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Isaac Y. Kim

MD, PhD, MBA
Professor of Urology; Professor, Urology; Chair, Urology; Chief, Urology; Co-Leader, Cancer Signaling Networks, Yale Cancer Center

Contact Information

Isaac Y. Kim, MD, PhD, MBA

Mailing Address

  • Urology

    P.O. Box 208058

    New Haven, CT 06520-8058

    United States

Yale Medicine

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Research Summary

My research is focused on lethal prostate cancer. Clinically, I am interested in the role of surgery in men with metastatic and high-risk prostate cancer. In the laboratory, my team is exploring various mechanisms of treatment resistance in prostate cancer cells.

Extensive Research Description

Clinical research: Role of surgery in men who present with metastatic prostate cancer.

Despite the significant advances made in prostate cancer treatment over the last two decades, a recent study demonstrated no significant improvement in outcome in men with newly diagnosed metastatic prostate cancer (mPCa). Indeed, the 5-year relative survival rate in patients who present with mPCa is only 28%. Given such dismal prognosis of mPCa, new ideas and novel approaches must be explored. In this regard, recently emerging data suggest that controlling the local primary disease may enhance survival in men with mPCa. Indeed, the hypothesis is that there exists and dynamic interaction between primary and metastatic prostate cancer and that the removal of the primary disease site will render the metastatic disease more vulnerable to systemic treatment. Therefore, I helped establish an international team to prospectively evaluate surgical intervention (cytoreductive prostatectomy) in men with de novo mPCa. This study will accrue up to 870 patients with metastatic prostate cancer.

Laboratory research: mechanism of treatment resistance in prostate cancer cells

Degrading androgen receptor (AR) and its variants, especially AR-V7, via the DNA-binding domain (DBD) is a promising yet unvalidated treatment strategy in prostate cancer (CaP). In approximately two-thirds of patients with the lethal castration-resistant prostate cancer (CRPC) refractory to second-line antiandrogen therapy (SAT), AR and AR variants remain potential therapeutic targets. We reasoned that AR’s DBD is the clinically optimal target for neutralizing both AR and AR variants for the following three reasons. First, the domain is retained in AR variants associated with castration resistance found in CaP, including AR-V7. Second, acquired mutations that confer antiandrogen resistance occur mostly in the ligand-binding and N-terminal domains (LBD and NTD, respectively), suggesting that targeting the DBD will be effective in this setting as well. Third, targeting AR-DBD will complement drugs currently in use or being investigated to block AR’s LBD and NTD. As our core strategy, we used the principle of proteolysis targeting chimera (PROTAC). As heterobifunctional molecules, PROTACs catalyze protein degradation by recruiting ubiquitin E3 ligase to promote polyubiquitination of protein of interest (POI) and its subsequent degradation in the proteasome. Because one PROTAC molecule can degrade up to 200 POIs, the standard target occupancy pharmacology does not apply, and a relatively lower drug level is sufficient to be active. Our team’s overall goal is to understand various mechanisms of resistance to androgen deprivation therapy in CaP. Currently, my lab is focused on validating AR-DBD directed PROTAC in degrading AR and AR-V7 and develop candidate molecules for clinical translation

Coauthors

Research Interests

Prostatectomy; Prostatic Neoplasms

Selected Publications

Clinical Trials

ConditionsStudy Title
ProstateRandomized Three-Arm Trial to Evaluate the Effect of Neoadjuvant Apalutamide Alone or in Combination With Abiraterone Acetate and GnRH Agonist on Enhancing Surgical Outcome of Nerve-Sparing Radical Prostatectomy in Men With High-Risk Prostate Cancer
ProstateSIMCAP (Surgery in Metastatic Carcinoma of Prostate): Phase 2.5 Multi-Institution Randomized Prospective Clinical Trial Evaluating the Impact of Cytoreductive Radical Prostatectomy Combined With Best Systemic Therapy on Oncologic and Quality of Life Outcomes in Men With Newly Diagnosed Metastatic Prostate Cancer
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