By Lewis Brissman for VCU Innovation Gateway
If you think of cancer as a grizzly bear, an attack isn’t the only danger you face. An equal worry is the hibernation.
Dr. Umesh Desai is – metaphorically, of course – targeting the beast in both states.
In the VCU School of Pharmacy, Desai is chairman of the Department of Medicinal Chemistry and a member of the Institute for Structural Biology, Drug Discovery and Development. For more than a decade, he has worked with VCU oncologist and researcher Dr. Bhaumik Patel at the root of the issue: the cancer stem cells that seed the disease. Their work shows promise for making chemotherapy and radiation more effective, and for targeting cancer recurrence in therapeutic and even preventive ways.
Researchers now realize that tumor development and growth are powered by a very small group of cancer stem cells. These CSCs can resist common treatments, so even if patients see promising results from initial therapy, CSCs can regenerate entire tumors or spur new ones.
“Chemotherapy and radiation depend on cancer cells that are multiplying,” Desai said. “But instead, cancer stem cells lie in wait – and they remain unaffected by these treatments. Years later, the stem cells may come alive again, like a hibernating bear. And we have cancer relapse with vengeance.”
To prevent recurrence, CSCs could be targeted to keep them in hibernation or to eliminate them entirely. Desai’s weapons are seeing results on both paths.
They come from a toolbox of molecules he initially developed when exploring how to mimic heparin, the body’s well-known blood thinner. His colleague Patel, who is associated with VCU’s School of Medicine and Massey Cancer Center, as well as the McGuire Veterans Affairs Medical Center, wondered about a wider application.
“I wanted to make an anticoagulant,” Desai said. “He said, ‘Wait a minute. Have you thought about cancer?’ It opened up a completely new path.”
With labels such as G2.2 and G5C, Desai’s sulfated flavonoids are based on natural compounds, found in many plants, that help the body ward off toxins. In animal research directed by Patel, G5C powerfully inhibited colorectal, pancreatic and lung CSCs, with no significant toxicity. That is key, because a major drawback of current chemotherapy drugs, in addition to potential recurrence, is that their high toxicity makes treatment difficult.
VCU Innovation Gateway helped Desai gain a patent for his work, with another patent pending. The IP is also available for licensing through the university’s technology-transfer office. “Dr. Desai’s technology could inhibit cancer stem-like cells without impacting normal cells, and target fundamental pathways crucial to their survival,” said Magdalena K. Morgan, Director of Licensing at VCU Innovation Gateway. “His IP holds promise for companies looking to treat colon, breast, pancreatic, lung, and brain cancers.”
To block cancer’s pathway from the stem cells, the sulfated flavonoids interact with CSC receptors that promote tumor growth. In Patel’s lab, grafts of human cancer cells, pre-treated with current anti-cancer drugs, were implanted into mice. G2.2 prevented tumor relapse in more than 80% of cases with different cell lines. The molecule also significantly reduced growth of the tumor grafts on its own, as well as when paired from the start with the anti-cancer drugs.
Beyond making cancer therapies more effective, Desai’s molecules could offer a path to prevent recurrence: Lab results also revealed the near absence of CSC growth when mice were pre-administered G2.2.
“We have shown that apoptosis – a natural way of cells simply dying – is occurring,” he said. “The cancer stem cells go from saying, ‘I need to keep working; I’m good to continue’ to saying, ‘OK, I’m done,’ in the manner of other cells that die naturally.”
Desai was able to modify G2.2 into G5C to allow for oral administration, which is a benefit in cancer treatment.
“The time frame between the first success of cancer removal and its recurrence years later is a huge issue,” he said. “Molecules that prevent this relapse represent the holy grail.”