The long-term objective of our research is to elucidate molecular mechanism of DNA damage response pathways, such as the Fanconi Anemia-BRCA (FA-BRCA) pathway, and their involvement in carcinogenesis. The FA-BRCA pathway is critical for DNA repair by homologous recombination and is needed to protect cells from DNA damage created by DNA-crossliking agents like the chemotherapy drug cisplatin. Cells with defects in the FA-BRCA pathway are sensitive to killing by cisplatin. Cisplatin is commonly used to treat ovarian, testicular, and other solid tumors and is particularly effective in tumors with defective DNA repair.
Understanding the biology of the FA-BRCA pathway and DNA repair in general can help refine the diagnosis and therapy of patients with cancer or with Fanconi Anemia. We are interested in identifying novel genes in the FA-BRCA pathway and DNA damage response and repair pathways in general. We are interested in understanding the function of these genes and the pathway in cell cycle checkpoints and DNA repair. We are also interested in determining the role of the FA-BRCA pathway in the pathogenesis of cancer. We would also like to identify small molecule inhibitors or agonists of the FA-BRCA pathway that may be used as novel chemotherapeutic agents or help increase clinical effectiveness of existing chemotherapeutic agents.
DNA damaging drugs, like cisplatin, have been used as chemotherapy for ovarian and other solid tumors especially in patients with defective FA-BRCA pathway. Resistance to these drugs poses a significant challenge for treatment of recurrent tumors. Understanding mechanisms that lead to drug resistance is an important step to ameliorate this problem. We have studied this problem in the context of BRCA1/BRCA2 deficient cancers. Additionally, it is essential that novel drugs that can be used either alone or in combination with existing drugs to treat resistant tumors are identified. We have carried out drug screens to identify such drugs.
MicroRNAs (miRNAs) have been shown to regulate many different biological processes. We are interested in identifying and characterizing miRNAs that regulate different components of DNA damage response and repair. Understanding how these miRNAs can modulate response of cancer cells to chemotherapy may provide insight into possible use of these agents to aid treatment of cancers. Additionally, we are trying to understand how expression of miRNAs may be regulated in response to cellular stress.