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Precision medicine is an emerging strategy for treating cancer, in which the unique mutations that occur in an individual’s tumor are used to select therapies that the tumor will likely be susceptible to.  For a new treatment called PARP-inhibitors, this strategy of identifying patients who will benefit has been highly successful.  However, a study by the Prostate Cancer Foundation (PCF) West Coast Dream Team has discovered that prostate cancer can become resistant to this precision therapy by over-writing the very mutations that caused them to be susceptible in the first place.

PARP-inhibitors are the best studied precision therapies in prostate cancer, and work against tumors with mutations in genes that repair damaged DNA — about 25% of metastatic prostate cancer cases.  These genes include BRCA1 and BRCA2, which are infamous for driving breast and ovarian cancer, when mutated.  For tumors to be susceptible to PARP-inhibitors, both copies of a DNA damage-repair gene need to be mutated (we inherit two copies of most genes – one from each parent).

A team led by Dr. Felix Feng, a PCF Young Investigator and physician-scientist at the University of California, San Francisco, investigated why two patients who had previously responded to the PARP-inhibitor olaparib, had relapsed.  Both patients had tumors with dual-copy mutations in the BRCA2 gene at the time of PARP-inhibitor prescription — one copy of the gene was lost through a mutation, while the second copy contained a mutation that caused the BRCA2 protein to be cut short and therefore nonfunctional.  Dr. Feng found that the tumors of both patients had developed resistance to olaparib by acquiring a second mutation in the mutated-but-present copy of the BRCA2 gene which negated the original protein-shortening mutation, and allowed for a working version of BRCA2 protein to be made.  This nulled susceptibility of the tumor cells to PARP-inhibitors.  Even more striking, was that within each patient, multiple different groups of tumor cells had gained unique BRCA2-restoring mutations to evade PARP-inhibitor therapy.

Dr. Feng performed these analyses using circulating tumor DNA, which is DNA from tumor cells that is released into the circulation and collected by a blood draw.  The use of circulating tumor DNA has only recently been achievable due to scientific advances, but has several advantages over tumor biopsies, including ease of collection, and representation of body-wide cancer burden as opposed to just the biopsied area.

These studies demonstrate that precision medicine can now be performed with simple blood draws – not only for making an original precision prescription, but for decrypting recurrent tumors and selecting therapies that will work better against these new, unique tumors.

This PCF-funded study was recently published in the scientific journal, Cancer Discovery.

Andrea Miyahira
Dr. Andrea Miyahira has a PhD in cancer immunology, and is Director of Research at the Prostate Cancer Foundation.

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