Isaiah Fidler, DVM, PhD, one of the world’s leading experts on brain metastasis, wowed a standing-room-only audience of neuroscience researchers Wednesday at the University of Cincinnati by illuminating what he hypothesizes is the lethal, long-hidden culprit behind brain metastasis.

The villain turns out to be a group of brain cells known as astrocytes – vitally important to human health in good times but destructive when confronted with cancer cells that have migrated (metastasized) from another part of the body, such as the breast or lung. Astrocytes, which exist only in the brain, communicate with encroaching cancer cells and then, in a cascade of untoward biological events, confer immunity upon the cancer cells, making them resistant to chemotherapy.

The result: most patients who experience brain metastasis succumb in a matter of months.

Dr. Fidler, Distinguished Chair in Cell Biology and Head of the Metastasis Research Laboratory in the Department of Cancer Biology at the University of Texas MD Anderson Cancer Center, presented his hypothesis in the inaugural lecture of the UC Brain Tumor Molecular Therapeutics Program, which is a part of the UC Brain Tumor Center and a close affiliate of the Mayfield Clinic. Dr. Fidler is also serving as an external advisor to the program’s new Scientific Advisory Board.

“The major death from cancer is not from a primary tumor but from metastasis,” Dr. Fidler said. “Metastasis is the ultimate expression of cellular anarchy. Metastases develop and survive because they exploit cells for their own gain.”

Resistance to chemotherapy has long been blamed on the “blood brain barrier,” Dr. Fidler noted. Scientists have theorized that the brain protects itself from toxic substances, including beneficial substances like chemotherapy, by effectively locking them out and thereby preventing them from permeating the brain. But Dr. Fidler disputes that theory. Pointing to an image of enormous, leaky blood vessels in a metastatic brain tumor, he noted that the blood vessels had ample permeability, so a barrier could not be the problem.

“Think about it,” Dr. Fidler said. “By the time we make a diagnosis, vessels in brain metastases are leaking. So the blood brain barrier is not an explanation for resistance, at least not for me. So I look for a different reason for resistance, and I’d like to blame the astrocytes. “Astrocytes have essential function,” he continued. “They transport nutrients from the blood to neurons (brain cells), they protect neurons, they participate in signal transmission, and they maintain homeostasis. Without astrocytes, a neuron will starve to death.”

However, he said, when the brain experiences damage, the astrocytes become activated and somewhat manic in their effort to help out. When a cancer cell invades from the breast or lung or from a melanoma, he said, astrocytes produce “a knee-jerk reaction.” They communicate with the cancer cells – actually touching them with their tentacles – and produce endothelins, peptides that travel through the tentacles to the tumor cells and bind to cell receptors. At that point the tumor cells are able to up-regulate (increase the quantity of) three survival genes that ultimately protect the cancer cells from chemotherapy.

The UC Brain Tumor Molecular Therapeutics Program, which was established in March 2011 with a $2 million gift from the Harold C. Schott Foundation and an additional $4.5 million in funding from UC, is a collaboration between the UC Cancer Institute and the UC Neuroscience Institute. Dr. Fidler agreed to serve as an external advisor because of his longtime interest in the metastatic process and because so few centers around the country are trying to understand and cure brain metastasis.

“Dr. Fidler is likely the world’s No. 1 expert on metastasis,” said Olivier Rixe, MD, PhD, Director of the Experimental Therapeutics Program and Professor of Medicine in UC’s Division of Hematology-Oncology. “In the 1980s he discovered all the key mechanisms to explain how a primary tumor can metastasize to another organ. More recently, he has focused on brain metastasis and has put forth explanations for why brain metastases are more difficult to treat and how they develop drug resistance.”

“Metastasis is a last frontier of cancer,” Dr. Fidler said, following the lecture. “Ten years from now, metastatic cancer will no longer be a black box.”

While at UC Dr. Fidler also helped evaluate grant presentations and offered insight into future research strategies and recruitments.

“We are fortunate to have Dr. Fidler visit to help us set our new Molecular Therapeutics Program on the right path,” said George Atweh, MD, Director of the UC Cancer Institute and Head of the Division of Hematology-Oncology. “We look forward to interacting with him and using his expertise to bring our program to the next level.”

“By asking prominent researchers like Dr. Fidler to become external advisors who evaluate and sometimes guide our research, we hope to accelerate our efforts and improve our ability to help patients who suffer brain metastasis,” said Ronald E. Warnick, MD, Medical Director of the UC Brain Tumor Center and Chairman of the Mayfield Clinic.

Dr. Fidler, a native of Jerusalem, chaired the Department of Cancer Biology at MD Anderson from 1983 to 2008. Prior to joining MD Anderson he served as head of the Biology of Metastasis Section at the National Cancer Institute’s Frederick Cancer Research Facility in Maryland.

Dr. Fidler was working in veterinary medicine at the University of Pennsylvania when his career swerved in the direction of human metastasis. A “dog person and cat person” with a love of horses, Dr. Fidler was unhappy spending so much of his time putting down animals whose cancers had metastasized. In a typical scenario, an animal was cared for by the family vet and then brought to Dr. Fidler after the cancer had spread.

Encouraged by his dean, Dr. Fidler left veterinary medicine, earned his PhD in human pathology at Penn and went on to become a supernova in the academic world.

At 75, he is still driven to find answers.

“When a physician says ‘I believe,’ it means he has no data,” Dr. Fidler said during a reception in his honor. “When you have data, you do not believe. You know.”

He exhorted his Cincinnati colleagues to continue their aggressive acquisition of data so that on his next visit, he will see results.

– Cindy Starr