Joe Bertino, Yale Cancer Center’s founding director

Bertino testified before the Senate-House Finance Committee in Washington on March 14, 1974 about the construction grant application and a core program grant application to establish a State Comprehensive Cancer Center at Yale. The total construction cost of the Cancer Center would be $6.2 million. 

Yale would offer a match, or $2.4 million, which is a proportion consistent with that offered by other institutions. The State of Connecticut would contribute $1.2 million and Yale University would contribute $1.2 million.

This would be a one-time-only request and no future building was now planned, but it was

assumed that in future years, the budget would increase and additional construction would be necessary.

There would also be a request for $6.2 million for a “core” program for 3 years and this annual budget would increase and did not require matching funds. The proposed comprehensive cancer center at Yale would be an important statewide resource. It would serve as a model for top quality cancer care and research and would be an invaluable resource to the individual cancer patient, the community physicians and other health care organizations and facilities.

Yale was officially established as a NCI comprehensive cancer center in May 1974 and Bertino became the first director of the YCCC. 

In a recording of Cancer Answers: The History of Chemotherapy, from July 6, 2008, Ed Chu interviews Vince DeVita about the history of chemotherapy. 

In this conversation, DeVita overviews Bertino’s impact on the field. 

“As a matter of fact, later in 1955, because of the interest in nitrogen mustard another drug was developed called methotrexate, which was also worked on here at Yale by Joe Bertino and people like you in the lab. 

“The Cancer Chemotherapy National Service Center was started in 1955, which was a national program to begin to screen chemicals for cancer in a major way so that the birth of chemotherapy here lead to development of a national screening program.”

In a new approach to cancer treatment, researchers are studying a form of gene therapy that may make bone marrow more resistant to chemotherapy, allowing for higher doses and better outcomes. 

“We are turning the tables,” said Joseph R. Bertino, MD, interim director and chief scientific officer of the Cancer Institute of New Jersey, at Yale Cancer Center grand rounds in May. “This therapy will allow for safer use of drugs and an increase in dosage. If we do this we can protect patients from a wide variety of chemotherapy drugs.” 

Bertino, who was director of the Yale Comprehensive Cancer Center from 1973 to 1975, said this approach calls for introducing a drug-resistant gene into hematopoietic progenitor cells. 

That could limit the drugs’ toxicity and preserve the marrow’s ability to produce infection fighting white blood cells. 

Oncologists would then be able to prescribe higher doses of chemotherapy, potentially leading to improved outcomes. Bertino said two clinical trials—one for lymphoma and another for pancreatic and breast cancer—are in the planning stages.

For some 60 years, Joseph R. Bertino, MD, researcher and former interim director and chief scientific officer at Rutgers Cancer Institute of New Jersey, has devoted his life to improving therapies for cancer and hematologic disorders and has contributed his expertise toward establishing the foundation of modern cancer research.

In 2018, he was recognized by the American Association for Cancer Research with a Lifetime Achievement Award for his significant fundamental contributions to cancer research, either through a single scientific discovery or a collective body of work. Recognizing a half century in the field at the time, Bertino was the subject of an interview that appeared in the spring 2013 edition of The Cancer Institute of New Jersey’s Oncolyte newsletter.

While having taken care of thousands of patients with lymphoma and other blood cancers, it is also at the laboratory bench where Joseph R. Bertino leaves an indelible impression. 

Motivated by the passing of a young nephew from leukemia and the patients he first cared for as a resident, Bertino has devoted most of his life to improving therapies for cancer and hematologic disorders. For more than 50 years he has contributed his expertise toward establishing the foundation of modern cancer research.

How far has cancer research come in the past half century? 

To put things in perspective, a form of nitrogen mustard, developed initially for military use, was considered “advanced” for its time in the 1940s. It was used to treat lymphoma and became one of the first modern chemotherapy drugs. 

Methotrexate, used in the treatment of both solid and non-solid tumors, was another early chemotherapy drug that led to successful treatment outcomes and would serve as a focal point in later years for Bertino’s work. 

Over the past few decades, safer and more effective chemotherapy agents have been developed, but this form of treatment was still in its infancy when Bertino first started his career.

Joseph R. Bertino, a physician who made fundamental discoveries in cancer biology, defined curative cancer treatment regimens, trained generations of influential cancer researchers, ran productive laboratories, and served as the inaugural director of Yale Cancer Center, died on Oct. 10. He was 91.

After Bertino was awarded the 2007 Pinedo Prize at the VU Cancer Center in Amsterdam, his friend and former fellow Bruce A. Chabner wrote in The Oncologist, a journal he edits: 

“Dr. Bertino began his remarkable career in research in Seattle in the late 1950s, where he worked with one of the great biochemists of that generation, Frank Huenneikens. 

“[Bertino] discovered that methotrexate exposure led to a rapid increase in the intracellular level of its target, probably an effect on dihydrofolate reductase (DHFR) transcription, and later, with Bob Schimke at Stanford, he reported the quite remarkable observation of gene amplification of DHFR, opening a whole new era in drug resistance research and unveiling an unexpected aspect of the plasticity of the tumor genome. 

“Many other important observations followed, both in the laboratory and in the clinic, including the evolution of high-dose methotrexate therapy and other aspects of methotrexate pharmacology. 

“Largely as a result of his work, this drug has become the stalking horse for understanding how cancer drugs work and why they fail.”

Joseph Bertino, MD, who served as Chair of Memorial Sloan Kettering Cancer Center’s Molecular Pharmacology and Therapeutics Program from 1987 to 2002, passed away October 11, 2021, at the age of 91. 

