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Zoltan Szallasi, MD
Senior Research Scientist, Informatics Program
Boston Children's Hospital
Assistant Professor of Pediatrics
Harvard Medical School
Seeking more effective treatments for breast cancer by identifying mutational signatures in human cancer.
An elaborate experimental system is employed to study the effect of a class of drugs called PARP inhibitors.
In studying tumor evolution, Dr. Szallasi's research may reveal new mechanisms of drug resistance and targets for drug development.
Genomic instability–the ability of tumor cells to accumulate gene mutations over multiple cell divisions–is one of the central driving mechanisms of cancer. The development of next-generation sequencing technology has allowed the detection of distinct mutational "signatures", which are collections of genetic changes that define the biology of a tumor.
One of the major goals of Dr. Szallasi's BCRF project is to create a cellular model system that mimics these mutational signatures towards the goal of designing more effective treatments.
His laboratory has assembled a panel of breast cancer cell lines that contain mutations in a variety of DNA repair pathway genes that are often mutated in breast cancer. They grow the cells for many generations (cell divisions) to increase the accumulation of gene mutations, thus mimicking the processes that lead to genomic instability in a human tumor. They then use next generation sequencing to identify gene changes that occurred over time, compare this to tumor mutation data from breast cancer patients, and correlate this information with clinical outcomes.
In the coming year, they will produce mutational signatures following the above-described experimental strategy, map out all relevant DNA repair pathway alterations in breast cancer, and test their diagnostic and therapeutic relevance, which will also involve developing the necessary bioinformatics tool.
They are especially interested in applying their newly acquired knowledge to a class of drugs called PARP inhibitors, which are useful in cancers with defects in DNA repair pathways. The investigators believe these mutational signatures may provide important information to aid in selecting the most effective therapy for breast cancer.
Dr. Szallasi received his Doctor of Medicine degree from the University of Medicine in Debrecen, Hungary, in 1988. He did postdoctoral research in molecular pharmacology of cancer at the National Cancer Institute. As a faculty member, first at the Uniformed Services University of Health Sciences and currently at Boston Children's Hospital and Harvard Medical School, he has become active in the high throughput analysis of breast cancer. He has published over 100 peer-reviewed articles, mainly on the molecular pharmacology and high throughput analysis of cancer.
Dr. Szallasi's group is interested in the application of high throughput measurements for cancer research. They implemented several methods that increased the reliability of microarray and next generation sequencing measurements. They are also interested in approaches that combine genomic scale measurements in a manner that describe essential cancer biology in a robust fashion. Dr. Szallasi is currently developing methods that determine and quantify specific DNA repair pathway aberrations in human tumor biopsies. This work led to a DNA aberration profile-based method that predicts response to platinum-based therapy with high accuracy, and which is currently in the final stages of comprehensive clinical validation.
BCRF Investigator Since