JANUARY 8, 1998

Media Contacts: Sarah Goodwin, 404/727-3366 - sgoodwi@emory.edu
Kathi Ovnic, 404/727-9371 - covnic@emory.edu

Many cancers are successfully treated with chemotherapy, radiation or immunotherapy when they are first diagnosed in their early stages. But when these cancers recur or become metastatic they often seem to resist the very same treatments that were successful the first time around. Using knowledge about cell biology and cancer genetics gained through his laboratory investigations, Emory University's Winship Cancer Center scientist Kapil Bhalla, M.D., is designing and using new drug combinations in clinical trials to try and overcome this resistance.

"The common cellular mechanism targeted by all forms of cancer therapy is apoptosis, or programmed cell death," explains Dr. Bhalla. "Apoptosis has an extremely important function in the development of different organ systems during embryogenesis, when its role is to eliminate damaged or excessive cells. In a developed organism, apoptosis is a genetically regulated mechanism designed to kill cells in response to noxious stimuli, which include all forms of cancer therapy."

Dr. Bhalla studies the specific triggering mechanisms of apoptosis, including the factors and genes that regulate it and how cancer cells with altered genes may become either more sensitive or more resistant to drug-induced apoptosis. Mutations or alterations that cause cancer cells to become cancerous, such as oncogenes or loss or alteration of tumor suppressor genes, also change the apoptotic threshold of cells, making them more resistant to anti-cancer agents. Since cancer cells usually acquire multiple genetic abnormalities in their progression from normal cells to cancer cells, they become more and more resistant over time.

"It is no wonder we cannot cure bulky metastatic cancer," Dr. Bhalla points out, "because by the time a cancer cell acquires a metastatic phenotype it has acquired many genetic hitches which make it resistant to apoptosis by several different mechanisms."

Now that he has a better understanding of these genetically regulated mechanisms of resistance, however, Dr. Bhalla believes he is better armed to provide improved therapies to raise the apoptotic threshold. His research focuses on how drugs target and injure cancer cells and how they engage the apoptosis program within the mitochondria (energy factories) of the cell. He has learned that anti-cancer drugs engage the apoptotic program by first causing DNA damage and/or by affecting cell cycle progression (the process by which cells replicate their DNA and divide). Since cancer cells are often constantly dividing, drugs that affect cell cycle progression and the division process could effectively trigger apoptosis.

Dr. Bhalla's work focuses on two classes of drugs: anti-microtubule drugs, or taxenes, which include the highly successful Taxol (paclitaxel) and newer analogs such as taxotere, and nucleoside analogs, which include the important anti-leukemic drug Ara-C. He has designed new clinical trials for breast cancer and esophageal cancer that combine taxenes with other anti-cancer drugs in a way that maximizes apoptosis. He also is examining the biopsy material of patients before and after treatment to study the genes that regulate apoptosis due to the action of these drugs.

Using a nucleoside analog drug, gemcitabine, which he studies in the laboratory, Dr. Bhalla has conducted early trials in pancreatic and gastric cancers with "very gratifying responses." Through an NIH grant, he will test these new combinations through carefully designed clinical trials before they become standard treatment. In the future he hopes to address diseases like chronic myelogenous leukemia, a cancer that responds to chemotherapy in its chronic stage but becomes resistant to the apoptotic effects of therapy in its acute phase, requiring patients to undergo bone marrow transplantations.

Dr. Bhalla is working with Emory biochemist Al Merrill, Ph.D., to understand how analogs of sphingolipids (complex fats that are essential to the healthy functioning of cells) can regulate the threshold for apoptosis in the lining of the colon. Cancer cells in the colon go through a gradual progression from mildly abnormal cells in the lining of the duct to full-blown cancer cells over a period of time. Dr. Merrill has shown that the development of colon cancer in mice fed with certain sphingolipids is inhibited because the sphingolipids lower the apoptotic threshold.

Understanding the reasons for resistance to apoptosis also opens up new possibilities for combing chemotherapy with gene therapy, says Dr. Bhalla. "For example, one of the very important common tumor suppressor genes whose function is lost in cancer cells is the P53 gene. This mutation causes resistance to apoptosis in a variety of anti-cancer drugs and radiation therapy. By restoring the function of this gene, we can again sensitize these cancer cells to anti-cancer drugs and develop a combination of drugs that can overcome any resistance to apoptosis."

The ability of any anti-cancer strategy to induce apoptosis becomes a readout for defining better treatment, Dr. Bhalla comments. Because this is a mechanism-based approach, it is far more rational than just randomly mixing anti-cancer agents together to see what works.


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