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Geoffrey M. Wahl

 

Geoffrey M. Wahl

Geoffrey M. Wahl

Professor
Gene Expression Laboratory

"We are studying the genetic basis of the origin and progression of cancer and developing new strategies to tailor-make drugs based on the genetic signature of a patient's tumor."

Cancer is the second leading cause of death in the United States, but the revolution in our understanding of cancer etiology holds the promise for significant therapeutic advancements in the future. There are, however, two significant impediments to effectively treating cancer. First, cancer is often detected when it is very advanced. Second, cancer cells are often genetically unstable, enabling them to develop resistance to anti-cancer drugs at alarming rates. Research in Wahl's lab addresses both issues.

Wahl and his team showed that cancer cell genetic instability often involves disabling a stress response pathway controlled by the key tumor suppressor, p53. P53, a transcription factor that regulates the activity of genes, is activated by many of the stresses, such as DNA damage, that promote cancer cell development. Once activated, it stops cell division or, if the damage is too severe, induces a cell death program. While the p53 gene is mutated in 50 percent of human cancers, it is normal in the others. Yet, in the latter, the protein's function is still compromised by excessive levels of either Mdm2 or Mdmx, both negative regulators of p53 function. Currently, the lab is developing new strategies to develop chemicals that interfere with Mdm2 and Mdmx to free p53 from their disabling grip. The researchers are also working on mouse models to understand p53's role in various normal cell types, and how Mdm2 and Mdmx control its activity. Such models will provide valuable resources for testing the drugs that target Mdm2 and Mdmx.

Recent studies hint that cancers may originate by mutation of normal stem cells, or conversion of proliferating progenitor cells back into a stemlike state. Wahl and his team are developing new strategies to identify, isolate, and molecularly characterize the stem cells that initiate mammary development. Their long-term goal is to determine whether these cells contribute to breast cancer and, if so, to identify markers on them that can be used diagnostically. Gaining a better understanding of the pathways that drive their growth will provide new therapeutic targets for the treatment of breast cancer.

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Left to right:
Ben Spike, Jennifer Lin, Samantha Cheung, Dannielle Engle, Taneashia Morrell, Geoffrey M. Wahl, Rose Rodewald, Vivian Wang, Mark Wade, Leo Li

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Geoffrey M. Wahl

Geoffrey M. Wahl

Professor
Gene Expression Laboratory

Geoffrey M. Wahl, a professor in the Gene Expression Laboratory, is studying the genetic basis of the origin and progression of cancer and why tumors become resistant to drugs.

The underlying mechanisms of the genetic instability of cancer cells, and of their ability to develop resistance to anti-cancer drugs have remained a mystery to cancer biologists for the better part of a century. Wahl has found evidence that the instability derives from mutations in key genes that determine when it is safe for the cell to begin the important process of duplication of the genetic material. Such mutations also prevent cancer cells from responding to treatments commonly used in therapy that produce DNA damage, such as ionizing radiation. This increases the chances that a mutant cell will be produced every time it tries to reproduce itself. While this gives cancer cells many advantages for growth under stressful conditions, it also provides novel routes for the development of new anti-cancer therapies. The lab is now investigating how p53 is regulated, as 50% of human cancers express wild type p53 that is functionally compromised. Their efforts center on the use of in vitro systems and genetically modified mice to understand the contributions of two related proteins, Mdm2 and Mdm4 (Mdmx) to p53 regulation. Previous studies have shown that these proteins are essential for controlling p53 activity, and that they are frequently over-expressed in cancer cells as a way to mitigate p53 function in tumors containing wild type p53 genes. A goal of these studies is to develop drugs that antagonize Mdm2 and Mdmx to treat patients when tumors over-express these proteins. Another area of investigation concerns the identification and isolation of stem cells that are required to form each of the different types of cells in organs such as the mammary gland. This is important as the special properties of such cells, including their abilities to self-renew and to divide infrequently may enable them to contribute to cancer formation and to drug resistance.

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