Future of Cancer Lies in Tumor 'Bar Code'

Proteins Studied for Disease Treatment Clues

Proteins are the fabric of life - they provide the bricks and mortar of our cells, and run day-to-day operations. When these functions go awry - when too much or too little protein is produced - illness can arise.

Biologists have estimated that 98% of disease is caused by something wrong in the proteins that genes produce - so oncology researchers are honing in on the proteins involved in the development and progression of cancer.

The hunt is on at M. D. Anderson Cancer Center to find such "markers" of cancer - a barcode of proteins or genes that identifies cells that have turned cancerous and gives hints as to how a patient's unique tumor can be treated.

"In the next five to 10 years, proteins in a patient's tumor will tell us what is important to know about the nature of their cancer and how it should be treated, and gene and protein screens will be used to help direct therapy," says Gordon Mills, M.D., Ph.D., chair of the Department of Molecular Therapeutics.

The promise - and the problems

The idea that specific genes and proteins can be used to diagnose cancer and dictate treatment is exciting to cancer clinicians and researchers. Markers are "the apple pie and motherhood of molecular cancer research," says M. D. Anderson pathologist Stanley Hamilton, M.D., head of the Division of Pathology and Laboratory Medicine. "And perhaps even more than genes, proteins are the ultimate participants in the molecular processes important to cancer."

But even as scientists work to find the specific genes and proteins that signify cancer spread or benign tumors, they have a long row to hoe:

Researchers estimate that each gene can give instructions for as many as 100 different proteins.

Investigators are also finding that the biology of a cancer cell is changeable, so that genes and proteins switched on in a cancer cell one day may not be active the next day.

Hamilton says that despite published studies that identify markers of interest, most have not been validated. "The markers are just not good enough yet," he says. "The studies may show they are highly biologically significant, but not clinically significant." Still, success stories exist.

They include two drugs:

Gleevec, which is designed to shut down the crucial genetic/protein pathway involved in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST).

Herceptin, which treats metastatic breast cancer driven by a gene known as HER2. HER2 produces too much of a protein that tells cells to divide. Protein markers of these cancers also proved to be the switch that could turn the disease off.

M. D. Anderson researchers are using the most advanced techniques, such as DNA microarrays and proteomic technology, to find genes and proteins that are specific to cancer that may eventually offer a potential target for drug treatment.

Breast cancer

Breast cancer researchers at M. D. Anderson are using both proteins and genes to help determine which chemotherapy will work best - before treatment begins.

A landmark study led by Lajos Pusztai, M.D., Ph.D., an assistant professor in the Department of Breast Medical Oncology at M.D. Anderson, is one of the first to show that a genetic profile of a breast cancer tumor can help direct therapy.

Using cells taken from 24 early-stage breast cancers, Pusztai and his colleagues discovered 74 genes associated with a cure when a common chemotherapy regimen known as Paclitaxel/FAC was used. From those genes, they created markers to predict the outcome in 21 newly diagnosed patients and found the test was 75% accurate in forecasting which women would respond to FAC.

Now investigators are testing the gene screen in a larger randomized study at M. D. Anderson. If this study validates the utility of the gene screen, a predictive test may be available for widespread use in two to three years, Pusztai says. He adds that he expects the test to be more than 80% accurate.

Colon cancer subtypes

Figuring out which colon cancers are more or less dangerous is the research focus of Robert Bresalier, M.D., professor and chairman of the M. D. Anderson Department of Gastrointestinal Medicine and Nutrition in the Division of Internal Medicine.

Bresalier and colleagues have found several proteins associated with colon cancer metastasis. Galectin-3, which acts as a "glue" that helps cells stick together, "looks quite good as a potential marker for colon cancer," Bresalier says. Another family of proteins, called mucins, is overproduced in most colon cancers, but Bresalier has found colon tumors that produce specific mucin subtypes are associated with a poorer prognosis.

"Our department is working at a variety of levels to identify markers, including these two, to help us detect colon cancer earlier and to refine our ability to determine prognosis," he says. "Although the data we have so far are exciting, they are preliminary. There are no magic bullets yet."

The road ahead

Experimental Therapeutics Professor Walter Hittelman, Ph.D., is a basic researcher at M. D. Anderson who studies the potential of biomarkers to help thwart even the initial development of cancer. He views the progress made with the combined protein research activities conservatively but also with hope.

"We are early in this field, and its history has been a little optimistic," Hittelman says. "There will be different rates of discovery for different types of cancer, but we are getting there."