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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.
As tumors evolve, they acquire mutations in genes that control processes that support tumor growth and promote malignant behavior, such as being able to invade tissue, avoid the immune system and form new tumors at distant organ sites. Advances in technologies such as deep sequencing of DNA allow scientist to probe the mutation landscape of tumors and individual tumor cells. Dr. Szallasi applies this and other technologies to map genetic “signatures” in breast cancer cells. These signatures can be used for new drug development and to select the right drug for each patient.
Full Research Summary
Genomic instability results from the accumulation of gene mutations over multiple cell divisions and is one of the central driving mechanisms of cancer. The result of genomic instability is a tumor cell genome that is distinctly different from that of normal cells as well as other tumor cells. It also allows the tumor to adapt quickly, for instance to resist anti-cancer therapies. While this is seen as a tumor advantage, it can also be a vulnerability.
The development of next-generation sequencing technology has allowed scientist to probe deep into the tumor genome to identify “tags” or mutational "signatures". One of the major goals of Dr. Szallasi's BCRF-supported research is to create a cellular model system that mimics these mutational signatures. Such a system will help accelerate the design of more effective treatments. He is especially interested in a class of drugs called PARP inhibitors, which are useful in cancers with defects in DNA repair pathways, including triple negative and all BRCA-driven breast cancers.
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.
Using this process, Dr. Szallasi’s team developed methods to characterize the alterations in the DNA repair pathway in breast cancer. Such methods are needed to identify those patients most likely to respond to PARP inhibitor therapy. They believe it will also be helpful in identifying drugs for patients with triple negative 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