatment Failure; Therapies, Investigational; Genetics, Drug Evaluation, Preclinical, PTEN Phosphohydrolase, 610, 500, Prostatic Neoplasms, Androgen Antagonists, Antineoplastic Agents, Mice, Transgenic, Models, Biological, Article, Translational Research, Biomedical, Mice, Cell Line, Tumor, Benzamides, Nitriles, Phenylthiohydantoin, Androgens, Animals, Humans, Orchiectomy, Signal Transduction
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