Cancer is notoriously difficult to treat largely because of its remarkable ability to adapt. Much like a shapeshifting supervillain, some cancer cells can change their identity and behaviours—a process known as cell state plasticity—to hide and survive the threat of treatments.
With $9 million in renewed funding through a Terry Fox New Frontiers Program Project Grant (PPG), a Toronto-based team of researchers will tackle this challenge by uncovering how cancers adapt and resist treatment, with the goal of developing therapies that block these processes and improve long-term outcomes.
The renewed funding builds on the highly successful PPG established under the leadership of Dr. Jeffrey Wrana at the Lunenfeld-Tananbaum Research Institute (LTRI). As the program enters its next phase, Drs. Liliana Attisano and Daniel Schramek will lead the multidisciplinary team in advancing discoveries on cell state plasticity toward new therapeutic strategies.
“Overcoming treatment resistance is one of the biggest challenges in cancer research,” says Dr. Attisano, professor and principal investigator at the University of Toronto. “Our goal is to destroy cancer’s ability to adapt, making today’s therapies more effective and creating longer lasting responses to prevent tumour recurrence.”
The project will build on years of discovery revealing a “master switchboard” that cells use to maintain their identity. Known as the Hippo pathway, this communication network tells healthy cells what they should become (hair follicle, skin, breast tissue, etc.), when to grow, and when to stop. When those signals break down—or the network is compromised by cancer—cells can lose their specialized identity, become far more adaptable, and grow uncontrollably.
They also discovered that some tumour cells have an adverse reaction to chemotherapy and temporarily enter a resistant state. While most cancer cells are destroyed, a small number of them adapt, switching on repair mechanisms to endure treatment before returning to a state where they can then regrow the tumour. To combat this, the team developed pre-clinical drugs to block the signals—or switches—driving this adaptive response, and their early studies have shown they’re successful in making cancer cells more vulnerable to chemotherapy.
This adaptability appears to be critical not only in treatment resistance, but also in the earliest stages of cancer when normal cells first become cancerous.
“What is becoming increasingly apparent is that this loss of cellular identity is one of the earliest events in cancer development. Long before you can detect a tumour under a microscope or in the clinic, cells are already beginning to change,” says Dr. Schramek, senior investigator at LTRI and Deputy Director of Discovery Research at Sinai Health.
“If we can understand and prevent that change, we have an opportunity not only to overcome treatment resistance, but to stop cancer before it starts.”
Over the next five years, the team will work together, across disciplines and institutions, to better understand cellular behaviour in breast and colorectal cancer, using cutting-edge technologies to create detailed maps of the Hippo pathway and the broader networks it communicates with.
They will then use these three-dimensional maps and previous drug discovery efforts to design and test new drug therapies that block the signals cancer cells use to shapeshift, grow, and survive chemotherapy.
“If successful, this research will shift cancer care from reactively treating existing tumour cells, to actively preventing cancer from adapting and escaping treatment,” says Dr. Schramek. “While our immediate focus is on breast and colorectal cancers, these therapeutic strategies have the potential to improve outcomes in a wide variety of other cancers.”
The renewed program reflects the continued growth of a highly collaborative research team. Alongside Drs. Attisano, Schramek, and Wrana, long-standing team members Drs. Anne-Claude Gingras (LTRI) and Frank Sicheri (Sinai Health) continue to play key leadership roles. The renewed program also welcomes a new generation of investigators, including Drs. Hartland Jackson, Kieran Campbell, and Diane Haakonsen from LTRI, and Dr. David Cescon from University Health Network. Together, the team brings expertise spanning cell biology, proteomics, structural biology, computational biology, cancer genomics, translational oncology, and drug discovery. The program is further strengthened through a close partnership with the Ontario Institute for Cancer Research (OICR), whose internationally recognized drug discovery expertise will help accelerate the translation of fundamental discoveries into promising new therapeutic strategies.