The major theme of our work is how DNA repair processes are disrupted in human cancers and how this can be exploited therapeutically. Most DNA repair pathways involve sensing and signaling as well as direct repair proteins, and the upstream signaling to activate homologous recombination may be determined by both double-strand break processing as well as chromatin remodeling. Homologous recombination is often dysregulated in human tumor cells by a variety of mechanisms. Homologous recombination involves many nuclear proteins, including the breast cancer susceptibility genes, BRCA1 and BRCA2, whose function is inactivated in familial breast or ovarian cancers. BRCA1 and BRCA2 both play roles in homologous recombination (HR) although at different steps in the repair pathway. The primary function of homologous recombination may be to restart stalled replication forks, blocked by particular types of DNA damage, or to repair gaps behind the replication fork. There are many vital proteins involved in this DNA repair pathway that are under investigation within the projects of the laboratory.
I additionally serve as the clinical science leader on the MSK SPORE in Genomic Instability in Breast Cancer. As part of the programmatic research efforts in this SPORE our laboratory is involved in efforts to define DNA repair defects in breast cancer with greater reliability and resolution, and to personalize the treatment of breast cancer patients whose tumors display homologous recombination DNA repair-related defects according to their genetic and genomic features. Our hypothesis is that different types of DNA repair defects result in the use of distinct back-up DNA repair mechanisms, which themselves result in specific genomic signatures and sensitivity to different therapeutic agents. The ultimate goal of this project is to personalize the treatment of breast cancer patients whose tumors display homologous recombination DNA repair-related defects according to their genetic and genomic features. We seek to substantially improve the outcome of these poor prognosis patients and direct the deployment of therapeutic agents either already approved (e.g. olaparib) or already in clinical trials (e.g. ATR-inhibitors).
We have a wide range of projects that can be broadly grouped in the following areas:
Defining new targets in HR-deficient cancers. BRCA-deficient cells lacking homologous recombination (HR) are dependent on alternative, often error prone mechanisms, to sustain replication and prevent the formation of DNA intermediates that require HR. Given the incomplete understanding of compensatory mechanisms that allow for HR-deficient cancer cells to sustain replication, we recently conducted a genome-wide CRISPR inactivation screen in unperturbed BRCA2-/- vs BRCA2+/+ cells to identify genes that are synthetically lethal with BRCA2 loss of function. In addition to genes known to be synthetically lethal with BRCA2 loss of function (e.g. POLQ and RAD52), this screen revealed several novel leads that have opened significant new areas of research for the laboratory.
Mechanisms underlying genomic signatures of HR-deficiency. Cancer genomes harbor mutational and structural rearrangements that are jointly shaped by DNA damage and repair mechanisms. Accumulating evidence suggests that genetic alterations in DNA repair-defective tumors reflect the scars of backup repair pathways needed to maintain cellular viability. Detailed analysis of the patterns of mutations and structural rearrangements present in BRCA1/2-deficient tumors has allowed for the delineation of genomic signatures that reflect deficient repair by homologous recombination (HR). In collaboration with Marcin Imielinski and Jorge Reis-Filho, we are investigating the backup repair mechanisms responsible for genomic scarring in HR-deficient tumors.