A team of scientists partly funded by the Terry Fox Research Institute has shown that nearly half of all patients with peritoneal mesothelioma (PeM), an extremely rare and often fatal form of cancer that originates in the peritoneal lining of the abdomen, may benefit from immunotherapy.
Their work, published in Genome Medicine (February 2019), is being heralded as a breakthrough by some of the top people in the field, according to Dr. Colin Collins, a University of British Columbia Professor and Senior Scientist at the Vancouver Prostate Centre and the paper’s senior author.
“There are currently few options for effective long-term therapy for most patients with PeM,” Dr. Collins said. “While surgery has to date been the most effective treatment prolonging life for those who are appropriate candidates, the surgery is complex and is not a viable option for many patients. Now there's evidence that up to half of those patients may be candidates for immunotherapy or DNA repair-based therapy.”
To reach this conclusion, Dr. Collins and his team put together a cohort of 19 tumour samples – the largest cohort of PeM studied yet – and ran comprehensive genome, transcriptome and proteome analyses on the samples. What they found is promising: nearly half of the samples shared a common trait – the deletion of a gene known as BAP1. Upon further testing, it became evident that this led to an inflammatory tumour microenvironment, making the subset of patients with BAP1 haploinsufficiency ideal candidates for immune checkpoint blockade therapies.
“Our findings reveal BAP1 to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification,” said Dr. Raunak Shrestha, a postdoctoral fellow at the Vancouver Prostate Centre and the paper’s co-first author. “This provides a comprehensive foundation for improved management of a subset of PeM patients.”
A rare focus
How does a team of long-time prostate cancer researchers make a finding that may revolutionize care for an extremely rare cancer that is estimated to affect less than 25 people a year in Canada?
According to Dr. Collins, it happened by chance: a friend asked him and his close collaborator Dr. Yuzhuo Wang to help his daughter, who was in her last stages of the disease. Despite doing their best to help, her clock eventually ran out, but that didn’t stop her grateful father from asking Drs. Collins and Wang whether they would coordinate research on PeM.
With funds from several organizations the team was able to get the “D.E.W. Project” (named after the young woman’s initials) up and running. Infrastructure and technology developed through a TFRI-funded prostate cancer grant played a central role in this recent success, according to Dr. Collins and Mark Weintraub, the young woman’s father.
“To achieve a success like this takes many factors and individuals, but funding is always key—particularly for a relatively rare disease,” said Weintraub. “To have so many organizations contribute to this project, including the Terry Fox New Frontiers Program, demonstrates the best of collaborative research. We are humbled and inspired that such an important breakthrough could result from a collective determination that something positive for others would emerge from our tragic loss.”
The team now hopes that ongoing clinical trials for this disease will adopt stratification based on BAP1 status to test the effects of immunotherapy on patients. They also hope to continue their research into the development of more prognostic and diagnostic tools for this deadly disease.
“Five years ago, we had limited knowledge of this disease, and now it appears there may be hope for an effective treatment for possibly half of all patients with PeM,” Dr. Collins said.
In addition to this, the team is also looking into the effects that BAP1 haploinsufficiency has on other types of cancers, including kidney and skin cancers, to determine if it can be used as a prognostic biomarker for the use of immunotherapy.
“In the future, our study might help explain some of the common mechanisms of cancer and cancer treatment in PeM and beyond,” Dr. Shrestha said.
BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma
Raunak Shrestha, Noushin Nabavi, Yen-Yi Lin, Fan Mo, Shawn Anderson, Stanislav Volik, Hans H. Adomat, Dong Lin, Hui Xue, Xin Dong, Robert Shukin, Robert H. Bell, Brian McConeghy, Anne Haegert, Sonal Brahmbhatt, Estelle Li, Htoo Zarni Oo, Antonio Hurtado-Coll, Ladan Fazli, Joshua Zhou, Yarrow McConnell, Andrea McCart, Andrew Lowy, Gregg B. Morin, Tianhui Chen, Mads Daugaard, S. Cenk Sahinalp, Faraz Hach, Stephane Le Bihan, Martin E. Gleave, Yuzhuo Wang, Andrew Churg and Colin C. Collins
This study was partly funded by the Terry Fox New Frontiers Program Project Grant in Targeting the adaptive molecular landscape in castrate-resistant prostate cancer