By Jeff Kelley

Medical researchers typically play the long game, spending years (and years and years) exploring an idea that could move beyond the laboratory to improve human life. At Virginia Commonwealth University, Umesh Desai knows the playing field well.

For more than three decades, Desai, Ph.D., a professor and chair of the Department of Medicinal Chemistry in the School of Pharmacy, has investigated one of biology's most intricate and least understood molecular families - and the potential to prevent cancer relapse. Desai and a collaborator have pioneered development of a VCU-owned molecule, nicknamed G2.2, that targets colorectal cancer stem cells, and ongoing pre-clinical studies are a key step toward an Investigational New Drug submission to the Food and Drug Administration.

"Even today, people don't fully understand glycosaminoglycans," Desai said, referring to the long, sugar-based polymers that coat the surface of virtually every human cell, where they regulate processes from blood clotting and inflammation to growth and immune signaling. "There is so much unknown and unexplored around GAGs. The critical thing that I have tried to bring about in this field is to think of glycosaminoglycans as potential drugs and therapeutic agents."

"When you see a discovery like G2.2, you realize the power of long-term research," said Magdalena Morgan, Ph.D., director of licensing at VCU TechTransfer and Ventures, which has secured domestic and international patent protection and facilitated engagement with potential industry partners. "G2.2 is not just a molecule, but a platform that could change how we think about preventing cancer recurrence. Supporting projects like this is why we do what we do."

For Desai and others around the world studying GAGs, their structural complexity and importance in maintaining normal biology make them a promising target for drug discovery.

Desai's laboratory at the VCU Center for Drug Discovery is developing synthetic versions of GAGs that mimic natural ones. The goal is to create drugs that maintain therapeutic power while avoiding the variability and toxicity associated with natural forms of GAGs, such as the blood thinner heparin. His group has published more than 200 peer-reviewed papers, holds multiple patents and is widely recognized for advancing this specialized area of medicinal chemistry.

G2.2 is the result of Desai's collaboration with Bhaumik Patel, M.D., a physician-scientist at the Central Virginia VA Health Care System that is affiliated with VCU Massey Comprehensive Cancer Center. Patel studies colorectal and other gastrointestinal cancers. Desai and Patel are both Massey research members in the developmental therapeutics program.

"Cancer relapses. Patients walk out of surgery or chemotherapy thinking they are free of cancer, and five years later, it relapses intensely," Desai explains. "Cancer stem cells are essentially like a hibernating bear. During wintertime, the bear enters the den and hibernates. No matter how powerful the gun you may have, it will never touch the bear. It's very similar - chemotherapy and radiation don't touch cancer stem cells because they are essentially hibernating."

Desai and Patel believe G2.2 represents a new approach to treatment, with the molecule drawing cancer stem cells out of dormancy and then destroying them.

Through a series of studies spanning more than a decade, Desai and Patel discovered that G2.2 mimics a specific GAG fragment that interacts with a key regulator of cancer cell survival. By binding to that receptor, G2.2 disrupts downstream signaling and activates a pathway that forces cancer stem cells into death.

Desai and Patel say G2.2 can be used in conjunction with chemotherapy or on its own to prevent cancer relapse.

"In multiple preclinical models, we've observed a near-complete elimination of dormant cancer stem cells in colorectal cancer, with similar activity seen in lung, brain, renal and pancreatic cancers," Patel said.

G2.2 also shows a strong safety profile and seems to stimulate the immune system, triggering antigen-reactive T-cells that enhance the body's own anti-tumor defenses.

Desai and Patel's research is supported by the National Institutes of Health, the Department of Veterans Affairs and the VCU Office of the Vice President for Research and Innovation's Commercialization Fund.

For Desai, whose career has bridged chemistry and medicine, G2.2 represents a proof of concept - that rationally designed carbohydrate mimetics can modulate complex biological systems with precision. If successful, this approach could redefine how medicine targets not only cancer relapse but also clotting disorders, inflammation and viral infections.

"My work is exciting, the work is rewarding, and we believe it will be even more rewarding in the next few years as we hope to realize this molecule's potential," Desai said. "VCU and Massey have been incredibly supportive. Work is fun when one is supported."