Michael Wigler, PhD

2009-2010 BCRF Project:
(made possible with generous support from Play For P.I.N.K.)

Genomic and epigenetic alterations are a hallmark of breast cancer. Dr. Wigler and colleagues have made great progress in gene identification, subtyping cancers by their genomic and epigenetic states, and examining the clonal substructure of tumors. This project is dedicated to continuing this fundamental progress while at the same time using this information to identify the patients who will respond best to particular treatments. One major step in this process is determining which patients are at greatest risk from their cancers. Another step is monitoring the recurrence of disease, and the response of patients to their subsequent treatments.

To that end the Wigler laboratory applied its knowledge and technologies in the past year to patients from clinical trials with the goal of identifying the key genetic markers dictating patient response to therapy with combinations of paclitaxel and trastuzimab. That work, employing microarray technology, made significant progress and gained funding from government sources. The microarray work has also provided a basis for the next leap in tracking and treating breast cancer, the genomic analysis of individual tumor cells, both within tumors and metastases and in other bodily tissues, using the new generation of highly parallel DNA sequencing. The success of this project will increase the breast cancer survival rate, and be widely applicable to most other forms of carcinoma.

In 2009-2010, the Wigler lab will continue the analysis of tumor heterogeneity, in particular to gain insight into the mechanisms of tumor progression and self seeding, and to more clearly establish the relationship between primary cancers and their metastases. The tool of choice will be single cell sequencing, a method Dr. Wigler's team established during the previous funding period for frozen samples. Technical objectives for the next period will be to adapt this tool to cells and microdissected explants from tumors that were preserved in the histopathology lab by standard formalin fixation, and to expand the informatics methods for translating the sequence data to genomic information. The short-term clinical objectives are to determine if tumor heterogeneity and pattern of growth can be used as markers for disease progression. Longer term clinical objectives include possible therapeutic interventions based on the ability of cancers to hone in to new sites of growth.

Mid-Year Progress Report:
Dr. Wigler applied his knowledge and cutting-edge technologies in the past year to patients from clinical trials with the goal of identifying the key genetic markers dictating patient response to therapy. That work, which employs microarray technology, made significant progress and gained funding from government sources. The microarray work also provided a basis for the next leap in tracking and treating breast cancer, namely the genomic analysis of individual tumor cells. The Wigler Laboratory is moving swiftly to exploit next-generation sequencing, and developing methods for single cell analysis that will be applicable to understanding metastasis, the nature of cancer progression, and early detection of occurrence and recurrence of breast cancer. The success of this project will increase the breast cancer survival rate, and be widely applicable to most other forms of carcinoma.

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.