A righteous purpose
Massey scientist Rick Moran retires after more than four decades in cancer research
“We have a righteous purpose,” says Richard “Rick” Moran, Ph.D., a preeminent scientist at VCU Massey Cancer Center. “I ask my research students to walk through the oncology clinic every day to refresh their memories as to why we are here. The patient is the very real endpoint for research.”
For 22 years, Moran has been a pillar at Massey, helping to lead the cancer center as the associate director for basic research and co-leader of the Developmental Therapeutics research program. He also holds the Paul M. Corman, M.D., Chair in Cancer Research and is a professor of pharmacology and toxicology at the VCU School of Medicine. After working in the field of cancer research for more than four decades, Moran is retiring this December.
“Rick’s contributions to Massey Cancer Center have been truly invaluable and too numerous to list,” says VCU Massey Cancer Center Director Gordon Ginder, M.D. “Beyond his own outstanding scientific contributions, he has provided exemplary and selfless leadership in his administrative roles at Massey. His wise counsel on the leadership team and his mentoring of new investigators leave a strong legacy.”
Moran has led a prolific career, publishing more than 100 articles (with four more currently in preparation) in a variety of academic journals, such as Cancer Research, the Journal of Biological Chemistry and the Proceedings of the National Academy of Sciences. His research has been funded by multiple grants from the National Institutes of Health (NIH) and the National Cancer Institute (NCI), and he has served on grant review boards for the NIH/NCI, Leukemia Society of America and others. He has been recognized with several awards, including by the Leukemia Society of America and the VCU School of Medicine.
An expert in folate-based enzymes and in drug discovery and development, Moran has focused his research on the biochemistry and molecular biology underlying cancer therapeutics and the search for and design of more selective cancer drugs. He was instrumental in the discovery and development of three classes of folate antimetabolites (drugs that interfere with cell division and the growth of tumors and that were the first effective chemotherapeutic agents discovered): (1) pemetrexed (Alimta), (2) raltitrexid (Tomudex) and (3) lometrexol.
Moran’s research career began when he was 16 years old working in a pharmacology and toxicology laboratory on the outskirts of Boston, where he was born and raised. He was employed there from high school through college. He enjoyed the lab and the opportunity it afforded him to work under researchers from Harvard, MIT and Tufts. So after receiving B.S. degrees in chemistry and mathematics at Boston College, Moran enrolled at The State University of New York (SUNY) at Buffalo for a Ph.D. in pharmacology.
While at SUNY Buffalo, Moran joined the lab of William Werkheiser, who was a pioneer in the development of the pivotal chemotherapeutic drug methotrexate (Trexall, Rasuvo) and who was on faculty at Roswell Park Memorial Institute. Moran had been working in Werkheiser’s lab for two years when he was drafted in 1969 to serve in the U.S. Army during the Vietnam War. But his draft board offered military deferment if he continued professional employment in cancer research. Moran quit the Ph.D. program and began working full-time in Werkheiser’s lab. Three years later, Moran re-enrolled in school. But a year after he started the Ph.D. program for a second time, Werkheiser died of a heart attack at a work Christmas party. At a critical point in his Ph.D. program, Moran was suddenly without a research mentor. Not letting that hold him back, he asked the department chair, Enrico Mihich, to serve as his mentor. Not only did Mihich agree, but he also allowed Moran to take over and run Werkheiser’s lab, an unusual occurrence for a graduate student.
Werkheiser taught Moran the importance of mentorship. Werkheiser had told him, “The role of the mentor is to turn out researchers who are better than you.” Moran took that message to heart and let it guide him as he taught and mentored dozens of Ph.D. and post-doctoral students throughout his career. That commitment earned him the “Distinguished Mentor Award” from the VCU School of Medicine in 2009.
Following the completion of his Ph.D. degree in 1974, Moran was a post-doctoral fellow in the lab of another research pioneer who was responsible for the discovery of the chemotherapy 5-fluorouracil (Adrucil), Charles Heidelberger, a professor at University of Wisconsin-Madison. Moran worked with Heidelberger for two years in Madison and then followed him to the University of Southern California (USC) in Los Angeles.
After his post-doctoral studies, Moran joined the faculty at USC and started his own lab at Children’s Hospital Los Angeles. His lab began by studying tumor heterogeneity (differences between cells within a tumor) and to what drugs an individual tumor would respond. But Moran was ahead of his time, and without the right tools or technology, he soon realized that his research goals of individualizing chemotherapy were unrealistic. So he transitioned his focus to an obscure enzyme of folate metabolism, folylpolyglutamate synthetase (FPGS), that ended up being the key to the activity and selectivity of the folate antimetabolites, central to the therapeutics of acute leukemias and to the synergism between 5-fluoruracil and folinic acid, a combination that became standard therapy for colon cancer.
After a series of earthquakes destroyed the building where his lab was housed, Moran moved to the Kenneth Norris, Jr. Cancer Center at USC. He was appointed co-leader of the cancer center’s Developmental Therapeutics program in 1989, and he became a full professor in 1992. It was during his time at USC that Moran and his team played a role in the discovery of raltitrexid and discovered the activity of lometrexol. Raltitrexid is now used for the treatment of refractory colon cancer in Asia and Europe, but not in the U.S. The drug was proven to be as effective as 5FU/leucovorin, the standard of care; but, since it is not more effective than standard therapy, it did not receive FDA approval.
