null RI-MUHC leads study to identify a novel mechanism driving aggressive prostate cancer
This international research collaboration may lead to a shift in the clinical management of patients with an aggressive, deadly prostate cancer
Recently published in Nature Communications, researchers from the Research Institute of the McGill University Health Centre (RI-MUHC) present a study that may lead to improved clinical outcomes for prostate cancer patients who do not respond to standard treatments. Working with an international team of scientists, the study focused on the role of the oncogenic transcription factor MYC and its interplay with the androgen receptor.
Prostate cancer is the most commonly diagnosed cancer in Canadian men, with an estimated 24,600 men diagnosed in 2022. Although most men with prostate cancer do successfully manage their disease, about 4,600 Canadian men die each year of prostate cancer, making it the third leading cause of cancer-related death among men.
The goal of this study was to gain insights into molecular factors that drive prostate cancer initiation and the subsequent progression to metastatic cancer, for which therapeutic options are currently limited. The team focused on a protein named “MYC,” an oncogenic transcription factor. Normally, MYC regulates the expression of certain genes, but in prostate cancer, this protein is often aberrantly overexpressed. The subsequent reprogramming of cellular programs drives disease progression.
“MYC is like a maverick conductor in an orchestra. If its expression is dysregulated, it can still make prostate cells play a melody. The only issue is that this is no longer the melody on the program,” says David Labbé, PhD, junior scientist in the Cancer Research Program at the RI‑MUHC and assistant professor and William Dawson Scholar at McGill University, who co-led this study with researchers at the Dana-Farber Cancer Institute.
Androgens are male sex hormones, key in supporting the growth of prostate tumours, he explains. Drugs known as androgen receptor signaling inhibitors block the activation of the androgen receptor by androgens and successfully suppress tumour growth, but not for all patients.
“Surprisingly, although both MYC and the androgen receptor are central to prostate cancer etiology, we knew very little about their interplay,” adds Labbé.
To study this question, the researchers leveraged single-cell technologies to map the expression of about 20,000 genes from thousands of individual cells and used a genetically engineered mouse model of prostate cancer. They discovered that when MYC protein is overexpressed, the expression of genes driven by the androgen receptor is shut down in prostate cells. Through a series of next-generation sequencing technologies and bioinformatics analyses, the research team also identified the molecular basis of this phenomenon.
“In technical terms, what we see is the selective pausing of the RNA polymerase II at androgen receptor controlled genes, basically preventing the androgen receptor program from being played by the musicians,” explains Nadia Boufaied, PhD, a research associate in David Labbé’s laboratory. “In more general terms, this means that it is no longer the androgen receptor that is in control of prostate cancer growth. Rather, MYC has taken over.”
The cornerstone of prostate cancer treatment is that the androgen receptor is in control. This is why drugs such as androgen receptor signaling inhibitors are used for prostate cancer treatment. The pressing question that the researchers next addressed was, when MYC has taken over, is a patient’s response to current therapies impacted?
Using multiple datasets of both molecular and clinical data from 1,418 patients, the team found that when MYC had taken over the androgen receptor program, these patients were more likely to progress to a metastatic, castration-resistant prostate cancer. These patients were also more likely to be non-responsive to treatment with androgen receptor signaling inhibitors and were more likely to succumb to their disease.
“Taken together with other recent advances in this field, our findings provide hope that prostate cancer patients could benefit from precision oncology approaches to provide a significant therapeutic benefit in the management of aggressive prostate cancer characterized by MYC dysregulation,” says David Labbé.
While targeting MYC is something that researchers have attempted unsuccessfully for decades, David Labbé’s 2019 Nature Communications publication showed that dietary intervention to reduce saturated fat consumption is one possible means of dampening the MYC transcriptional program, and potentially increasing the effectiveness of treatments like androgen receptor signaling inhibitors for patients who do not respond to standard treatments.
“Further work will be needed in the coming years to define the best path forward to translate these findings into clinical practice, but in this era of personalized medicine, we hope that treatment for these patients can soon be adapted accordingly,” concludes Labbé.
About the study:
Read the publication in Nature Communications.
In addition to Nadia Boufaied, co-first author of this study, contributers include Tarek Hallal, Anna de Polo, Walaa Alahmadi and Janie Larocque from the Labbé laboratory.
The authors gratefully acknowledge support from the Cancer Research Society, the Prostate Cancer Foundation, the Fonds de Recherche du Québec – Santé and the Canadian Institutes of Health Research, as well many other organizations as listed in the original publication. The Labbé laboratory is also grateful to the support from the McGill University Health Centre Foundation and the Montreal General Hospital Foundation.
May 13, 2022