“Around 35,000 people die in the U.S. from advanced prostate cancer each year. For these patients, their cancer has become resistant to all current forms of therapy,” says Dr. Stephen Plymate, Professor in the Division of Gerontology and Geriatric Medicine at the University of Washington School of Medicine and senior author of a recent paper in Molecular Cancer Therapeutics, that tests a new compound to treat advanced, metastatic prostate cancer. Current standards of care for prostate cancer include surgery and radiation therapy for localized, early-stage disease. In advanced disease, androgen-deprivation therapy (ADT), such as abiraterone and enzalutamide, are used, which block the male sex hormones that fuel the growth of prostate cancer. However, prostate cancer cells eventually acquire resistance to these drugs, and so investigators are looking for new treatment options for these patients.
“The discovery of BKIDC-1553, our prostate cancer drug candidate, was unexpected because the mechanism of action was a complete surprise,” says Dr. Plymate. “Drs. Dustin Maly, Wes Van Voorhis, and Kayode Ojo at UW had been working on a series of anti-parasite molecules that inhibit parasite kinases. They noted some of these molecules also inhibited a human protein kinase, PKD, that is implicated in prostate cancer.” They asked Dr. Plymate’s team to examine whether any of the compounds might work against prostate cancer. As hoped, the compounds inhibited the growth of many different prostate cancer cell lines. Furthermore, the compounds showed activity in prostate cancer cells that are resistant to current prostate cancer drugs. The best results came from BKIDC-1553, their current lead compound.
To better understand how BKIDC-1553 works, they modified the molecule so that it no longer inhibited its intended target. Despite losing its ability to inhibit PKD and other protein kinases, the BKIDC variant still displayed potent activity against prostate cancer cells. Follow-up studies revealed that BKIDC-1553 selectively inhibited glycolysis that is required for prostate cancer cells to grow, particularly those that are advanced. Previous attempts to develop glycolysis inhibitor drugs have been unsuccessful due to systemic toxicity, as glycolysis is an essential process for healthy, normal cells to grow. Dr. Plymate’s team discovered that BKIDC-1553 activity depends on hexokinase 2 (HK2), an enzyme that is absent or expressed at low levels in most normal cells in the body. However, it is significantly upregulated in metastatic prostate cancer. Importantly, their compound showed a lack of toxicity in rodents and canines when administered orally at therapeutic doses. Thus, BKDIC-1553 will likely have selective toxicity only in prostate cancer cells.
Looking to the future, the major focus of Dr. Plymate and his team’s research is assessing whether BKIDC-1553 can be developed for human Phase 1 clinical trials. “Towards this aim, we have had positive discussions with the FDA as to what additional data are required to move forward with our investigational new drug application, the first step to a Phase 1 trial, and we are pursuing funding to make this happen,” says Dr. Plymate. “We are incredibly grateful to the Cancer Consortium and its members for access to patient-derived prostate cancer models and the metabolomic analysis that was key to our findings. Further, multiple discussions with members of the Prostate Cancer Consortium provided us with invaluable input to determine the surprise mechanism of action and to plan the clinical development process.” Other important questions are also being addressed. Do additional therapeutic targets exist for BKIDC-1553? Could BKIDC-1553 be used in other tumors, besides prostate cancer, where glycolysis is an important part of the tumors’ metabolism? What are the potential biomarkers for patient selection? Could a common imaging technique that uses radio-labeled glucose uptake be used to screen patients for treatment with BKIDC-1553? What therapies could be combined with BKIDC-1553 to increase the chance of cure? Overall, the future looks bright for targeting glycolysis in prostate cancer.
The spotlighted research was funded by the Lopker Family Foundation, WE-REACH, University of Washington, National Institutes of Health, US Department of Defense and US Department of Veterans Affairs.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Stephen Plymate, Dustin Maly, Lucas Sullivan, Cynthia Sprenger, and Takuma Uo contributed to this work.
Uo T, Ojo KK, Sprenger CCT, Soriano Epilepsia K, Perera BGK, Damodarasamy M, Sun S, Kim S, Hogan HH, Hulverson MA, Choi R, Whitman GR, Barrett LK, Michaels SA, Xu LH, Sun VL, Arnold SLM, Pang HJ, Nguyen MM, Vigil ABG, Kamat V, Sullivan LB, Sweet IR, Vidadala R, Maly DJ, Van Voorhis WC, Plymate SR. A compound that inhibits glycolysis in prostate cancer controls growth of advanced prostate cancer. Molecular Cancer Therapeutics (2024)