The primary objectives of my research program in Applied Genomics and Cancer Therapeutics (AGCT) are to understand the genetic basis of cancer and to translate this knowledge into clinical applications in the early detection and treatment of cancer. To support these objectives, my current research focuses on three areas:
A. Genomics of ovarian cancer: Although genetic alterations are considered a hallmark of cancer, specific genetic alterations serve as “drivers” in cancer progression while others are considered “passenger” mutations. Advances in the identification of “driver” genetic alterations in cancer will lead to the development of novel therapeutic targets to effectively treat cancer, and it is a prerequisite in the era of “Personalized Medicine” or “Precision Cancer Medicine.” My research focuses on the characterization of genetic mutations from cancer genomes to identify driver mutations and the development of experimental therapeutics that target driver genes in ovarian cancer. We are developing tools to perform variant calling from RNA as well as from formalin-fixed archived tumor samples, translocation detection from mate-pair sequencing, and phylogenetic analyses to understand the evolution and progression of ovarian cancer.
B. Functional Genomics: Resistance to chemotherapy in metastatic disease settings is a major contributing factor to the high rate of mortality in ovarian cancer. The primary objectives of this research focus are to identify genes and biological pathways regulating ovarian cancer metastasis and chemotherapy resistance and to identify novel therapeutic targets to treat advanced ovarian cancer. To achieve these goals, we have generated a genome-wide custom cancer toolkit (tumor-derived cDNA library from 10 tumor samples collected from women with chemotherapy-resistant ovarian cancer), and we are performing genome-wide ORF screens to identify driver genes that promote chemotherapy resistance. In addition, we are using complementary genome-wide RNAi screening to identify genes that modulate ovarian cancer metastasis and chemotherapy resistance and to identify synthetic lethal phenotypes to overcome chemotherapy resistance.
C. Molecular Cancer Therapeutics: The Cancer Genome Atlas studies also identify FOXM1 as a candidate gene that is overexpressed in 84% of high-grade serous ovarian cancer. High levels of FOXM1 expression in this disease suggest it may serve as a therapeutic target, analogous to Her2 in breast cancer, Abl in leukemia, and Braf in melanoma serving as therapeutic targets in respective diseases. We are defining the regulatory feedback loop between FOXM1 and MYC and how this nexus contribute to adaptive therapeutic stress response and drug-tolerant cellular archetype. Finally, we are developing a rational combination of targeted therapies to exploit vulnerabilities in high-grade serous ovarian cancer. In particular, we are focusing on adaptive stress response and unfolded protein response as targets of vulnerabilities in ovarian cancer.