Frequent genetic changes in receptor related to prostate cancer care could cause treatment resistance

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Wednesday, November 30, 2016

Frequent genetic rearrangements in the androgen receptor could be limiting treatment options for prostate cancer patients, according to new research out of the University of Minnesota. Currently, the main treatment for prostate cancer inhibits androgen receptor activity. However, the new paper identified frequent rearrangements in the metastases of prostate cancer, allowing cancer cells to accumulate a variety of receptor forms and increasing resistance to treatments.

The paper is published in the latest issue of Nature Communications.

“We knew genetic rearrangements in the androgen receptor occurred in laboratory models of prostate cancer progression, and this could promote therapeutic resistance,” said Scott Dehm, Ph.D., associate professor in the Department of Laboratory Medicine and Pathology in the University of Minnesota Medical School and a member of the Masonic Cancer Center, University of Minnesota. “An outstanding question was if this reflected a mechanism of therapeutic resistance in prostate cancer patients, or whether it was unique to laboratory models.”

Dehm, the senior author on the paper, partnered with University of Minnesota collaborators Christine Henzler, Ph.D., Yingming Li, M.D., and Rendong Yang, Ph.D., to test prostate cancer tissue. They obtained a diverse collection of tissues from the University of Washington and University of Texas Southwestern Medical Center and, using advanced genomics technologies developed at the University of Minnesota, took a closer look for the presence of androgen receptor genetic rearrangements.

"International consortia have performed genomic sequencing of hundreds of prostate cancer specimens with the goal of identifying genetic drivers of disease development, progression and therapeutic resistance,” said Dehm. “Remarkably, these studies missed a major type of alteration in one of the most important genes in prostate cancer, the androgen receptor. This underscores the importance of hypothesis-driven research, even in the current era of large-scale cancer genomics."

Dehm and his collaborators hope to utilize the findings to develop clinical trials testing whether detection of genetic rearrangements in the androgen receptor can predict resistance to therapies. They also hope the findings will lead to new treatment strategies for prostate cancer patients resistant to current therapies.

“Our work argues new treatment strategies should focus on inhibiting activity of the variant forms of the androgen receptor arising from these genetic rearrangements,” said Dehm.

Funding for this study was provided by National Institutes of Health grants: R01CA174777, PO1CA085859 and PO1CA163227, T32GM008244, and the Pacific Northwest Prostate Cancer SPORE (P50CA97186), U.S. Department of Defense Prostate Cancer Research Program grant W81XWH-15-1-0430, as well as the Richard M. Lucas Foundation. Dehm also holds the Apogee Enterprises Chair in Cancer Research.