Building Foundations for Understanding Drug Mechanisms in Oncology

OncologyLive, Vol. 20/No. 16, Volume 20, Issue 16

A 2018 Giants of Cancer Care award winner for Drug Development, Joseph R. Bertino, MD, was an early pioneer in developing the understanding of methotrexate and its administration in cancer. His work has served as a platform for much broader investigation into the optimal use of other cancer agents. Along the way, Bertino has mentored many leaders in oncology and hematology and earned international recognition.

Joseph R. Bertino, MD

What would Joseph R. Bertino, MD, do if he couldn’t work in science or medicine? He’d play a lot of golf.

“If I were better at it, I’d go on the golf tour,” he said. “I’m average.”

In medical oncology and research, however, Bertino has been a champion. He has pioneered drug research, spending his career delving into the mechanisms of drug resistance, with a particular focus on methotrexate, which is used to treat breast and lung cancers, certain cancers of the head and neck, some types of lymphoma, and leukemia. He helped develop the use of leucovorin to aid patients experiencing blood cell disorders that result from high doses of methotrexate. In addition, he built foundations for other investigators to explore a broader range of drug mechanisms for treating diverse cancers.

“My first love has always been hematology and blood diseases,” Bertino said. While completing his fellowship at the University of Washington in Seattle, Bertino worked under Clement A. Finch, MD, the school’s first chief of hematology, and Frank M. Huennekens, PhD, a biochemistry assistant professor and a pioneer in developing the understanding of folate metabolism and dihydrofolate reductase, the target of methotrexate. Bertino mentored and trained many of the current leaders in the field of cancer research—a career highlight. “The major thing I’ve done is to train good people who have gone on to exceed my accomplishments,” he said.

His Life's Work

Today, Bertino is a university professor of medicine and pharmacology at UMDNJRobert Wood Johnson Medical School in New Brunswick, New Jersey, and is the interim director of the Cancer Institute of New Jersey.

He looks back on a breakthrough moment during a sabbatical year at Stanford University in California in 1976: While working in the laboratory of Robert Schimke, MD, a professor of biological sciences, he and graduate school students Rodney Kellems, PhD, and Frederick Alt, PhD, discovered how gene amplification could produce more dihydrofolate protein and result in methotrexate resistance. “Gene amplification as a mechanism of resistance had widespread implications to other drugs,” Bertino said.

Building on that research, Bertino would devote his career to studying the mechanism of drug action and resistance to better help those with different kinds of cancer. He spent decades in leadership roles at various institutions. He joined the Yale School of Medicine in 1961 under the direction of Arnold Welch, MD, PhD, as an assistant professor, picking up promotions and tenure throughout the 1960s. He was named the chief of the Section of Oncology and Chemotherapy in 1966 and a full professor in the Department of Medicine and Pharmacology in 1969—positions he held through 1986.

“Yale was a great experience,” he said, emphasizing “the strong colleagues, the outstanding pharmacology department, a great department of medicine and a great place to work.” The department was unusual in that most of the faculty were interested in cancer pharmacology. He also was, for a short time, the first director of the Yale Cancer Center.

After Yale, Bertino joined Memorial Sloan Kettering Cancer Center (MSK) in New York, New York, in 1987 to work with John Mendelsohn, MD, and build the institution’s molecular pharmacology and therapeutics program, as well as work with more patients and patient samples. “They have large numbers of patients there,” he said. Working with Mendelsohn and MSK’s president and chief executive officer, Paul Marks, “was a great experience,” he said.

By 2002, a former Yale colleague, William “Bill” Hait, MD, PhD, recruited Bertino to the nascent Cancer Institute of New Jersey. “It was an opportunity to build the cancer center and recruit young people,” Bertino said. He held positions as associate director, chief scientific officer, and interim director from 2007 to 2008.

Today, Bertino sees just a few patients and spends most of his time doing research and teaching. “There are still a lot of interesting things going on, and I love working. It keeps me young,” he said, adding, “I miss seeing patients. I liked the personal interaction, and patient problems have stimulated my lab research.”

