A team of researchers at Roswell Park Comprehensive Cancer Center, led by Dhyan Chandra, Ph.D., has discovered a new therapeutic target for neuroendocrine prostate cancer, a rare and hard-to-treat form of prostate cancer.

Their findings, published in the journal Oncogene, suggest that a set of processes known as the mitochondrial unfolded protein response, could be an Achilles' heel for this often-deadly cancer type, and may point the way to a new treatment approach.

"There is an urgent need to identify and develop treatment approaches for this often-deadly subtype of prostate cancer," says Dr. Chandra, Professor of Oncology in the Department of Pharmacology & Therapeutics at Roswell Park.

"Patients with castrate-resistant neuroendocrine prostate cancer are typically treated the same as other small cell cancer subtypes—with platinum-based therapeutics such as cisplatin and carboplatin, but nearly all cases will become resistant to this treatment."

The standard first-line treatment for patients with prostate cancer involves repressing the main driver of prostate cancer—the androgen receptor (AR) signalling axis. However, prostate cancer cells evolve in response to androgen deprivation therapy (ADT).

A subset of surviving cancer cells can transform from one cell type to another—from an AR-positive epithelial cell type to an AR-negative neuroendocrine cell type. Because neuroendocrine transdifferentiated prostate cancer cells do not express AR, they are inherently resistant to standard-of-care ADT.

Mitochondria are key cellular structures that produce and distribute energy throughout the body. They are armed with a built-in protein quality control system—the mitochondrial unfolded protein response, or UPR^mt—that helps them maintain function even when component proteins within get damaged or start to malfunction due to cancer or other abnormalities.

In preclinical studies, Dr. Chandra and his team found that the activity and assembly of energy-producing functions of mitochondria are highly dysfunctional in castrate-resistant neuroendocrine prostate tumours.

However, upregulation of key UPR^mt components—such as heat shock protein 60 (HSP60)—suggest activation of compensatory stress signaling.

Clinically, expression of key UPR^mt components correlate with both disease progression and pervasiveness. Importantly, the team discovered that genetic deletion or pharmacologic inhibition of key UPR^mt chaperon HSP60 reverted neuroendocrine prostate cancer cells back to an epithelial-like state and reduces tumor burden in vivo.

The study's first author, Jordan Woytash, Ph.D., previously a doctoral candidate working in Dr. Chandra's lab, discovered that HSP60-dependent aggressive neuroendocrine prostate cancer characteristics are associated with upregulation of β-catenin signalling.

β-catenin is a multifunction protein that acts as a transcriptional coactivator and regulator of cell-cell adhesion to promote stemness and metastasis in many cancer types including neuroendocrine prostate cancer.

β-catenin is notoriously difficult to target pharmacologically. Interestingly, inhibition of HSP60 represses β-catenin expression and signaling both in cancer cells and in vivo tumours by modulating mitochondrial metabolism.

"Historically, β-catenin has been considered an undruggable target," says Dr. Chandra. "The observation that β-catenin signaling is tied to HSP60-regulated mitochondrial bioenergetics, and can be targeted via HSP60, provides a new therapeutic avenue for cancers driven by aberrant β-catenin signaling."

The researchers also discovered that processes enabling mitochondrial biogenesis (synthesis of new proteins)—including HSP60 upregulation—are among the mechanisms of resistance to cisplatin therapy, since cisplatin damages mitochondrial DNA and subsequently bioenergetics in addition to nuclear DNA.

HSP60 inhibition not only renders neuroendocrine prostate cancer cells back to a cisplatin-sensitive state but also increases sensitivity to other mitochondrial-toxic drugs such as doxorubicin.

"Our work demonstrates that castrate-resistant neuroendocrine prostate cancer relies on mitochondrial quality control to sustain tumour growth, metastatic potential and cisplatin resistance," notes Dr. Chandra.

"These findings provide alternative treatment approaches for castrate-resistant neuroendocrine prostate cancer that does not respond to androgen-modulating or current chemotherapeutic agents, possibly with existing drugs."