He was a true giant in the field of cancer biology who helped usher in a new era in drug-resistance research, and a dedicated physician who treated thousands of patients with lymphoma and other blood cancers. 

He was also an exceptionally kind, beloved mentor and colleague who helped launch the careers of many physicians and scientists who went on to become prominent leaders in cancer care and research.

Dr. Bertino served as past president of AACR and ASCO and was the founding editor of the Journal of Clinical Oncology, now the premier oncology journal. He also received numerous honors and awards during his 60-year career, including the 2018 AACR Award for Lifetime Achievement in Cancer Research.

Among Dr. Bertino’s most notable scientific accomplishments were his pioneering studies of the drug methotrexate, which led to greater understanding of why some cancer drugs work and others fail. 

His work revealed that use of methotrexate leads to an increase in a protein called dihydrofolate reductase that causes cells to block the drug from attacking the cancer. This observation of “gene amplification” at work paved the way for a multitude of therapeutic advances and helped Dr. Bertino earn an international reputation for his role in finding treatments for leukemia and lymphoma.

In 1961, he joined the faculty at Yale in Pharmacology/Medicine where he held several positions, including the first Director of Yale Cancer Center in 1973. 

He stepped down from this position when he was awarded an American Cancer Society Research Professorship in 1975.

Joseph R. Bertino, MD, a past president of the AACR and a Fellow of the AACR Academy whose research on drug resistance led to lifesaving new treatments for leukemia and lymphoma, died October 11, 2021, at the age of 91. 

Born in Port Chester, New York, on August 16, 1930, Bertino earned his medical degree from the State University of New York Downstate Medical School in Brooklyn in 1954. After a fellowship at the University of Washington, he joined the faculty of Yale University School of Medicine in 1961 and served there until 1987. 

His tenure included serving from 1973 to 1975 as director of the Yale Cancer Center. He then joined Memorial Sloan Kettering Cancer Center and worked there until he joined the Rutgers Cancer Institute of New Jersey in 2002. At Rutgers, he was senior adviser to the director of the cancer institute and University Professor of Medicine and Pharmacology at Robert Wood Johnson Medical School. 

From the early days of his career, Bertino’s research focused on drug resistance, particularly as it pertained to methotrexate, a chemotherapeutic agent for blood cancers and various other malignancies. 

Bertino and colleagues reported that dihydrofolate reductase (DHFR) gene amplification was an important driver of methotrexate resistance. These seminal findings helped explain why some cancer drugs work, while others fail, and paved the way for new cancer treatment regimens to be introduced into the clinic. 

Bertino’s research dedicated to hematologic malignancies led to his becoming closely involved with the Lymphoma Research Foundation, where he served as founding chair of the organization’s Scientific Advisory Board. 

In recent years, his research was dedicated to novel drug development for solid tumors and drug target identification for rare lymphomas.

ASCO is saddened by the passing of Joseph R. Bertino, MD, FASCO, who played a pivotal role in the organization’s history. He served as the Society’s president from 1975-1976 before becoming the founding editor-in-chief of the Journal of Clinical Oncology. 

In an editorial printed in the premiere issue, published in January 1983, Dr. Bertino wrote, “The aim of the Journal of Clinical Oncology is to be a focus for communication for research pertaining to the clinical disciplines of oncology.” Today, the journal is ASCO’s flagship publication, serving readers as the most credible, authoritative, peer-reviewed resource for oncology research.

“Dr. Bertino did it all—major scientific discoveries, organization and professional leadership, teaching, and clinical care—with a rare grace and dignity. He made everyone feel respected and motivated everyone to contribute their best,” ASCO CEO Clifford A. Hudis, MD, FACP, FASCO, said.

In the wider field, Dr. Bertino’s best known contribution was his discovery—together with Robert N. Schimke, MD, Rodney E. Kellems, PhD, and Frederick W. Alt, PhD—that gene amplification was a mechanism of methotrexate resistance; specifically, the DHFRgene was found to be a mechanism for overproduction of dihydrofolate reductase. 

Later, while at Memorial Sloan Kettering Cancer Center, Dr. Bertino’s continued research of methotrexate yielded the discovery that defective uptake of methotrexate and low-level amplification of DHFRcaused resistance to the drug in patients with leukemia and soft-tissue sarcomas. 

This and other discoveries eventually led to new analogues and treatments for these patients.

My dear friend and mentor, Joseph R. Bertino, MD, died Sunday, Oct. 10, 2021, in New Brunswick, NJ, after an extended illness.  

He remained active in his laboratory until the last days of his struggle, as one would expect, knowing his passionate commitment to research. Joe was a unique man, one of the early physician scientists comfortable in a basic laboratory, active in the clinic throughout his career, and “translational” in his work to better the treatment of cancer.  

Joe’s career and impact have been described in detail in a recent interview in the Cancer History Project. He grew up in Port Chester, NY, one of three brothers, all of whom excelled in school and sports. 

Joe attended the Cornell as a 6’2” basketball player, a big guy in those days, found his love for science as an undergraduate, and attended medical school SUNY Downstate Medical School after his junior year in college. Following his medical residency at the University of Washington Hospitals, he discovered his true calling in the laboratory of Frank Huennikens, a brilliant biochemist who loved basketball and folic acid. 

Joe and Frank described the induction of dihydrofolate reductase by methotrexate in 1959. How that induction occurred was not clear, only later to be resolved when in 1977 Joe, on sabbatical from Yale, partnered with Schimke, Rod Kellems, and Fred Alt in the discovery of gene amplification.

This research represented a major breakthrough in understanding how tumors become resistant to targeted agents such as methotrexate, 5-fluoro-uracil, and even more contemporary targeted drugs.