Disrupting the Pathways to Cancer

Dr. Yolanda Sanchez is discovering novel compounds that shut down the molecular pathways leading to cancer

Our cells communicate with each other along pathways using the language of chemical signals. The pathways deliver signals that tell cells whether to grow or die. But some cells escape this normal process through mutation, causing the signals to fail and go haywire.

Focus article photo

Dr. Sanchez's research team, from left to right: Anna M. Morenz, Shu (Alice) Pang, Dr. Sanchez (seated), Matthew D. Wood, Saryah Azmat, and Elizabeth Pereira, PhD. Lab members not shown are Rachael N. Labitt, Nathan L. Wong, and Yaa F. Obeng-Aduasare.

The mutated cells—cancer cells—ignore the normal signals, causing them to grow uncontrollably. But where does the communication fail?

In normal, non-cancerous cells, researchers have discovered many of the complex pathways that allow signals to be transmitted from outside the cell surface all the way into the cell's interior and nucleus, which houses the genes. The nucleus interprets a signal by turning on and off genes that create proteins to carry out the response to that signal. For example, if a cell receives the signal to divide, the nucleus interprets the signal by turning on the genes that make the proteins that drive cell division. Mutation of the pathway genes can lead to a faulty signal along these pathways. Some mutations short-circuit the pathway so that the signal to divide is stuck "on" inside the cell, which will ignore any signals from the outside. In recent years, scientists have been intensely studying chemical compounds that disrupt these complex signals when they go awry, which may lead to a new type of cancer drug.

One pathway, known as "RAS," is a major signaling pathway in cell growth and proliferation—and mutations in the RAS pathway are likely responsible for several different cancers. Dr. Yolanda Sanchez, an associate professor of Pharmacology and Toxicology at Dartmouth Medical School and Director of the Cancer Center's Molecular Biology Shared Resource, is refining our understanding of the RAS machinery to effectively shut down faulty signals in cancer. To accomplish this, Sanchez and her colleagues model cancer-associated mutations of the RAS pathway in common brewer's yeast cells, which have similar behavior to cancer cells. Specifically, Sanchez studies changes in the RAS pathway known to be associated with certain cancers. Called 'driver mutations,' these are "mutations that the cancer cell can't live without," explains Sanchez. The cancer cell must have these mutations to survive and uses them to disrupt cell growth, division, and death, which makes them 'immortal' and able to grow unchecked, as in a tumor.

Because yeast cells have similar pathways to human cells but divide more quickly, Sanchez can rapidly study many compounds that could disrupt the faulty RAS pathway by using "high throughput" screening tests to look for compounds that can inhibit cells with a faulty RAS signal. The beauty of these compounds—called "hits" in these screens—is that they don't affect the growth of normal cells, which makes them attractive starting points for new cancer therapeutics. The action of these compounds on the cell is "like hitting the red 'kill switch' on a motorcycle when you are in danger," Sanchez says. "This immediately kills the cell or shuts down its division."

Since 2006, Sanchez and her collaborators have screened approximately 11,000 compounds that could inhibit cells with this mutation to stop the growth of cancer. The trick is to find the most potent chemicals that inhibit the mutant cell, but not the normal cell. To date, Sanchez and her colleagues have narrowed their search to about 50 of the most potent molecular compounds in the yeast model. The same compounds are studied in human cells by their partners at the Children's Hospital Medical Center at the University of Cincinnati.

There are several cancers that could be targets for these compounds. Faulty RAS pathways play a "driver" role in cancers of the nervous system, pancreas, and lung, and right now there are no effective ways to treat those cancers. "The project's initial goal," Sanchez says, "is to identify molecules with the potential to be developed as the basis for cancer therapeutics."

Much more work remains for Sanchez and her colleagues. So far, the potent compounds discovered have shown great promise in the yeast and human cancer models. Because it is possible to identify specific mutations in tumors, "inhibiting cells with mutations in cancer pathways is expected to be far more effective and less toxic than currently available therapies based on cytotoxic agents that damage both the cancer and normal cells," Sanchez says. Her research and the work of others in this area are showing significant promise for developing potent effective anti-cancer therapy in the coming years.

April 15, 2010