From his days as the head of Metastasis Biology at the National Cancer Institute, to his current work at MD Anderson exploring new therapeutic approaches to challenging diseases such as brain cancer, his name has been heavily imprinted on the timeline of “firsts” in the quest to understand how cancer spreads.
Most recently, the professor of Cancer Biology published his team’s findings on a potential new therapeutic approach to treating glioblastoma, a fast-growing and incurable form of brain cancer. The study indicated that combining the oral chemotherapy drug temozolomide (TMZ) with macitentan, a drug originally approved for treating pulmonary hypertension, significantly reduced brain cancer cells in mice.
“In five separate studies, 96% of mice treated with both drugs had no evidence of disease,” says Fidler, “whereas all mice in other groups died.”
Fidler’s group previously showed that tumors that spread to the brain after originating elsewhere in the body tricked brain cells called astrocytes into protecting the cancer, making the tumors resistant to chemo. In this latest study, Fidler explored whether astrocytes — key to providing oxygen and nutrients to neurons — and brain endothelial cells, which form the inner lining of blood vessels, actually shield brain tumor cells from TMZ.
The results, Fidler believes, may very well represent a significant new therapeutic approach for treating glioblastoma.
An unlikely start
The path that Fidler followed — from his native Jerusalem via Oklahoma State University, where he earned his degree in veterinary medicine — did little to indicate his future as a pioneer of metastasis biology.
“I wanted to be a surgeon. But in Israel in the late 1950s and early 1960s, our education emphasized that we must ‘return to earth,’” he said in a 1999 profile that appeared in the Journal of the National Cancer Institute. “We had enough lawyers and doctors, and the nation encouraged people to be farmers. I compromised. If I couldn’t be a human surgeon, I might as well be a veterinarian.”
After working as a surgical oncologist at the University of Pennsylvania’s School of Veterinary Medicine, he earned a doctoral degree in human pathology at the university’s School of Medicine. Nine years later, Fidler joined the NCI, where he headed Metastasis Biology. The institute was the site of some of his early and innovative work in unraveling the riddles of how cancer spreads.
A new understanding
In cancer firsts, Fidler and Margaret Kripke, Ph.D., MD Anderson professor emerita of Immunology, are noted for their groundbreaking studies that demonstrated tumors are composed of different, unrelated cells.
Fidler, who joined MD Anderson in 1983, also showed that metastases are non-random biologic events whose outcomes depend on the interaction between tumor cells and the cellular environment in which they exist. This cellular environment is called a microenvironment and includes the normal cells, molecules and blood vessels that surround and feed a tumor. A tumor can change its microenvironment, and the microenvironment can affect how a tumor grows and spreads.
By uncovering the complex underpinnings of these biological processes, Fidler showed that metastasis isn’t random.
Thanks to the historical — and ongoing — work of Fidler and scientists like him, tumor microenvironments are now a field of intense investigation and a promising new incubator for innovative therapeutic solutions to some of the most deadly cancers.
Fidler’s NCI work was based largely on the findings of English surgeon Stephen Paget, who identified the role of host-tumor cell interactions and is credited with developing the “seed and soil” hypothesis in 1889. He likened the spread of cancer to seeds spread by the wind. Not all seeds germinate, and not all cancer cells metastasize. Just as seeds need the right soil, Paget postulated that cancer cells needed the right “host.”