Cellular Stress and Cancer: Understanding the

Connections

Albert Fornace, Jr., MD, who came to Georgetown University Medical Center (GUMC) in late 2006 after years of ground-breaking research at the National Institutes of Health (NIH) and at Harvard School of Public Health, has spent his career trying to understanding precisely what happens to cells when they are stressed or injured.

Waters Corporation Award

Cells are subject to numerous forms of stress, everything from sunburn to chemicals to ionizing radiation. When these occur, protective cellular mechanisms are activated. Damaged cells either repair themselves, cease reproduction, or self-destruct. As Fornace has shown, this happens when stress-related signals inside the cell alter expression of multiple genes involved in cell-cycle control, programmed cell death, and DNA damage processing.

When these protective mechanisms fail or go awry, and damaged cells continue to reproduce, the result may lead to cancer and other disorders. Fornace’s findings have revealed important biological processes underlying the progression of these pathologies.

“Cancer still is a rare event considering the number of cells at risk,” explains Fornace. “And what we’re focusing on is the stress signaling pathways and the regulatory mechanisms that prevent the development of cancer as well as detection of pathway perturbations that can contribute to cancer diagnosis and perhaps to monitor therapeutic outcome.”

Fornace, professor of oncology at Georgetown Lombardi Comprehensive Cancer Center and professor of biochemistry and molecular & cellular biology at GUMC, is one of the most highly cited researchers in the field of molecular biology and molecular oncology. He has published more than 280 papers and serves on the editorial boards of eight journals, including Cancer Research, DNA Repair, and Molecular Cancer Research. He also holds eight patents for technologies therapeutic targets and therapeutic models for treatment and prevention of cancer.


Mapping an Intricate Network of Signals

To map the intricate network of signals that are activated when a cell is stressed, he is currently employing an investigative approach known as metabolomics, which seeks to identify biomarkers—telltale molecular byproducts of cellular chemical interactions—in blood, urine, saliva, sweat, or tissue samples.

“Metabolomics lets us see the small molecules and metabolites that are basically driving the cell,” explains Fornace, “It’s a snapshot of current physiology. It shows us a new level of the cell that wasn’t possible to see until just a few years ago when the technology became available. So when combined with what we know about the genes, proteins, and RNA, we have a holistic, systems view of the cell’s functioning, signaling, and responses to stress.”

Fornace oversees a multitude of funded projects for stress-signaling studies, which include major metabolomics components. Notably, Fornace heads a $5-million award established by NASA Specialized Center of Research, which studies the risk of gastrointestinal cancer due to space radiation in astronauts.


Georgetown Named ‘Center of Innovation’

Waters Corporation has named the metabolomics program at Georgetown University Medical Center (GUMC), co-directed by Fornace and Amrita Cheema, Ph.D., as a participant in its “Centers of Innovation Program.” Waters’ program acknowledges and supports innovations and breakthroughs in health and life science research. Says Tim Riley, PhD, vice president of strategic innovation, Waters Division and program director of Waters Centers of Innovation program: “We are very pleased to be associated with Dr. Fornace’s laboratory and an elite academic medical center such as Georgetown University Medical Center.”

With support from the NIH and the Department of Energy’s Low-Dose Radiation Research Program, Fornace and his laboratory team have developed a broad-spectrum gene testing and metabolomics system to monitor for cellular stress responses due to radiation or toxins. In studies of cells that have been exposed to ionizing radiation, they have identified new p53-regulated genes and also dose-rate gene responses. This approach may enable rapid screening of exposure in the event of bioterrorism or nuclear contamination. In addition, it holds promise for toxicological assessment of new pharmaceutical agents, a major impediment in the pharmaceutical industry’s drug development pipeline.

Fornace explains, “With these tests we are able to look at the early stress responses in cells, independent of toxicity. That means we know about specific signaling events well before cells start dying.” Such knowledge may herald the advent of the Holy Grail of the systems approach to medicine—a way to predict and prevent the progression of disease.

In the meantime, Fornace sees the opportunity at GUMC, with it’s growing portfolio of strategic multidisciplinary investigative partnerships, for accelerating pivotal advancements in translational research.

By Frank Reider, GUMC Communications
(Published October 20, 2011)