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What causes lung cancer?
Lung cancer is a protean disease with multiple contributory causes. Most involve critical changes in gene function that lead to disturbances in the complex and highly orchestrated molecular interactions that govern cell function. The 2007 Joan’s Legacy Grant recipients are investigating these genetic changes as well as the role of specific molecules that adversely influence cellular function.
Dr. E. Alejandro Sweet-Cordero will be investigating the role of a gene called K-Ras in lung cancer. Mutations in the K-Ras gene are associated with lung cancer but the mechanism by which they cause the disease is poorly understood. Clarifying the exact chemical pathway governed by this gene may provide specific molecular targets for new drug therapies. Dr. David Kwiatkowski is studying two specific genes called TSC1 and TSC2. Mutations in these genes are associated with both benign and malignant lung tumors. Little research has been done on these genes even though they are abnormal in about 25% of all lung cancers. Like the K-Ras gene, better understanding of the TSC genes may enable new therapies to be developed. Dr. Matthew Topham is investigating the role of an inflammatory protein called COX-2 that is produced by another mutated gene, EGFR. If COX-2 is found to enhance tumor growth, anti-inflammatory agents and other COX-2 antagonists could be used to slow lung cancer growth.
Dr. Carla Kim is taking a different approach and investigating the role of “cancer stem cells”. Although these cells represent only a small fraction of the cells within a tumor, they are believed to be the ones responsible for tumor growth, as well as being more resistant to conventional chemotherapy. Her goal is to isolate them from lung cancer specimens so that they can be studied with the intent of developing more effective chemotherapy. Dr. Federico Innocenti is investigating the tissue environment surrounding cancer cells that promotes their growth. Blood vessels are a major component of this environment, and he is studying a specific gene that promotes blood vessel growth. His goal is to develop inhibitors to this gene that will prevent development of the blood vessel infrastructure necessary for cancer cell growth.
Why are non-smoking women more susceptible to developing lung cancer than men?
Dr. John Heymach is also studying drugs that undermine the development of surrounding blood vessels that nourish tumors. It is apparent that men and women with lung cancer react differently to these agents. He believes these differences are related to the role of estrogens in women and seeks to explain the mechanism by which this occurs. Dr. Raffaella Sordella is investigating the connection between estrogen and lung cancer, because more women develop lung cancer than men, with post-menopausal women particularly susceptible. She is investigating whether normal estrogen levels protect cells from becoming cancerous in the lungs, and whether this protection is lost with declining estrogen production after menopause.
How can we do a better job of treating lung cancer?
One problem in designing effective lung cancer treatments is that the disease is so diverse. It has many causes as well as varied responses to any particular treatment plan. Dr. Neil Hayes seeks to develop screening tests that will characterize each patient’s tumor based on its unique genetic profile. It will then be possible to correlate response to chemotherapy and also long-term survival based on specific tumor characteristics. Dr. Hayley McDaid is working on understanding the particular molecular characteristics of lung cancers that may be sensitive to a new class of drugs called MEK-inhibitors. By profiling the genetic traits of tumors that respond to this type of drug, Dr. McDaid hopes to be able to identify a subset of people with lung cancer that will benefit from MEK-directed therapies.
What new approaches could produce a cure?
Dr. Mark Fuster is investigating whether drugs that block two common molecular pathways stimulated by mutated cell surface receptors (EGFR and heparin sulfate) will slow tumor growth when used together. This dual approach could prove more effective than either approach alone. Dr. Yixuan Gong is investigating the molecular pathways that are normally involved in programmed cell death. The goal is to develop drugs that will increase the effectiveness of this pathway and assist other established drugs, such as Tarceva, that can initiate the cell death pathway in lung cancer cells. Dr. Bingcheng Wang is studying the gene EphA2, which has a tumor suppressor function in normal cells. It is present in an inactivated form in some lung cancers. He seeks to restore EphA2 function by supplying missing molecules that the gene normally creates.
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