Tumor Metabolism Breakthrough Could Unlock Precision Chemotherapy for Aggressive Cancers
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A new understanding of the link between tumor metabolism and drug efficacy is poised to revolutionize precision chemotherapy, offering hope for more targeted and effective cancer treatments. Researchers have identified a key vulnerability in certain cancer cells, paving the way for drugs that selectively attack tumors while sparing healthy tissue.
The quest for chemotherapy drugs that precisely target cancer cells without inflicting collateral damage remains a central goal of modern oncology. This latest research, published in Nature Communications, represents a significant step forward in achieving that ambition. Scientists have demonstrated a crucial connection between how tumors process energy – their metabolism – and how effectively drugs engage with cancer cells.
Targeting PRMT5: A New Avenue for Cancer Treatment
The study centers on PRMT5 (protein arginine methyl transferase 5), a gene-regulating protein long considered a promising target for drug development. In healthy cells, PRMT5 interacts with a molecule called SAM. However, approximately 10 to 15 percent of all cancers exhibit a mutation in the MTAP gene. This mutation causes PRMT5 to bind with a different molecule, MTA, creating a unique vulnerability.
“Selectivity is one of the most critical challenges in cancer therapy, as most treatments also damage healthy cells, and this leads to dose-limiting toxicities and reduced therapeutic effectiveness,” explained a senior researcher involved in the study. This altered interaction presents an opportunity to develop drugs that specifically target cancer cells with the MTAP mutation, leaving normal cells unharmed.
NanoBRET Technology Reveals Metabolic Insights
To capitalize on this discovery, the research team developed a novel method to quantify the interaction between compounds designed to inhibit PRMT5 and its binding partner – MTA in tumor cells, or SAM in healthy cells. This was achieved using NanoBRET (Bioluminescent Resonance Energy Transfer), a well-established biosensor technology.
The team’s approach allowed them to observe, in real-time, how different PRMT5 inhibitors behave under varying metabolic conditions. This insight is crucial for understanding why certain inhibitors are more effective in cancers lacking MTAP. The University of Oxford team developed CBH-002, a specialized probe used in conjunction with NanoBRET to report drug target engagement within live cells.
“CBH-002 could measure various PRMT5 inhibitor types in live cells, prompting us to test its sensitivity to the cofactor SAM,” stated a postdoctoral researcher at the Centre for Medicines Discovery at the University of Oxford. “When we discovered the probe’s ability to sense metabolite levels, it established its utility as a metabolic biosensor. Through collaboration with Promega, we demonstrated how MTA influences drug selectivity, revealing why certain inhibitors are so effective in MTAP-deleted cancers.”
Uncompetitive Inhibition: A Novel Mechanism
The research team believes they have identified a new class of tumor-specific drugs that operate through an “uncompetitive” or “cooperative” mechanism. This means the drugs only bind to the PRMT5 enzyme complex when it’s associated with the metabolite that accumulates specifically in cancer cells, effectively limiting activity to tumor tissue.
“Our work shows a new class of tumor-specific drugs that acts uncompetitively or cooperatively—that is to say only binds to the enzyme complex related to the cancer—with a metabolite that accumulates only in cancer cells, limiting activity to tumor tissue,” a lead researcher explained. “To our knowledge, this is the first time anyone has characterized this type of uncompetitive inhibitor mechanism directly in live cells.”
According to another senior scientist, “This provides unprecedented insight into why certain inhibitors are much more effective in cancers lacking MTAP and paves the way for highly targeted cancer treatment in the future.” He likened the breakthrough to “turning on the lights inside the cell so we can finally see which key actually fits the lock.”
Collaborative Effort Drives Innovation
This groundbreaking research was a collaborative effort involving Stony Brook University’s Center for Advanced Discovery of Drug Action, the University of Oxford’s Centre for Medicines Discovery, Boston University, and the Promega Corporation. The success of the study hinged on the use of Promega’s NanoBRET® Target Engagement (TE) technology, designed to identify inhibitors that selectively target cancer cells.
The research was supported by funding from several scientific organizations and agencies, including the National Institutes of Health (NIH). This work represents a significant advancement in the field of cancer research, offering a promising new direction for the development of more effective and less toxic cancer therapies.
