Dr. Joseph Bertino's Breakthrough Work in Methotrexate Resistance Led to Understanding Why Cancer Drugs Work or Fail 

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If you look at our medical journals, half the papers now come from scientists in other countries. It’s good to see countries other than the U.S. participating in scientific research and contributing to the welfare of cancer patients, but we don’t want to lose our leadership in the field.

—Joseph R. Bertino, MD

Looking over his 5 decades in clinical oncology and research, ­Joseph R. Bertino, MD, says his greatest professional satisfaction comes from seeing his former students and oncology fellows go on to achieve great success in their own medical and research careers. It is a fitting sentiment since Dr. Bertino credits his early mentors, including Clement A. Finch, MD, the first Chief of Hematology at the University of Washington School of Medicine, with helping launch his career in oncology, a career that remains dedicated to improving the lives of patients suffering from hematologic cancers.

First Physician in the Family

Born in Port Chester, New York, on August 16, 1930, Dr. Bertino was the youngest of three sons born to Joseph and Mamie Bertino. Having emigrated from Italy to the United States just before World War I, it was important for his parents to see their son go to medical school and become the first physician in the family, said Dr. Bertino. Although interested in chemistry and biology in high school, it was not until he was accepted to Cornell University that he decided to pursue a career in medicine.

During medical school, Dr. Bertino became determined to understand the causes leading to the development of hematologic cancers, especially leukemia and lymphoma. In 1958, 4 years after graduating from SUNY Downstate Medical School in Brooklyn, New York, he moved to Seattle, where he began his fellowship training with Dr. Finch, who was an expert on red cell and iron metabolism, and Frank M. Huennekens, PhD, an Assistant Professor of Biochemistry.

“Clem Finch was really forward-thinking and allowed his fellows to work with basic scientists in the laboratory, something that really wasn’t done back then. And to be under the mentorship of Dr. Huennekens, who was one of the great enzymologists of his day, was a big start for me,” said Dr. Bertino.

Understanding Drug Resistance

It was Dr. Huennekens’ pioneering work in folate metabolism that led to Dr. Bertino’s understanding of how the chemotherapy drug methotrexate worked and would later contribute to his breakthrough research in cancer drug resistance. Three years later, Dr. Bertino was offered a joint appointment in the Departments of Pharmacology and Medicine at Yale University School of Medicine. Under the leadership of Arnold Welch, MD, PhD, the Department of Pharmacology at Yale was outstanding, with many exceptional faculty members who were interested in cancer pharmacology.

Dr. Bertino served as the first Director of the Yale Cancer Center from 1973 to 1975 but relinquished his post when he was named an American Cancer Society Research Professor. At Yale, his studies in chemotherapy drug resistance began in earnest, and he discovered that methotrexate exposure led to an increase in dihydrofolate reductase (DHFR).

In 1976, Dr. Bertino took a yearlong sabbatical to work with Robert N. Schimke, MD, in the Department of Biological Sciences at Stanford University. During that time, he and his colleagues Dr. Schimke, Rodney E. Kellems, PhD, and Frederick W. Alt, PhD, discovered that gene amplification was a mechanism of methotrexate resistance, which ushered in a new era in drug resistance research.

“It was an exciting time because DNA was thought to be stable and we didn’t expect to see a change in DHFR gene copy number in the resistant cells. The fact that multiple DHFR genes popped up as a mechanism of overproducing dihydrofolate reductase was groundbreaking at that time,” said Dr. Bertino.

Finding New Targets in Rare Lymphomas

Dr. Bertino left Yale in 1987 to become Head of Developmental Therapy and Clinical Investigation at Memorial Sloan-Kettering Cancer Center, where his research on drug resistance in leukemia and soft-tissue sarcomas found that defective uptake of methotrexate and low-level amplification of the dihydrofolate reductase gene were causes of resistance. It was the result from this and other studies that have led to the development of new therapies for leukemia and lymphoma, earning Dr. Bertino international recognition for his accomplishments.

In 2002, one of Dr. Bertino’s former fellows at Yale, William N. Hait, MD, PhD, who was the founding Director of the Cancer Institute of New Jersey at the Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, asked Dr. Bertino to join the institute as Associate Director.

Today, Dr. Bertino is the Chief Scientific Officer of the institution (which is now known as Rutgers Cancer Institute of New Jersey) and the American Cancer Society Professor of Medicine and Pharmacology at the Rutgers Robert Wood Johnson Medical School, where the focus of his research is centered on new drug development for solid tumors, especially prostate cancer and small cell lung cancer. He is also working to find new targets for T-cell lymphomas and for a rare subtype of B-cell lymphoma called double-hit lymphoma.

“Double-hit lymphoma is a subset of large B-cell lymphomas that overexpress both Myc and Bcl-2 and has a very bad prognosis,” said Dr. Bertino.

Dr. Bertino and his colleague Alexei Vazquez, PhD, and his graduate student Philip Tedeschi, recently showed that Myc stimulates growth by increasing expression of serine and glycine metabolism and folate mitochondrial enzymes, providing an explanation for methotrexate sensitivity in tumor cells that are rapidly proliferating. Myc also stimulates proliferation of double-hit lymphomas, and while initially sensitive to methotrexate and other drugs, Bcl-2 and family members protect the malignant cells from dying, explained Dr. Bertino.

“Treating this disease is very difficult, and we are now studying the tumors and trying to understand how best to treat them by attacking cell proliferation and inhibiting the antiapoptotic proteins,” said Dr. Bertino.

Stellar Career

In 1975, Dr. Bertino was named President of ASCO, and in 1983, was the founding Editor-in-Chief of the Journal of Clinical Oncology. In 1995, he served as President of the American Association for Cancer Research (AACR). He is also the recipient of numerous awards, including ASCO’s David A. Karnofsky Memorial Award, the AACR-Joseph H. Burchenal Memorial Award, the American Cancer Society Medal of Honor for Research, and the Jeffrey A. Gottlieb Memorial Award.

In addition to a stellar career in medicine, Dr. Bertino has had a rich personal life. He and his wife Mary Patricia, who passed away in 2011, raised four children and saw their family grow to include eight grandchildren and two great-grandchildren.

The Future of Research

Although Dr. Bertino has had the satisfaction of witnessing the discovery of many effective treatments in both solid tumor and hematologic cancers over the past 60 years—a time that saw an increase in the number of cancer survivors jump from just 3 million in the early 1970s to nearly 14 million today—federal cuts in research funding threaten further progress, he said.

“If you look at our medical journals, half the papers now come from scientists in other countries. It’s good to see countries other than the U.S. participating in scientific research and contributing to the welfare of cancer patients, but we don’t want to lose our leadership in the field. We have so many opportunities now to make advances in cancer research, but progress will be slowed because we won’t be able to take advantage of some opportunities due to lack of funding.” ■