As a practicing genitourinary oncologist, Dr. Mostaghel has been involved in clinical trials for all phases of prostate cancer therapy, with a focus on understanding serum and tissue-based correlates of response and resistance to endocrine therapy in the neoadjuvant and advanced castration resistant prostate cancer setting. Primary research interests include studies of intracrine steroid synthesis in human and xenograft model systems; the role of constitutively active AR splice variants in resistance to endocrine therapy; the role of non-canonical adrenal androgens and the non-canonical activity of steroid metabolizing enzymes in prostate cancer progression; the contribution of transport proteins to tumor drug/androgen levels and prostate cancer progression; and the potential for exploiting evolutionary dynamics to delay outgrowth of resistant cells and prolong treatment response to endocrine therapies.

Dr. Mostaghel’s active projects include: 1) Analysis of serum hormone data in the phase III CHAARTED trial of docetaxel and androgen suppression for newly diagnosed metastatic prostate cancer; 2) Xenograft studies evaluating the efficacy of novel agents targeting i. the AR N terminus (as the target of all currently approved AR inhibitors is the C terminal ligand binding domain which is lost in truncated AR splice variants); ii. the adrenal enzyme CYP11A (upstream of CYP17A, the adrenal enzyme targeted by all available adrenal androgen inhibitors; inhibition of which may result in more complete steroid suppression); and, iii. Sigma1 (a novel scaffolding protein involved in tumor cell specific AR, lipid and protein homeostasis).

Funding for Dr. Mostaghel’s work comes from the National Institutes of Health, the Department of Defense and Essa Pharma, Inc.

…has been translational research evaluating mechanisms of sensitivity and resistance in genitourinary malignancies using tissue based hormonal and sequencing platforms. Through collaborations at the UW, Fred Hutchinson Cancer Research Center (FHCRC) and the VA, he and the group have evaluated tumoral upregulation of tissue androgens and the androgen receptor as relevant mechanisms of resistance to hormonal therapy. Multiple neoadjuvant studies of next generation agents have provided insights into the potential and limitations of targeting the androgen receptor. Through the VA Cooperative Studies Program (CSP) mechanism, he and members of the Urology Department have worked to improve cures for men with high risk prostate cancer using adjuvant chemotherapy (CSP553).

The most exciting current effort is leveraging the recent discovery that both prostate and bladder cancer have a much higher frequency of DNA repair defi ciency than previously recognized. Work from the UW/VA group has also discovered that approximately half of somatic defi ciency in DNA repair in prostate cancer arises from inherited “germline” lesions such as BRCA in ~ 15% of patients. Community and clinic focused efforts are underway both at VA and UW to provide access to germline and somatic sequencing for all men with advanced prostate cancer and to provide clinical studies evaluating the effi cacy of DNA damaging therapies such as platinum and PARP inhibitors, which can provide these men with the potential for “exceptional responses” to nonstandard therapies. The current germline screening studies were an outgrowth of a VA supported pilot study, which generated the data that led to successful funding of multiple studies of tumor sequencing and therapeutic studies.

Dr. Montgomery serves as Principal Investigator (PI) of a number of clinical studies and is a PI of the Northwest Prostate Cancer Specialized Program of Research Excellence (SPORE) through the National Cancer Institute at UW/FHCRC. He is a co-PI of the VA specifi c DOD proposal “Targeting the Subtype of Metastatic Prostate Cancer Defi cient in DNA Repair Capacity” and three VA specifi c/SIBCR administered projects through the Prostate Cancer Foundation: a) a collaboration with the Greater Los Angeles VAMC “A Phase 2 Study of Docetaxel and Carboplatin for treatment of patients with metastatic, castration resistant prostate cancer and germline or somatic DNA repair defi ciency”; b) a study of metastasis biopsy and sequencing “POPCaP Precision Oncology Biopsy Program – VA Puget Sound”; and, c) a POPCaP Network Center of Excellence award, which supports a consortium of six VA medical centers, all performing precision oncology studies in prostate cancer. These projects are focused on defi ning and leveraging molecular targets in veterans with advanced prostate cancer and are collaborative efforts with the Urology Department, GRECC and the other GU oncology members Steve Plymate, MD, and Elahe Mostaghel, MD, PhD. When not in the VA Prostate clinic, Bruce tries to keep up with his colleagues on biking expeditions around Vashon island and torturing his family with adventures in the great outdoors.