Buffalo, New York, USA., June 26, 2022 – A team of researchers at Roswell Park Comprehensive Cancer Center, led by Dhyan Chandra, PhD , have uncovered evidence that could lead to the development of a new treatment option for patients with metastatic, resistant or recurrent prostate cancer. Their findings, published today in the Journal of Clinical Investigation , suggest that mitochondrial unfolded protein response — a unique longevity function of mitochondria — could be a new target for the treatment and management of this patient population.
The standard first-line approach for prostate cancer typically targets the main driver of the disease — the androgen receptor signaling axis. While current therapeutic agents initially reduce tumor burden, disease recurrence is likely and, for patients with a hormone-resistant phenotype, drugs that target the androgen receptor are ineffective.
Dr. Chandra and his team found that two key components of the mitochondrial unfolded protein response (UPRmt) were necessary for the development of advanced prostate cancer. These included the heat shock protein 60 (HSP60), a mitochondrial chaperonin, and caseinolytic protease (ClpP), a mitochondrial protease.
“The HSP60-mediated chaperonin system facilitates protein folding, whereas ClpP protease degrades unfolded protein to maintain mitochondrial protein homeostasis, which is critically required for cancer cell survival and growth,” explains Dr. Chandra, while noting that HSP60 acts as upstream regulator of ClpP and HSP60 interacts with ClpP. “This suggests that a drug that interferes with the interaction of HSP60 and ClpP will disrupt cancer cell survival and block the growth and progression of prostate cancer.”
The researchers also identified a novel mitochondrial unfolded protein response inhibitor, DCEM1, that hampers HSP60’s interactions with ClpP in prostate cancer cells and tumors. In their preclinical studies, the authors show that this inhibition of HSP60-ClpP interaction impeded the development of resistant or aggressive disease. The study’s first author, Rahul Kumar, PhD , Research Associate at Roswell Park, discovered that using DCEM1 to disrupt the interactions between HSP60 and ClpP interferes with survival signaling and triggers metabolic stress, which results in the death of prostate cancer cells.
The team demonstrates that targeting the HSP60-ClpP axis — which is unregulated in prostate cancer irrespective of androgen receptor status — is a promising therapeutic approach for this patient population.
About Roswell Park
Roswell Park Comprehensive Cancer Center is a community united by the drive to eliminate cancer’s grip on humanity by unlocking its secrets through personalized approaches and unleashing the healing power of hope. Founded by Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. Learn more at www.roswellpark.org, or contact us at 1-800-ROSWELL (1-800-767-9355) or [email protected] .