Titles and Affiliations
Senior Research Scientist, Informatics Program
Boston Children’s Hospital
Assistant Professor of Pediatrics
Research area
Targeting deficiencies in DNA repair that can be exploited to treat aggressive breast cancers.
Impact
The goal of targeted therapy is to kill cancer cells without harming healthy cells and thereby reduce the risk that the patient will experience side effects from their cancer treatment. Tumor cells that have defects in DNA repair, and are thus unable to fix DNA damage, are good targets for drugs that cause DNA damage. BRCA-driven and some triple-negative breast cancers (TNBCs) harbor specific DNA repair defects that are targetable with a class of drugs called PARP inhibitors and DNA-damaging platinum-based drugs. Dr. Szallasi aims to develop and validate diagnostic tools to predict tumor response to therapy and to find new strategies to expand the use of PARP inhibitors and other DNA-damaging drugs to benefit more patients.
Progress Thus Far
Dr. Szallasi and his team found that breast cancers that harbor a defect in a type of DNA repair called nucleotide excision repair (NER) are particularly sensitive to cisplatin chemotherapy. This makes NER gene signatures a potential marker of tumors most likely to respond to this therapy. He and his team then combined two types of information—images of tumor tissue (histopathology) and measurements of proteins in the tumor (proteomics)—to better predict how tumors will respond to platinum-based chemotherapy. Using artificial intelligence (AI), the team found that analysis of both the images and protein data together was more accurate in predicting which cancers would resist platinum treatment compared to prediction from either type of data alone. Finally, the team found that BRCA2-mutant breast cancer is NER deficient and that the combination of PARP inhibitors and irofulven, a drug in a novel class of anti-tumor agents that inhibit DNA replication, shows a high level of therapeutic synergy. Since BRCA2-mutant breast cancers eventually progress on PARP inhibitors, this novel combination treatment may prove to be an effective treatment for such cases.
What’s next
Dr. Szallasi and his team will continue their work improving therapeutics targeting NER-deficient breast cancers and determine whether these tumors respond better to certain chemotherapies, like platinum-based drugs, or to irofulven and explore strategies to overcome PARP inhibitor resistance. They will also continue developing AI tools that combine tumor images and genetic data to predict how breast cancers respond to chemotherapy.
Biography
Zoltan Szallasi, MD 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.