He oversees a laboratory team of 7 who are investigating a mitochondrial folate enzyme that is overexpressed in cancer cells and an antibody conjugate that may have applications to treat triple-negative breast cancer. He is also studying a new platinum compound that may be successful in treating multiple myeloma.

Bertino praises his longtime teachers and colleagues for having helped his career progress. “I’ve been fortunate to have outstanding mentors, including Huennekens, Finch, and Welch, who have been very supportive,” he said. “At MSK, Marks and Mendelsohn were very good role models, as well. The message to young people is to have mentors who are interested in helping you along through your career and your life.”

Foundations: Family and Leisure

Bertino was born on August 16, 1930, the youngest of the 3 sons of Joseph Bertino, a shoemaker, and Mamie Posillipo. He grew up in Port Chester, New York, where he was a strong student, skipping 2 elementary school grades. He played basketball, football, and baseball in high school. He attended Cornell University in Ithaca, New York, and majored in chemistry.

“[Cornell was a] great experience. It’s a great school, demanding, and the scholarship there was very high,” he said. It prepared him well for medical school at Downstate Medical Center in Brooklyn, New York, where he attended on a scholarship after his junior year in college. He then interned at the University of Pennsylvania (Penn) Graduate Hospital; did his residency in medicine at the Philadelphia Veterans Affairs Medical Center, Pennsylvania; and was a hematology and biochemistry research fellow at the University of Washington School of Medicine in Seattle.

Bertino met his wife, Mary Patricia, in the early 1950s while at Penn. “[She was] a very attractive nurse, and she turned out to be a great person,” he said, laughing. Although he doesn’t recall much about their first date—“I was an intern; we didn’t do much”—they continued seeing each other for 2 years and married in 1956. Their 4 children, Fred, Amy Marie, Thomas, and Paul, are now in their late 50s and early 60s.

“It wasn’t easy,” Bertino says of the role his wife played. “I had a lot of respect for her. She was a great mother. I was away a lot, and she really took over and made sure that the kids were on a straight path.”

It seems that the path was a solid one. Their daughter is a molecular biologist at Massachusetts General Hospital in Boston, 1 son is a filmmaker, 1 heads a Boston advertising agency, and the third is a car collector. The family now includes 8 grandchildren and 2 great grandchildren, ranging in age from 4 months to 30. The oldest, Niia, is a singer, pianist, and songwriter and released her first album in 2017. Mary Patricia died in 2011 due to heart issues.

Traveling to spend time with family is a priority, Bertino said. His children are based in Massachusetts, Florida, and California, and he has a family home in the Adirondacks and another in Connecticut, where he spends his weekends. “I try to get family together,” he said.

He also spends time cheering for the Mets, watching mystery and classic films on The Movie Channel, and reading American historical novels, most recently about Ulysses S. Grant.

Awards and Predictions

Long recognized for his work, Bertino has earned numerous accolades. The short list: the American Cancer Society Medal of Honor, 2 awards from the Lymphoma Research Foundation, the ASCO Statesman Award from the American Society of Clinical Oncology, the Jeffrey A. Gottlieb Memorial Award for outstanding achievements from The University of Texas MD Anderson Cancer Center, and an American Association for Cancer Research lifetime achievement award.

Bertino has held many professorships, earned honorary degrees, and served on the editorial boards of many cancer research journals and as the founding editor of the Journal of Clinical Oncology. Today, he is on the editorial boards of Cancer Investigation, Clinical Cancer Research, Cancer Cell, and the Journal of Cancer Biology and Therapeutics.

The field holds much promise, Bertino believes. “We are moving toward precision medicine, coupled with harnessing the power of T cells. We have to learn more about how to make [the adverse effects associated with chimeric antigen receptor T cells and checkpoint inhibitors] easier on the patient. CAR T cells can cause serious reactions, and checkpoint inhibitors cause autoimmunity and different problems relating to that. They don’t work on the same tumors. We’re learning how new modalities will make them work in more patients and how you can combine them with other drugs. Things are moving at a really rapid pace!”

Bertino plans to contribute as long as he can. “I like to work hard,” he said. “I have been consumed by research and try to keep up with everything.”