Novel Research Method May Lead to Tailored Treatments for Late-stage Prostate Cancer
A study using a novel “co-clinical” approach that integrates data from hundreds of genetically engineered mouse models with clinical data from tissue samples of hundreds of patients with castration-resistant prostate cancer, has identified several molecular pathways underlying castration resistance. The study, published in Nature Genetics, was led by researchers from Beth Israel Deaconess Medical Center (BIDMC) and may offer the potential for the development of tailored therapies for late-stage prostate cancer patients.
Study Details
The genetically engineered mice underwent androgen deprivation therapy and then followed for several months. To determine the effectiveness of the therapy, the investigators subjected the mice to monthly imaging by CT-PET scans, MRI scans, or a combination of the two. Using the imaging data together with pathological, molecular, and genetic analysis of the various mouse tumors, the researchers found a functional link between the genetic makeup of the tumors and their response to therapy. The results helped the researchers define a new combination of molecular events used by the tumor to circumvent androgen deprivation therapy and found that the combined inhibition of the XIAP, SRD5A1, and AR pathways overcame resistance to androgen deprivation therapy.
The researchers then translated the information to their cohort of prostate cancer patients and found that the genetic and molecular data collected from the castration-resistant mice predicted the efficacy of the therapy in the human patients, revealing the same mechanisms of resistance in the poor responders as had been observed in the mouse models.
Could Lead to Tailored Treatments
“By integrating this data from the various relevant mouse models and from patient samples, we have identified XAF1-XIAP/SRD5A1 as a predictive and, most important, actionable signature for late-stage prostate cancer that has grown resistant to androgen deprivation therapy,” said senior author Pier Paolo Pandolfi, MD, PhD, Scientific Director of the Cancer Center at BIDMC and the George C. Reisman Professor of Medicine at Harvard Medical School in a BIDMC press release.
Dr. Pandolfi further stated, “As tumors with different genetic make-ups can develop different forms of resistance to treatments, our strategy could be summarized as divide et impera. Translated into a therapeutic approach this essentially means, stratify the patients based on genetics and molecular criteria, and then decide on a combination of treatments.”
The study was supported, in part, by grants from the National Cancer Institute, the Italian Association for Cancer Research, and a fellowship from the Istituto Toscano Tumori.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
