Funding from the Terry Fox Research Institute has allowed a team of researchers led by Dr. Sheila Singh, an oncological surgeon and researcher at McMaster University, to shed new light on how glioblastoma, a lethal brain cancer, evades current therapies.
The study, published in Cell Reports, found that some cancer cells undergo a mutational process during the first round of radiotherapy or chemotherapy that allow them to enter a dormant state known as minimal residual disease (MRD).
Using single cell sequencing, Dr. Singh’s team mapped this MRD state in five patients between 2018 and 2022. While each patient's MRD profile was found to be unique, the team was able to see how these unique features affected the trajectory to their cancer recurring, potentially opening the door to future treatments tailored to each individual with glioblastoma.
“The MRD state is the reservoir of disease that will generate its recurrence, and this is the first time it has been profiled in patients with glioblastoma,” said Dr. Singh, a professor of the Department of Surgery and director of McMaster’s Centre for Discovery in Cancer Research.
“Since we’ve discovered that every glioblastoma patient has a different route to recurrence, we have found that we can predict better therapeutic avenues,” she said. “Our long-term hope is fully deciphering the MRD condition of glioblastoma cancer cells, which will allow us to develop drugs that can really extend patients’ lives.”
Dr. Singh said that mapping one patient’s glioblastoma cell profile in its MRD state found that it would respond well to immunotherapy. Another patient’s cell profile showed the cancer was highly resistant to treatment.
However, all five patients monitored by Singh’s team did die. She said that at this time current therapies including surgery, radiotherapy and chemotherapy can only extend a patient’s life by 15 months on average.
Singh said that for other cancers, such as leukemia, the MRD state of cancer cells is already well-known. This is done by monitoring blood and bone marrow samples to check for cancer cells and if they have mutated or been damaged by treatment.
Profiling the MRD condition of leukemia cells allows clinicians to devise treatments tailored to each patient, ensuring the best possible outcome.
“When glioblastoma occurs, the patient is currently a black box and we don’t know the biology of their tumour, nor can we predict the progression from its original state,” said Dr. Singh. “We must do better for people with this cancer.”
Helping Dr. Singh in her research was co-senior author Jason Moffat from the University of Toronto, and McMaster biochemistry students Maleeha Qazi and Sabra Salim.
This story was prepared based on a press release provided by McMaster University.
Characterization of the minimal residual disease state reveals distinct evolutionary trajectories of human glioblastoma
Maleeha A. Qazi, Sabra K. Salim, Kevin R. Brown, Nicholas Mikolajewicz, Neil Savage, Hong Han, Minomi K. Subapanditha, David Bakhshinyan, Allison Nixon, Parvez Vora, Kimberly Desmond, Chirayu Chokshi, Mohini Singh, Amanda Khoo, Andrew Macklin, Shahbaz Khan, Nazanin Tatari, Neil Winegarden, Laura Richards, Trevor Pugh, Nicholas Bock, Alireza Mansouri, Chitra Venugopal, Thomas Kislinger, Sidhartha Goyal, Jason Moffat, Sheila K. Singh
This study was partially funded by a Terry Fox New Frontiers Program Project Grant to Targeting clonal heterogeneity in treatment-refractory glioblastoma with novel and empiric immunotherapies