Reinterpreting Established Science to Find Better Breast Cancer Drugs

Cancer researcher Neil Vasan, MD, PhD, sees nothing wrong with starting his research career investigating one of the most thoroughly studied protein families in oncology. Despite decades of prior work by others, he’s certain that phosphoinositide 3-kinases (PI3K)—one of the most mutated genes in breast and other cancers—have many more secrets to reveal.

“Proteins like PI3K will never cease to be important, given its critical role as a driver of almost all cancer types. While the PI3K field is mature, there are still numerous discoveries to be made that will ultimately have implications for cancer therapies and patients,” says Vasan, who joined Columbia in 2021 as assistant professor of medicine in the Division of Hematology and Oncology and as a member of the Herbert Irving Comprehensive Cancer Center.

Case in point: Vasan’s discovery just a few years ago that cancers with double PI3K mutations have important consequences for patients. Double mutations hadn’t really been examined in any gene before Vasan’s study—the technology wasn’t quite ready to answer the question—but the phenomenon turns out to be common in other cancer genes. And clinically important. In breast cancer, where these double mutations are particularly prevalent, Vasan found that women whose cancers harbored double mutations responded better to PI3K inhibitors, a finding that’s now being investigated further in multiple clinical trials with select patients who may have increased benefit from PI3K inhibitors.

A chemist's approach

Vasan’s projects often follow the kind of approach a chemist might take to biology. That’s no coincidence; he majored in organic chemistry as an undergraduate and remains deeply interested in it. “I still feel like I think like a chemist in a lot of ways,” he says. A class in structural biology sparked his fascination with proteins, which led him to pursue a MD/PhD. His timing couldn’t have been better; while studying protein structure in graduate school, the subject cropped up in the clinic as well.

“That was a really exciting time in oncology, because it was the start of targeted therapies in solid tumors,” says Vasan. Suddenly, practicing oncologists were discussing how particular amino acid changes in kinases affected their activity or binding to drug. “These were structural questions, and that, for me, was the real ‘aha’ moment, that these skills that I was learning in structural biology had a lot of relevance in oncology too,” Vasan says.

In his lab at the Herbert Irving Comprehensive Cancer Center, Vasan and his team are asking novel questions and bringing new techniques to bear on old ones. With PIK3CA, for example, which encodes the catalytic subunit of PI3K alpha, researchers have worked extensively on only a few mutations. “There are three very common mutations, but they only explain about 50% of tumors in patients,” says Vasan, adding that the other half of patients harbor an immense diversity of other mutations—thousands—in the same gene.

“So that means that 50% of patients with PIK3CA mutations have these rare mutations and we don’t know what they do or how they change PI3K inhibitor response,” he says. In one set of projects, Vasan’s lab is characterizing those mutations with a combination of proteomics, bioinformatics, and data from large patient cohorts.

The work should define the repertoire of patient mutations and guide the development of better PI3K inhibitors that have less toxicity, a problem that currently limits the dose that that can be used in patients.

Providing better options for breast cancer patients

Vasan’s lab research delves into the complexities of the cancer cell, but the goal of his research is always to provide better options for his patients. “In the clinic, my patients with breast cancer want therapies that will extend their lifespan while maintaining excellent quality of life,” he says. “So the prospect of multiplying the number of therapeutic options for my patients using basic science motivates my work in the lab.”

In his newest project—funded this year by an NIH Director’s New Innovator Award from the NIH Common Fund's High-Risk, High-Reward program—he hopes to compress the discovery process of new drug candidates for breast cancer from decades to just a few years. The research will extend his work on the PI3K kinase to the human genome's entire collection of 556 kinases, enzymes that represent one of the most important targets in cancer treatment. His innovative approach will not only identify novel kinases for therapeutic targeting but also identify the optimal mechanisms to inhibit those kinases.

In another project, his lab is taking a close look at certain druggable proteins in cancer cells to find new therapeutic vulnerabilities. But finding markers of drug sensitivity is harder than looking for markers of drug resistance. Vasan hopes a combination of functional genomics, bioinformatics, and large databases of patients’ tumor mutations and therapeutic responses will reveal more reliable biomarkers. “The goal here is that we’ll be able to find more patients who may respond to a particular drug,” he says.

Looking ahead, Vasan hopes to learn more about the basic biology of PI3K, and other kinases, to find more ways to exploit that biology to treat patients.

Continuing to discover new things about such a well-studied protein reminds Vasan of his experiences as a classically trained singer, an avocation he’s pursued since college.

“Many classical composers in the 20th century were very influenced by the composers of the past, reinterpreting older works in new ways,” he says. “I like to think that’s in line with what our lab does: taking important and well-known targets but using modern techniques and vantage points to make fresh new discoveries and breakthroughs in fundamental knowledge.”