New therapeutic strategies in the fight against advanced prostate cancer

Therapy resistance remains one of the biggest challenges in cancer treatment, and prostate cancer is no exception. In their latest study published in Genes & Development, Vincent Giguère, Ph.D. and his team at the Rosalind and Morris Goodman Cancer Institute (GCI) have identified a promising new target: ERRγ, a transcription factor whose downregulation of its activity is linked to one of the most aggressive subtypes of prostate cancer.

Prostate cancer is the most commonly diagnosed cancer among men in Canada, but not all forms of the disease behave the same way. Neuroendocrine prostate cancer is a rare and aggressive form of prostate cancer that often arises when conventional prostate adenocarcinomas develop resistance to hormonal therapies. Once this transition occurs, treatment options become extremely limited.

Despite the molecular nuances of neuroendocrine prostate cancer, research led by first author Ting Li, a post-doctoral fellow in Professor Giguère’s team, revealed a downregulation of ERRγ in mouse models of neuroendocrine prostate cancer as well as in a subset of patients, particularly those with functional loss of the tumour suppressor PTEN. ERRγ is a key transcription factor involved in regulating cellular energy metabolism, among other functions. Notably, ERRγ belongs to the same family of proteins than the androgen receptor, and thus an excellent target for drug discovery. Using genetically engineered mouse models, the researchers demonstrated that the loss of ERRγ accelerates the transition to the aggressive neuroendocrine form. Remarkably, restoring expression in human prostate cancer cells reversed this transition, validating ERRγ’s role at preventing progression of the disease toward a poor outcome.

To uncover how ERRγ is protective against neuroendocrine prostate cancer, the team used state-of-the art transcriptomic and metabolomic approaches to identify the genes and metabolic pathways it regulates. Among key findings, they observed that RET and EZH2, both previously associated with cancer progression, are upregulated when ERRγ is lost. Importantly, when Pr. Giguère’s team tested inhibitors for RET and EZH2 in both human and mouse pre-clinical models of neuroendocrine prostate cancer, they observed an enhanced anti-tumour activity with the combined treatment compared to the single agents.

These findings have major clinical implications. Currently, there are no effective therapies for patients whose prostate cancer evolves into the neuroendocrine subtype. By identifying ERRγ as a suppressor of this transition and potential benefit of combined RET and EZH2 therapy in select patients, Pr. Giguère’s group has opened the door to new therapeutic strategies that could improve outcomes for patients facing this aggressive form of the disease.

This study was conducted in collaboration with Pr. Jin-jian Lu of University of Macau and supported by the Canadian Institutes of Health Research, the Terry Fox Research Institute, the Cancer Research Society, Fonds de Recherche du Québec – Santé and Défi Canderel.

Full article: ERRγ impedes neuroendocrine prostate cancer development