Roswell Park Team Discovers New Treatment Target for Neuroendocrine Prostate Cancer
Dhyan Chandra, PhD, Professor of Oncology in the Department of Pharmacology & Therapeutics
Researchers at Roswell Park Comprehensive Cancer Center, led by Dhyan Chandra, PhD, Professor of Oncology in the Department of Pharmacology & Therapeutics, have identified a new therapeutic target for neuroendocrine prostate cancer, a rare and aggressive form of prostate cancer. Their findings, published in the journal Oncogene, highlight vulnerabilities in tumor cells stemming from mitochondrial unfolded protein response (UPRmt), revealing a potential pathway for innovative treatments.
“There is an urgent need to develop new treatment approaches for this often-deadly subtype of prostate cancer,” says Dr. Chandra. “Patients with castrate-resistant neuroendocrine prostate cancer are typically treated with platinum-based therapies like cisplatin, but resistance to these treatments is almost inevitable.”
A Challenge in Treatment Standard treatment for prostate cancer involves suppressing the androgen receptor (AR) signaling axis, the main driver of the disease. However, under androgen deprivation therapy (ADT), some cancer cells transition from AR-positive epithelial types to AR-negative neuroendocrine types, making them resistant to traditional therapies.
The Role of Mitochondria Mitochondria, vital for cellular energy production, maintain a protein quality control system known as UPRmt. Dr. Chandra’s team found that while mitochondrial function is highly dysfunctional in castrate-resistant neuroendocrine prostate cancer, components like heat shock protein 60 (HSP60) are upregulated to compensate for stress. This upregulation correlates with disease progression and treatment resistance.
Notably, inhibiting HSP60 through genetic deletion or pharmacological methods caused neuroendocrine cancer cells to revert to an epithelial-like state, reducing tumor burden in preclinical models.
The study’s first author, Jordan Woytash, PhD, uncovered that HSP60-dependent aggressive characteristics in neuroendocrine prostate cancer are tied to β-catenin signaling, which promotes metastasis and resistance. While β-catenin is traditionally considered an undruggable target, HSP60 inhibition effectively represses its signaling by modulating mitochondrial metabolism.
“β-catenin’s role in cancer is well-known, but targeting it directly has been challenging,” explains Dr. Chandra. “Our findings show that HSP60 can indirectly suppress β-catenin activity, opening new therapeutic possibilities.”
Implications for Treatment Resistance Cisplatin therapy damages both nuclear and mitochondrial DNA, but HSP60 enables tumor cells to resist this damage by supporting mitochondrial biogenesis. By inhibiting HSP60, researchers restored cisplatin sensitivity and enhanced the efficacy of other mitochondrial-toxic drugs like doxorubicin.
“Our work demonstrates that neuroendocrine prostate cancer relies on mitochondrial quality control to sustain growth, metastasis, and chemoresistance,” notes Dr. Chandra. “Targeting this pathway could lead to alternative treatments, potentially with existing drugs.”
Support and Funding This research was supported by grants from the National Cancer Institute (R01CA160685 and R01CA246437), the American Cancer Society (MBG-21-048-01-MBG and RSG-12-214-01), the Roswell Park Alliance Foundation, and the NCI’s Cancer Center Support Grant to Roswell Park (P30-CA016056).