Melanoma researcher covers all the bases
UCI Health dermatologist Anand Ganesan created new compounds that slow skin cancer growth
By Matt Coker
Dr. Anand Ganesan probably won’t be hanging from a ceiling `a la Tom Cruise in Mission Impossible, but the UCI Health dermatologist and School of Medicine professor of dermatology and biological sciences does compare part of what he does to a plot device in the 1996 action thriller.
“You know where the guy opens the switch box, there are all these wires coming down, and he’s trying to figure out which wire to cut to stop something bad from happening? That’s kind of what we’re trying to do: Cut the right wire to short- circuit cancer,” says the co-director of the Biotechnology, Imaging & Drug Discovery program at the Chao Family Comprehensive Cancer Center.
Ganesan says being a cancer researcher pays dividends when it comes to his own practice as a dermatologist. Unlike other health systems in Orange County, UCI Health has a roster of physicians who double as world-class researchers in their specialties.
“Most doctors don’t know how a drug is developed and what goes into the thought process of doing that,” Ganesan says. “Knowing that really helps guide my practice a lot more.”
Not to mix Tom Cruise movies, but the researcher/dermatologist is a top gun when it comes to embodying the CFCCC mission to facilitate and promote interdisciplinary and transdisciplinary cancer research across UCI; disseminate state-of-the-art cancer knowledge to caregivers, patients and families, and the public; train the next diverse generation of cancer researchers and care providers; and deliver the highest quality multidisciplinary clinical care to cancer patients.
This would not be possible, Ganesan says, without grants from the National Institutes for Health and UCI’s Anti-Cancer Challenge that have helped pave the way for his decade-plus research into identifying genes that are activated in cancer and developing ways to prevent them from sending the signals that spur the disease.
The Anti-Cancer Challenge, a ride-run-walk event that raises awareness and funds for pilot studies and clinical trials that support research at the CFCCC, provided Ganesan’s team with about $40,000 in seed money. That led to the development of a new drug to treat melanoma – which may have broad applications for other tumor types – that received substantially more funding from the NIH.
A $10 million, five-year National Cancer Institute grant recognizes the university’s deep expertise in biology, mathematics, chemistry and other research areas and led to the creation of the UCI Center for Cancer Systems Biology. The university is among just 13 research institutions nationwide that are part of the NCI’s Cancer Systems Biology Consortium.
“Our mission is to translate the findings of our research into treatments that can benefit patients, driven by a strong commitment to scientific discovery and clinical innovation,” Dr. Richard A. Van Etten, the CFCCC’s director, has said. “Institutions lacking their own research base can follow and adopt advances developed at NCI centers like ours, but they cannot lead in the same way as comprehensive cancer centers that integrate research with clinical care.”
For an idea of how this has played out for Ganesan and his team, their latest paper in Cell Reports, “New molecule holds promise of therapies for cancer and rare diseases,” builds on their 2017 Cell Reports paper, “Key mutation in melanoma suppresses the immune system,” which builds on their 2012 Cancer Research paper, “Researchers find cause of chemotherapy resistance in melanoma.”
Melanoma gets top billing because it is what Ganesan and his fellow dermatologists in sunny Southern California deal with most frequently.
“Fortunately, 90 percent of melanoma is curable by surgery,” he says. “Almost two-thirds of the other 10 percent we see is what we call Stage III disease, which means the tumor has moved to the lymph node but hasn’t moved to the rest of the body. The remainder of it is where the tumor has moved to the rest of the body.”
Ganesan and his fellow researchers are trying to develop new therapies for most patients with Stage III tumors. “The strategy scientists have taken initially was to say, ‘OK, these tumors have the same mutations as the metastatic tumors, so the immune system is potentially activated in the same way,’ ” he explains. “But mutation-directed therapies and immunotherapies for patients with metastatic tumors have side effects. Can we think of a way that we can target these tumors in a more direct fashion, targeting their ability to move, that’s more selective than for those that are starting to metastasize?”
Step one was establishing a genetic strategy, which was the point of the 2012 paper that identified a class of genes called CDC42 that are important in chemotherapy resistance and the function of some genes in tumor progression.
“These genes are like switches,” says Ganesan, returning to the Mission Impossible scenario. “We use the genetic approach to find out which wire is important or which signaling pathway is important. The next logical question is how do we cut it? How do we target the right switch? Switches go on and off, on and off, on and off, all the time. But they only do something that induces cancer when they’re on. So, how can we develop a drug to target these switches when they are on?”
It was a question perplexing Ganesan when he happened to be in Italy and met Marco De Vivo, group leader of the Molecular Modeling & Drug Discovery Lab at the Italian Institute of Technology (IIT) in Genoa.
“I told him about what I was working on,” Ganesan recalls, “and I said, ‘The switch is important, but how do I target it? How do I make a cancer drug out of it?’ And he said, ‘Oh, I think I could do that.’ I said, ‘Oh, let’s work together.’ So, then we started working together.”
They eventually identified the lead molecule to target the switch, based on computational models, and developed a drug that could bind to it to prevent it from sending a cancer signal. According to Ganesan, the research by the IIT and his own Ganesan Lab offers hope to Stage III patients who would have previously “fallen through the cracks.”
“We’ve made a new chemical that’s never been made before,” he says. “We show how the drug works. And we show that the drug slows cancer growth. But there’s still a journey from having a drug that does that in the models we have and having a drug that we give to people. That’s the journey we’re on right now.”
To take the leap from academic research to clinical therapy, Ganesan, De Vivo and two other partners started Alyra Therapeutics to develop the medication further. The startup is currently in fundraising mode.
To further explain how Ganesan’s research helps him as a practitioner, we shift from the movie theater to the pool hall.
“Great pool players line up three shots ahead of the shot they are playing,” he says. “Like the ball is here and they want to stop it in the right place so they can play the next ball and stop that shot so they can play the next one. That’s the way I think about drugs for patients. You are trying to figure out what will the patient respond to best – that’s your first shot – and when that person responds or does not respond, what do you do next? That’s your next shot, and you have all your shots lined up before you take the first one.”
As a drug developer, he goes through the same process.
“You hit the ball into the first one, and it bounces off where you want to line up the second shot,” he explains. “How are you going to get there? That’s kind of the way I think about things. It’s not just for melanoma or diagnostics of patients but also for other diseases that I treat. Conducting research has really changed the way that I think and care for patients.”
Coming up with therapies to make melanoma and the other diseases he treats less prevalent “is kind of the idea” of his research and practice, he notes. Because patients treated for melanoma often see it return at some point, the direction he is now taking is finding ways to keep it from developing in the first place. One way his team is doing that is by refining theranostics, in which imaging guides diagnostics.
“We are trying to apply theranostics to melanoma,” says Ganesan. “Immunotherapy is the gold standard of treatment. What that does is make the immune system fight the tumor and the tumor goes away. And when it does, it’s amazing because it could be a lifelong cure.”