This international research collaboration may transform the clinical management of patients with aggressive and fatal prostate cancer
Recently Posted in Nature CommunicationsResearchers from the McGill University Health Center Research Institute (RI-MUHC) have presented a study that may improve 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 oncogene transcription factor MYC and its interaction with the androgen receptor.
Investigator David Labe, PhD (center), research associate and co-author Nadia Boufayed, PhD (third from left), and interns in the Labey lab, are part of the Cancer Research Program at the McGill University Health Center Research Institute. (Photo courtesy of Carl Philippe Gerard)
Prostate cancer is the most common cancer diagnosed in Canadian men, with an estimated 24,600 men diagnosed in 2022. Although most men with prostate cancer successfully manage their disease, about 4,600 Canadian men die each year from prostate cancer The prostate, making it the third leading cause of cancer-related deaths among men.
The aim of this study was to gain insight into the molecular factors that drive the initiation of prostate cancer and the subsequent progression to metastatic cancer, for which treatment options are currently limited. The team focused on a protein called ‘MYC’, which is an oncogenic transcription factor. Normally, MYC regulates the expression of certain genes, but in prostate cancer, this protein is often aberrantly secreted. Subsequent reprogramming of cellular programs leads to disease progression.
“MYC is like a rebellious conductor in an orchestra. If its expression is dysregulated, it can still make prostate cells play a melody,” says David Lappé, Ph.D., junior scientist in the Cancer Research Program at RI-MUHC and Assistant Professor and William Dawson Scholar at McGill University, And who co-led this study with researchers at the Dana-Farber Cancer Institute.
He explains that androgens are male sex hormones, an essential component of supporting the growth of prostate tumors. Drugs known as androgen receptor signaling inhibitors block the activation of androgen receptors by androgen and successfully suppress tumor growth, but not for all patients.
“Surprisingly, although both MYC and the androgen receptor are essential in the aetiology of prostate cancer, we know very little about their interaction,” adds Labe.
To study this question, the researchers took advantage of single-cell techniques 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 the MYC protein is overexpressed, the expression of androgen receptor-driven genes in prostate cells is turned off. Through a series of next-generation sequencing technologies and bioinformatics analyses, the research team has also identified the molecular basis for this phenomenon.
“Technically, what we’re seeing is selective stopping of RNA polymerase II in genes controlled by the androgen receptor, essentially preventing the androgen receptor program from being turned on by musicians,” explains Nadia Boufayed, Ph. “Overall, this means that it is no longer the androgen receptor that controls the growth of prostate cancer. Instead, MYC has taken over.”
The cornerstone of prostate cancer treatment is that the androgen receptor is dominant. This is why drugs such as androgen receptor signaling inhibitors are used to treat prostate cancer. The burning question the researchers then asked was, when the MYC took over, was the patient’s response to current treatments affected?
Using multiple data sets of both molecular and clinical data from 1,418 patients, the team found that when MYC took over the androgen receptor program, these patients were more likely to progress to metastatic castration-resistant prostate cancer. These patients were also more likely to not respond to treatment with androgen receptor inhibitors and were more likely to develop their disease.
“In combination with other recent advances in the field, our results provide hope that patients with prostate cancer can benefit from micro-oncology approaches to provide significant therapeutic benefit in the management of aggressive prostate cancer characterized by MYC dysregulation,” says David Laby.
While targeting MYC is something researchers have tried unsuccessfully for decades, David Labe 2019 Nature Communications The publication demonstrated that dietary intervention to reduce saturated fat consumption is one possible means of inhibiting the MYC transcriptional program, possibly increasing the efficacy of treatments such as androgen receptor signaling inhibitors for patients who do not respond to standard treatments.
“More work will be needed in the coming years to determine the best path forward to translate these findings into clinical practice, but in the age of personalized medicine, we hope that the treatment of these patients will soon be adapted accordingly,” concluded Lappé.
Read the post in Nature Communications.
In addition to Nadia Boufayed, co-first author of this study, contributors include Tariq Hilal, Anna de Polo, Walaa Al-Ahmadi, and Jani LaRoc of Labbee Lab.
The authors gratefully acknowledge support from the Association for Cancer Research, the Prostate Cancer Foundation, Fonds de Recherche du Québec – Santé and the Canadian Institutes for Health Research, as well as the many other organizations included in the original publication. Labbé is also grateful for the support of the McGill University Health Center Foundation and the Montreal General Hospital Foundation.