'Great Potential'

Many successful researchers cite the influence of a mentor who inspired and advised them—and that’s especially true for Dr. Kevin O’Rourke, PhD ’17. Even though he’s still an MD-PhD student, Dr. O’Rourke cites numerous people who have helped guide him on his path. They include an AP biology teacher at his Massachusetts boarding school who sparked his interest in science; a Harvard geneticist who let him shadow her for two days, showing how a scientific discovery could change the course of a patient’s disease; and a Middlebury College professor who taught him about grant writing and the research process and gave him the opportunity to be first author on a scientific paper as an undergraduate. Says Dr. O’Rourke, now in his third year of MD studies at Weill Cornell Medical College: “I owe a huge debt of gratitude to them all.”

As a student in the Tri-Institutional MD-PhD Program, Dr. O’Rourke has continued to benefit from strong mentors such as Memorial Sloan Kettering Cancer Center biologist Dr. Scott Lowe under whom he conducted his doctoral research. It was in Lowe’s lab that Dr. O’Rourke contributed to promising pre-clinical investigations related to colon cancer—including one project, described in a paper he co-authored, that was featured on the cover of Cell and called one of Memorial Sloan Kettering’s top discoveries of 2015. More recently, his work earned him a coveted honor as one of Forbes’s “30 Under 30” in healthcare for 2017. “Kevin has great potential, in part because he bridges that space between physician and scientist,” says Dr. Luke Dow,  an assistant professor of biochemistry in medicine at the Sandra and Edward Meyer Cancer Center, with whom Dr. O’Rourke worked for several years. “He’s always focused on what’s most relevant and important to get us toward helping patients, while remaining thoughtful about the research and trying to advance scientific understanding at a basic level.”

Colon cancer is the second most deadly type of cancer in the United States, and its patients are in desperate need of more effective treatments. While people with other types of cancer—like melanoma, lung cancer and brain cancer—have benefitted from new targeted drugs in recent years, doctors don’t have similar options for treating colon cancer, particularly in its later stages. “While clinical care has gotten better in the last 15 years and increased screening has provided better outcomes,” Dr. O’Rourke says, “there’s very little we can do when someone has an advanced form of the disease.”

In the Lowe Lab, Dr. O’Rourke and Dr. Dow (who was then a postdoc but now has his own lab) collaborated on complementary projects related to metastatic colon cancer, work that could both contribute to developing better early detection methods and help scientists create safer, more effective therapies. The first—chronicled in the paper that made the cover of Cell—is focused on a gene called APC, which plays a prominent role in colon cancer. The team knew that when APC is inactivated in a mouse model, colon cancer develops. But they didn’t know what would happen if they could turn the APC gene back on while other genetic mutations remained intact. They did so, and saw that it triggered every tumor to either shrink or disappear. The next step, Dr. O’Rourke says, is for scientists to develop a drug that can turn the APC gene back on in human patients with colon cancer, as the team was able to do in mice.

While working on the APC project, Dr. O’Rourke was surprised to learn that researchers in the colon cancer field were using an outdated and inadequate mouse model—a realization that led him to his second preclinical project. Introduced in the mid-90s, this model’s mice develop benign tumors in the small intestine instead of malignant ones in the large intestine. “It’s the best model available,” Dr. O’Rourke says, “but the tumors don’t grow in the same place as they would in people, and they’re not cancerous.” So he devoted himself to creating a new and better mouse model of colon cancer in the hope of making it available to fellow researchers worldwide.

Dr. O’Rourke developed a protocol that requires growing organoids—three-dimensional tissue cultures—from either mice or human-derived colon cancer samples, which must be genetically engineered to inactivate the APC gene before being implanted into a mouse’s colon using a quick, non-surgical procedure. The organoids then behave as they would in human colon cancer: they begin as precancerous lesions in the innermost layer of the colon, then invade deeper layers of the colon and finally spread to the liver—all within two months, instead of the one to two years typical in older models. Dr. O’Rourke’s protocol also gives researchers the flexibility to genetically alter organoids so they can test the genes of their choosing, then transplant the organoids into research mice with relative ease. Scientists in Dr. Dow’s lab have started conducting experiments using the new model, which was the subject of a paper Dr, O’Rourke published in Nature Biotechnology in June, as have researchers at Memorial Sloan Kettering and in Boston and Spain. “I don’t want to oversell it,” Dr. O’Rourke says, “but we envision that this model, which costs less than previous models and more accurately simulates colon cancer with speed and ease, should enable a lot of labs to finally run the test they’ve been wanting to run.”