The origins of lometrexol begin with Edward Taylor, a renowned chemist at Princeton who had been working for seven to eight years to develop an inhibitor of thymidylate synthase. The compound didn’t work as intended, so Taylor sent it to Moran to, in Moran’s words, “play with it and see what it could do.” Moran found that the compound was the world’s first folate antimetabolite that potently inhibited de novo purine synthesis, a known, important target for cancer drugs. The day after Moran called Taylor to inform him of this finding, Taylor sold the rights to the compound to pharmaceutical corporation Eli Lilly and Company. The compound was lometrexol. Eli Lilly tested lometrexol in mouse models and human xenografts, and all but one of 18 had complete responses. The company then tested lometrexol in clinical trials, but it had high toxicity that was prolonged and cumulative.
Around this same time, Moran bumped into David Goldman, then director of VCU Massey Cancer Center and the world’s leader in studying the transport process of how folates enter cells. Moran had tired of LA and he was looking for more leadership opportunities. Knowing that Moran was on the job market, Goldman began to recruit him to Massey. Moran knew a handful of researchers at Massey, including Goldman and Steven Grant, and he was attracted to the high quality of their work. He was also attracted to Massey’s growth potential and its need for mid-level leadership at the time. Moran joined Massey in 1993 as co-leader of the Developmental Therapeutics research program and has held that role ever since. (He was later appointed the associate director for basic research at Massey in 1998.)
In 1995, a Massey oncologist and clinical researcher, John Roberts, M.D., (now at Yale), led a clinical trial at Massey using lometrexol in combination with folic acid, which solved the problem of toxicity. By then, however, the patent had expired, so lometrexol went nowhere.
But the research team of Moran, Taylor and Eli Lilly had learned important lessons through the process of developing lometrexol. Consequently, Eli Lilly asked Taylor to “explore the chemical space” around this lead compound, which he did in collaboration with Moran. They discovered another compound in this space that had broad-spectrum activity against tumors, was easier to synthesize and had interesting biochemistry. This compound was pemetrexed. In clinical trials in Germany and England and eventually in the U.S., it was found to be very active against mesothelioma. The FDA approved pemetrexed for the treatment of mesothelioma in spring 2004. Then, after thoracic oncologists experimented with the drug for the use of other lung cancers, the FDA approved it for second-line therapy for non small-cell lung cancer (NSCLC) in fall 2004. A Phase 3 clinical trial in 2008 demonstrated that pemetrexed was better than the standard therapy, so the FDA approved the drug as a first-line therapy for non-squamous NSCLC in combination with cisplatin and folic acid.
Moran went on to make many more important discoveries at Massey. For example, he discovered the mitochondrial folate transporter, the missing link in folate intracellular compartmentalization. He returned to studying pemetrexed and solved the dilemma of why it works in lung cancer, a set of cancers for which other antifolates were inactive. His most recent research discovered why more than half of all cancers have mutations or loss of function of the p53 gene are so driven towards uncontrolled growth and why pemetrexed was active in lung cancers.
An important collaborator for Moran has been his wife, Shirley Taylor, Ph.D., director of the Biological Macromolecule Shared Resource Core and member of the Cancer Molecular Genetics research program at Massey as well as associate professor of microbiology and immunology at the VCU School of Medicine. He met Taylor at Children’s Hospital Los Angeles where she was working in the lab of one of his colleagues, having come from South Africa two years prior. She served her post-doctoral fellowship at California Institute of Technology (Caltech) in the same lab in which Moran spent an early sabbatical in 1985 with Norman Davidson, the pioneer of genomic cloning. Moran and Taylor have offices and labs at Massey side by side, and they have worked together on projects over the course of their careers. An epigenetics and molecular biology expert, Taylor has been an integral part of Moran’s work.
Moran considers himself fortunate that his career has been punctuated by many “eureka moments,” which kept him passionate about cancer research. But more than anything, the real incentive for his work was that he could see that his research had an affect on people. “I could see that people were living longer because of it,” he says.
Moran expects that what he’ll miss most in retirement is intellectual stimulation. But he is excited for the next chapter. He looks forward to redefining himself, even though he admits that the notion is a little scary. And he’ll cheer on the cancer scientific field from the sidelines.
Moran has considerable hope for the future of cancer research. Despite the fact that recent research shows that cancer is harder and more complex than previously thought (because multiple genetic mutations cause cancer, not just one mutation), he thinks there has never been a better time to be a cancer scientist. “Before the mapping of the human genome, it was like developing drugs in the dark,” he says. “Now we can see.”
Moran believes that technological advancements and “a lot of talented, smart people working together” will lead to considerable progress. “The kids being born today won’t fear cancer like we have,” he optimistically predicts. “The majority of cancers will be cured in their lifetime.”
He’s been right about a lot of things in his career. Here’s hoping that he’s right about that.