Everyone knows the adage “reduce, reuse, recycle.” Sorting tin cans and glass bottles into the right receptacle means less waste, less pollution, and a more sustainable future for our planet and population.
It may come as a surprise to most, however, that recycling can also be applied to cancer drugs. Existing therapeutics designed to target specific biomarkers or pathways could be effective for other treatment applications, leading to exciting new discoveries hidden in plain sight.
Stanford Cancer Institute member Steven Corsello, MD, assistant professor of medicine, has long focused on repurposing cancer drugs. He is the senior author on a recently published study showing that an anti-cancer drug originally developed to cause a toxic buildup of iron inside cells instead acts by blocking essential growth molecules from being transported within the cells, causing the cancer cells to die.
One of the Corsello Lab's key initiatives involves collecting previously tested drugs and evaluating their potential for new therapeutic applications.
“We have a long-standing interest in using existing drugs to define molecular mechanisms,” Corsello said. “In my lab, we take systematic phenotypic approaches to discover cancer vulnerabilities.”
In this case, a systematic phenotypic approach involves a comprehensive analysis of cancer cells to gain a broad understanding of the interplay between their genetics, reactions to drug treatments, and physical traits.
In this project, supported by the Stanford Cancer Institute’s SCI Innovation Awards, the Corsello Lab employed gene-editing technology and proteomics (the analysis of all proteins in a cell or organism) to determine the mechanism of action for the cancer-killing drug PRLX-93936. This previously discontinued drug was tested in human cancer clinical trials and induced cellular death by an unknown mechanism. The team discovered that the drug actually functions as a “molecular glue,” meaning it stimulates interactions between proteins that wouldn’t normally be in contact with each other. In this case, the new protein-protein interactions occur within pancreatic cancer cells, inducing targeted protein degradation that causes the cancer cells to stop growing and ultimately leads to cellular death.
So, how does the drug work?
The uninhibited growth of cancer cells relies on continuous protein production. Proteins are assembled in the cell nucleus by molecules that have entered through the nuclear pore complex, an essential structure that controls the transportation of molecules into and out of the nucleus. This creates a potential opportunity to target and degrade the nuclear pore complex, thereby stopping protein production by blocking mRNA transport out of the nucleus and ultimately killing the cancer cell.
The study found that PRLX-93936 binds to TRIM21, a cancer cell protein that tags and signals the nuclear pore complex for degradation. This novel mechanism was shown to be effective in animal models of pancreatic cancer.
This newly identified and unexpected mechanism offers a potential path to improved outcomes."
“Pancreatic cancer remains, unfortunately, a very challenging malignancy to treat, with high rates of intrinsic resistance to chemotherapy as well as a high risk for recurrence, even for patients who present with early-stage disease and are candidates for surgery,” Corsello explained. “To date, the insufficient number of unique molecular targets amenable to intervention has been a critical barrier to improved pancreatic cancer treatments. This newly identified and unexpected mechanism offers a potential path to improved outcomes. We are excited by the translational potential of this discovery.”
The promising results have led to a collaboration with Stanford Cancer Institute member Nathanael Gray’s lab, supported by Stanford’s Innovative Medicines Accelerator, that yielded substantial improvements in drug activity and properties.
Corsello’s findings highlight the power and clinical promise of repurposing existing drugs for new indications, and chart a path forward for a new class of cancer therapeutics born from reimagining existing drugs with next-generation biology models.
“We’re very excited about the potential to learn about the underlying chemical biology by which these mechanisms work, and whether we could, in the future, think about other indications or targets using this approach,” Corsello said.
Funding for this research was provided by The Stanford Cancer Institute, Damon Runyon Cancer Research Foundation, National Cancer Institute, Stanford Innovative Medicines Accelerator, and Stanford University C-ShaRP.
