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    Genomic research may explain resistance to immunotherapy

     

    “Based on our research so far, we are fairly certain that immune evasion mediated by the PPARγ/RXRα pathway affects patient responses to checkpoint inhibitor therapy for MIBC. However, because all of the checkpoint inhibitors that are approved for treating bladder cancer act via the PD-1/PD-L1 pathway, we are now repeating our experiments using an antiPD-1 inhibitor in the context of PPARγ over-expression,” said Dr. Daugaard, of the University of British Columbia, Vancouver.

    “In addition, we have launched a drug development program at the Vancouver Prostate Centre to develop a small molecule targeting PPARG as a possible therapeutic approach to restore immunosurveillance and increase response to checkpoint immunotherapy.”

    Dr. Daugaard, who is also a senior scientist at the Vancouver Prostate Centre, noted that the small molecule drug development program at the Vancouver Prostate Centre has a history of success. In 2015, it licensed a novel small molecule anti-androgen receptor agent to Roche for commercial development as a treatment for drug-resistant prostate cancer.

    Read: Physical inactivity raises bladder cancer risk

    Meanwhile, Dr. Daugaard and colleagues are engaged in several other lines of research involving PPARγ/RXRα. Whether activation of the PPARγ/RXRα heterodimer affects immune inhibition mechanisms of other tumors or is a phenomenon that is specific to luminal bladder cancer is one of the questions they are investigating. Dr. Daugaard told Urology Times that so far, overexpression of PPARG has not been found in prostate cancer, but its potential presence has not yet been ruled out, and analyses of renal cell carcinoma are also ongoing.

    In addition, they are trying to determine whether the RXRA hotspot mutations are innate or acquired after initiation of treatment for cancer.

    “The answer to this question has been unclear because the genomics databases that we have investigated include specimens from both treated and untreated patients. Analyses of a lot more samples will be needed,” Dr. Daugaard said.

    More from Urology Times:

    Chemo instillation reduces bladder Ca recurrence

    QoL better with bladder Ca immunotherapy vs. chemo

    Robotic vs. open cystectomy: How PFS, OS compare


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