40 Years of Pushing the Boundaries of Cancer Science

40 Years of Pushing the Boundaries of Cancer Science

The Wistar Institute Cancer Center

When The Cancer Act of 1971 was signed into law on December 23 of that year, the United States began an investment that would transform medicine. Through the law, the National Cancer Institute was empowered to support centers of research and teaching. At a time when little was known about the biology of cancer or the genetics that drive the disease, it was a revolutionary investment in science and medicine.

Forty years later, our perception of cancer has been transformed through knowledge. Prevention, early detection, and improved therapies have reduced the death rate from most forms of cancer. Throughout the last 40 years, Wistar has been on the leading edge of the fight against cancer, a search for both a cure and the fundamental root causes of the disease.

From Viruses To Cancer

The earliest mention of The Wistar Institute’s interest in opening an NCI-designated Cancer Center appears in the minutes of the September 24, 1971 meeting of Wistar’s board of managers, as David Kritchevsky, Ph.D. (a pioneer on the role of cholesterol in heart disease) reported:

“The federal government currently plans to launch a substantial program to determine a cure for cancer. The Institute…is in an excellent position to participate in the government’s program provided it can obtain additional research space.”

Wistar researchers in the 1970sEvents progressed rapidly. By May 1972, the board reported that Wistar’s $3 million NCI grant was approved, reflecting “…the extreme high standing of the Institute, Dr. Koprowski and his staff.” As part of the NCI grant agreement, the Institute would be obliged to raise an additional $1.5 million for construction of what is now known as the Cancer Research Building. Wistar would raise these funds through a capital campaign led by legendary Philadelphia Councilmember Thatcher Longstreth.

[At left: Wistar researchers in the 1970s. At far left in the dark shirt: Hilary Koprowski, M.D. Front center, with dark glasses: David Kritchevsky, Ph.D.]

With that, Wistar became one of the first NCI-designated Cancer Centers in the nation and the first in Philadelphia. Today, Wistar is one of only seven Cancer Centers across the country purely devoted to research.

How could Wistar, which had become renowned in the 20th Century for developing animal models for research and vaccines, become a Cancer Center? The answer rests in a major division in the cancer research commu­nity at the time, one between those who saw viruses as the major cause of cancers and those who pointed to environmental and chemical causes.

In 1972, Frank Rauscher Jr., Ph.D., who had widely published on the viral causes of certain cancers, was appointed NCI Director. According to his son, Frank Rauscher, III, Ph.D., a professor in Wistar’s Gene Expression and Regulation Program, “Along one side of the hallway, you had researchers like my father showing how viruses cause cancers, and along the other you had folks painting the backends of mice with tar showing chemical causes of cancer.”

By the early 1970s, virology related to cancer science had become a significant part of Wistar’s research portfolio. It was an area of study encouraged by then-Director Hilary Koprowski, M.D., an internationally recognized leader in vaccine development, having overseen the creation of vaccines against polio, rubella, rabies and other diseases.

The Monoclonal Antibody Era

Koprowski’s unique style of leadership had its benefits. According to Meenhard Herlyn, D.V.M., D.Sc., professor and leader of Wistar’s Melanoma Research Center, his own research path was reorganized in the mid-1970s, when Koprowski returned from a conference in Europe excited about new advances in “monoclonal antibodies.”

Immune cells guided by monoclonal antibodies attack tumor cells.Monoclonal antibodies are clones of immune cells engineered to produce a single, specific antibody — a complex, Y-shaped protein that the immune system uses to identify and mark potential targets.

At Wistar, monoclonal antibodies would be used as a tool for molecular virology and tumor biology, but researchers soon saw their potential as a new sort of targeted therapeutic, one that could be developed to bind to, say, a protein involved in cancer.

“The idea was that monoclonal antibodies could be a magic bullet — a means of targeting cancer cells so that the immune system will recognize them,” said Herlyn. “The technology changed cancer research, but not necessarily as a magic bullet. Wistar was one of the first to show the utility of monoclonal antibodies as a research tool.”

Herlyn joined senior colleagues such as Carlo Croce, M.D., and Walter Gerhard, M.D., in developing hybridomas, cells made by fusing antibody-producing B cells of the immune system with myeloma cells — a form of cancerous B cell. These hybridomas would serve as tiny factories for producing a single variety of antibody, which could bind to a specific target in the body, such as a particular protein. Wistar rapidly progressed to the forefront of this line of research and, in 1979, the Institute licensed its monoclonal antibody technologies to Centocor — a suburban Philadelphia drug company now a subsidiary of Johnson & Johnson — for drug development.

