Sanjay Gupta, PhD, of Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center will receive $962,000 over three years to investigate drug resistance mechanisms in prostate cancer. The funding is part of the Department of Defense’s Idea Award program, that aims to improve quality of life by decreasing the impact of cancer on active duty service members and their communities.

Gupta will use the award and clinically-approved drugs to develop a safe, efficacious, and cost-effective combination therapy for castrate-resistant prostate cancer (CRPC). Gupta is the Carter Kissell Professor and Research Director in the Department of Urology, a research scientist at the Louis Stokes VA Medical Center, and a member of the Case Comprehensive Cancer Center.

“Castrate-resistant prostate cancer is the deadliest form of prostate cancer,” Gupta said. “It often emerges after a man has one or both testes removed, as a tumor begins to adapt to low androgen levels.” CRPC tumors can also emerge following medications that suppress androgens—hormones only found in males. The median survival rate for men diagnosed with CRPC is less than two years.

A CRPC tumor adapts to low androgen levels by either producing its own androgens, or altering androgen receptors on the surfaces of tumor cells. Treatments for CRPC are sequential: patients normally receive chemotherapy, immunotherapy, radiation therapy, and ultimately medications to modulate androgen signaling inside cancer cells. Clinical trials to test the safety and efficacy of CRPC medications are ongoing.

Said Gupta, “New generation androgen signaling inhibitors will offer an initial positive response, but that is followed by drug resistance and clinical progression. Patients usually relapse within a year.” Gupta’s study will test whether medications that target slightly different signaling pathways could be used to help overcome drug resistance.

Gupta will study simvastatin and metformin—two drugs that appear promising in his preliminary studies. Together, the drugs weaken CRPC cells and halt metastasis. Simvastatin works by blocking the rate-limiting enzyme for cholesterol synthesis, called HMG-CoAR (3-hydroxy-3-methylglutaryl-Coenzyme A). Metformin activates AMP kinase (5’-adenosine monophosphate kinase), a so-called “master regulator” of androgen signaling in prostate cancer cells.

Together with colleagues, Gupta will test whether the enzymes HMG-CoAR and AMP kinase represent novel therapeutic targets for CRPC—particularly CRPC that is already resistant to existing androgen inhibitor drugs. The researchers will transplant drug-resistant CRPC patient samples into mouse models and determine if changing the enzymes' levels via medications offers therapeutic benefits.

The studies will not only fundamentally advance the field of androgen signaling, but could help lay a foundation for clinical trials into new therapeutic options for CRPC. “Our ultimate goals are prolonging survival, minimizing complications, and maintaining quality of life for these patients,” Gupta said.

Gupta’s collaborators in the newly funded study include Gregory T. MacLennan, PhD, Matthew Cooney, MD, Pingfu Fu, PhD, and Vinay Varadan, PhD, all Case Western Reserve School of Medicine faculty and Case Comprehensive Cancer Center members, and Eswar Shankar, PhD, cancer biologist in the Department of Urology at Case Western Reserve School of Medicine.


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