Components of mitochondrial stress response could be key to overcoming resistant/recurrent prostate cancer
- Researchers uncover an androgen-independent driver of prostate cancer
- Mitochondrial HSP60 and ClpP are required for disease progression
- Targeting these mitochondrial components is a promising therapeutic approach
BUFFALO, N.Y. — 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.
“Patients with hormone-refractive prostate cancer are typically treated with taxanes such as docetaxel or cabazitaxel, but outcomes are overwhelmingly poor in those with advanced disease, nearly all of whom will see their cancer return following initial treatment,” says Dr. Chandra, Associate Professor of Oncology in the Department of Pharmacology & Therapeutics at Roswell Park. “There is an urgent need to identify and develop treatment modalities for prostate cancer that do not rely on targeting the androgen receptor signaling axis.”
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.
“This study provides strong evidence for developing a novel drug for the treatment of metastatic and resistant prostate cancer,” notes Dr. Chandra. “Since the current androgen deprivation and taxane-based therapies are not effective, these findings provide alternative treatment approaches for prostate cancer that do not rely on androgen receptor signaling axis.”
This work was funded by grants from the National Cancer Institute (R01CA160685, R01CA246437, R01CA207757, R01CA234162, R01CA237027, R01CA240290 and P30CA016056) and American Cancer Society (MBG-21- 048-01-MBG and RSG-12-214-01–CCG), with additional support from donations to Roswell Park.