Michael Wigler, PhD

2007-2008 BCRF Project:
Made possible with generous support from Play For P.I.N.K.

Dr. Wigler's laboratory at Cold Spring Harbor Laboratory published its first survey of breast cancers from Scandinavian countries, establishing a correlation between "genome instability" and disease free survival. They established the utility of copy number measurements in a clinical setting to determine choices of therapy by showing its rough equivalence to interphase FISH, which is the current standard for evaluating the suitability of patients for Herceptin therapy. By compiling copy number measurements from New York metropolitan patients with breast cancers, the Wigler lab is poised to evaluate whether ethnicity or geography impact the molecular mechanisms of breast cancer. They prepared summary lists of all the genes commonly mutated in breast cancer to serve as a directory for future therapeutic targets. Finally, the Wigler lab began examining DNA methylation patterns in breast cancer cells, a key indicator of possible involvement of epigenetics in the etiology of the disease.

Genomic rearrangements are a hallmark of breast tumors. Dr. Wigler's project is dedicated to mapping these rearrangements at very high resolution, identifying the key cancer genes that drive them, and using this information to identify which cancers will respond to particular treatments. The clear benefit to patients will be the increased therapeutic success resulting from application of the right drug to the right tumor. The researchers have made great progress in the mapping and gene identification process. This year they will apply this knowledge to patient samples from clinical trials with the goal of identifying the key genetic markers that dictate patient response to therapy with combinations of paclitaxel and trastuzumab.

Additional project beginning 1/1/08, funded through BCRF
Adjuvant chemotherapy can be highly effective for some breast cancer patients, but not all patients are equally responsive to all chemotherapies, and all chemotherapies have a cost to the patient in money and quality of life. Therefore, it is a major goal for breast cancer research to identify biomarkers, which are aspects of a tumor that will identify that tumor as susceptible to a given chemotherapy, enabling oncologists to secure the best effect for the patient. Bringing a new cancer drug to market might take 15 years from its discovery, but tools, such as biomarkers, that make existing drugs more effective can be utilized in a clinical setting in a fraction of that time.

Dr. Wigler's previous work showed that tumors have characteristic patterns or profiles that can be used to group tumors into classes. He and his team believe these profiles, generated by ROMA microarray analysis, have the best potential to identify biomarkers reflecting the genetic state of tumors and, further, that combining microarray profiling with clinical studies can show which profiles are biomarkers for effective chemotherapy. It is the researchers' goal to (1) identify such biomarkers in breast tumors; and (2) produce a simplified and, therefore, less costly array to use clinically to direct chemotherapy for real patients in real time.

Mid-Year Progress Report:
The Wigler laboratory at Cold Spring Harbor Laboratory progressed from its first published survey of breast cancers from Scandinavian countries, to studies aimed at understanding the genes involved in the establishment and progression of breast cancer. They initially established a correlation between genome instability and disease free survival. They established the utility of copy number measurements in a clinical setting to determine choices of therapy by showing its rough equivalence to interphase FISH, the current standard for evaluating the patients’ suitability for Herceptin therapy. They prepared summary lists of all the genes commonly mutated in breast cancer to serve as a directory for future therapeutic targets. Finally, the Wigler laboratory made progress in determining the DNA methylation patterns characteristic of different classes of breast cancer cells, a key indicator of possible involvement of epigenetics in the etiology of the disease.

Bio:
Dr. Wigler grew up in Garden City, on Long Island, New York. He attended Princeton University as an undergraduate, and Columbia University for graduate studies. After graduate school, he commenced his independent scientific studies at Cold Spring Harbor Laboratory, where he continues his work to this day. He is a recipient of numerous awards and honors, and is a member of the National Academy of Science, the American Academy of Arts and Sciences.

While Dr. Wigler was a graduate student, he developed effective and flexible methods for engineering animal cells, a method that is the basis for the production of medicinally useful proteins even today. After moving to Cold Spring Harbor Laboratory, Dr. Wigler continued his studies of gene transfer, exploring the integration of foreign DNA and the stability of gene expression in transfected cells, demonstrating the inheritance of DNA methylation patterns, and isolating the first mammalian genes, such as the ras oncogenes, using DNA transfer and genetic selection. His laboratory was among the group that first showed the involvement of members of the ras gene family in human cancer. Subsequently, Dr. Wigler used yeast as model genetic systems for the study of signal transduction pathways and oncogenes, culminating in the elucidation of the ras oncogene pathway in yeasts and humans.

In the early nineties, Dr. Wigler and collaborators developed the first method for encoded combinatorial chemical synthesis, a method that is used today for drug discovery, and developed a powerful method for DNA difference analysis called RDA. This method has led to the identification of many new oncogenes, tumor suppressors and pathogens.

Dr. Wigler continues to work in the area of cancer and human genetic disease, and most recently has developed microarray based hybridization methods for comparing the genomes of diseased and healthy cells.