The primary focus of the Chien Laboratory in Applied Genomics & Cancer Therapeutics (AGCT) is to:
- understand fundamental biological pathways contributing to the molecular carcinogenesis of ovarian cancer, and
- to develop effective therapies that target critical vulnerabilities/dependencies in ovarian cancer.
Applied Genomics
We are interested in applying genomic and functional genomic approaches to understand critical driver genes, synthetic lethalities, and biological pathways contributing to cancer evolution and drug resistance in ovarian cancer
- Driver genes: TP53 is the most frequently mutated gene in high-grade serous ovarian cancer, the most common subtype of ovarian cancer. We are developing pan-cancer analyses to understand how germline, inherited variations in the coding region of TP53 affect the function of mutant p53 and to develop cancer therapies that target specific p53 mutants.
- Synthetic lethality: Synthetic lethality concept now allows a rational development of therapies that exploit functional deficiencies and dependencies caused by tumor suppressor mutations and epigenetic/genetic rewiring of cancer genomes. We used CRIPSR-based genome-scale screens and identified genetic vulnerabilities in ovarian cancer cells that enhance PARP inhibitor sensitivity. We are currently focusing on vulnerabilities in cancer cell metabolism to cause DNA replication stress and oxidative stress to enhance sensitivity to PARP inhibitors.
- Biological pathways: The FOXM1/MYC nexus represent a critical biological pathway in high-grade serous ovarian cancer. This cooperation between FOXM1 and MYC facilitates cell growth, DNA replication, and resistance to oxidative stress caused by altered cancer cell metabolism. We are focusing on how epigenetic changes caused by FOXM1/MYC nexus can be exploited for therapies in ovarian cancer. TGF-β pathway represents another critical biological pathway that promote adaptive resistance to chemotherapy by facilitating epithelial-mesenchymal plasticity, “stemness”, and cancer cell dormancy. We are currently investigating the TGF-β/HTRA1 nexus and how epigenetic changes in HTRA1 in cancer cells alters the cellular response to TGF-β signaling with regard to epithelial-mesenchymal plasticity, “stemness”, and cancer cell dormancy.
Cancer Therapeutics
- Targeting TP53 mutants: We are developing new strategies to develop new chemical entities to restore wildtype function of p53 or to inhibit the gain-of-function properties of specific p53 mutants.
- Inducing “BRCAness”: Inherited and acquired mutations in BRCA1 and BRCA2 in cancer cells create synthetic lethality in cancer cells when these cells are treated with PARP inhibitors. In some cases where BRCA1 or BRCA2 are not mutated but the homology recombination (HR) repair pathway that they regulate is deficient in cancer due to alterations in other genes involved in HR repair pathway, these cells are characterized as having “BRCAness” because they are also sensitive to PARP inhibitors. We are developing new strategies cause tissue-specific “BRCAness” in cancer cells so that they become sensitive to PARP inhibitors.
- Protein quality control (PQC): Due to alterations in cancer genomes and altered metabolism, cancer cells are highly reliant on protein quality control pathway to rid of damaged, misfolded, and mutated proteins. Recent genome-wide synthetic lethal screens in ovarian cancer also identified components of PQC as new vulnerability targets in ovarian cancer. We are developing combination strategies to target PQC in ovarian cancer.