Today, numerous drugs against cancer and other diseases — both in use and currently in development — resulted from the monoclonal antibody revolution introduced by Wistar and its contemporaries. For example, monoclonal antibodies against Il-12, a signaling molecule discovered by Wistar’s Giorgio Trinchieri, M.D., have led to both cancer drugs and Stelara, a medication to treat the skin disease psoriasis.

The very concept of today’s modern “targeted therapies” owes its existence to researchers in places like Wistar who turned the potential of monoclonal antibodies into a medical reality.

The Genomics Era and Beyond

Virology may have gotten Wistar into the cancer business, but neither viruses nor chemicals are the sole cause of these diseases. While clinicians did note that some cancers seemed to be hereditary, it was not until the 1970s that emerging laboratory technology could link specific genes encoded in DNA to forms of cancer. Cancer is driven by DNA, science would learn. Genetic errors — whether spurred by viruses, radiation, or chemicals — fuel the disease.

In the mid-1980s, researchers at Wistar and around the world began using emerging tools to ferret out oncogenes — genes thought to cause cancer. Experiments would eventually begin to show the research world that most of these “bad” genes were largely either “broken” through mutation or, similarly, poorly managed by the clockwork regulatory mechanisms (perhaps affected by mutation) that had gone awry.

“I for one began moving away from monoclonal antibodies in the mid-1980s, turning more toward the genetics of cancer, particularly melanoma, and the mechanics of disease,” Herlyn said. “By the late 1990s and early 2000s, with new technologies we were able to demonstrate the role of genes, such as BRAF, in driving the disease.”

By the early 1990s, Wistar’s strategic recruitments began to bring aboard the next generation of young scientists devoted to both charting the genes associated with cancer and solving the molecular structures of the proteins responsible for cancer function and gene regulation. While tumor immunology and monoclonal antibody development remained a major portion of the Institute’s work, programs in genetics and gene regulation began to take shape at Wistar.

Cancer science was rocketed forward with the publication of the first draft of the human genome by the Human Genome Project in 1999, which sequenced the entire complement of human genes. In fact, the publication itself, while significant, is almost secondary to the technology developed in the process. Scientists are now able to sequence tumors or screen the entire genome for particular mutations.

Not only do Wistar scientists explore the genes and proteins responsible for cancer, they look at entire systems of interrelated genes — signaling pathways that drive tumor formation and spread. Simultaneously, Wistar researchers have made significant advances in our understanding of how genes are regulated — turned on or off. Wistar is also a leader in the emerging field of epigenetics — the study of how modifications made to DNA can change gene regulation — a process often linked to cancer.

For Herlyn, his work has nearly come full circle. Through Wistar’s Melanoma Research Center, which he leads, scientists are exploring how to develop drugs that hit multiple targets along the tangle of interrelated signaling pathways that drive cancer. Where a single drug might allow the tumor to “rewire” signaling pathways, thus allowing it to return after an initial bout of therapy, experiments have shown that the options for tumors to escape quickly diminish when you attack multiple pathways.

Setting Up the Next 40 Years of Discovery

GroundbreakingThis autumn, Wistar is a year into a major expansion project, its first since the construction of the Cancer Research Building, which opened in 1974. Forty years on, in 2014, the Robert and Penny Fox Tower will open its doors to serve the next generation of cancer researchers.

The Wistar of the future, according to Cancer Center Director Dario C. Altieri, M.D., honors the Wistar of the past through its commitment to independent research and its spirit of innovation. As Altieri explains, Wistar is transition­ing to a new paradigm — one that expands Wistar’s talented pool of researchers to include those with a diverse array of scientific skills, who could then be deployed in teams to meet new scientific challenges.

“Forty years ago, we did not know what we did not know about cancer, and Wistar has played a vital part in furthering the scientific understanding of the biology that underlies this set of diseases,” said Altieri, who is also Wistar’s chief scientific officer and Robert and Penny Fox Distinguished Professor. “At its 40th anniversary, The Wistar Institute is uniquely positioned to fully realize the potential of science in developing new tools to detect and beat cancer.”

“This is where cancer science is heading, and it is our job to provide scientists with tools, funding, and facilities that will make this happen.”