Determine the Origin of Ovarian High-grade Serous Carcinoma- the Tubal Paradigm
1) Determine whether the serous tubal intraepithelial carcinoma (STIC) is the precursor lesion in most of ovarian high-grade serous carcinoma (HGSC) using clinicopathological and molecular genetic approaches as well as genetically engineered mouse models. 2) Identify and characterize the pre-STIC lesions in normal fallopian tube (NFT) epithelium. 3) Apply novel technology to detect STIC using intra-uterine brush and cervical cytology specimens. 4) Assess whether commonly prescribed drugs can prevent or delay STIC formation in the mouse STIC model.
Elucidate the Pathogenesis of Endometriosis and Endometriosis-related Ovarian Neoplasms
1) Validate the possible endometrium-committed progenitor cells as the origin of endometriosis. 2) Deep sequencing analysis of endometriotic lesions to reveal molecular alterations that are associated with clinical aggressiveness and recurrence. 3) Demonstrate the pathogenesis how an endometriotic lesion becomes transformed and progresses to ovarian clear cell and endometrioid carcinomas, with a special focus on studying the role of ARID1A and PTEN inactivation mutations.
Unravel The Molecular Landscape of Ovarian and Uterine Cancer- Why Some Become Aggressive and Lethal?
1) Apply next-generation sequencing and state-of-the-art molecular genetic methods to explore the global molecular alterations of different types of ovarian and endometrial carcinomas at different biological contexts. 2) Identify mechanisms behind development of resistance to chemotherapeutic drugs in ovarian cancer. 3) Elucidate clonal evolution and intra-tumoral heterogeneity as a function of host selective pressures and their contributions to disease aggressiveness. 4) Reveal the molecular alterations that programs ovarian serous borderline tumors to become low-grade serous carcinomas and discover the molecular markers that predict such malignant transformation.
Study Why Loss of ARID1A Tumor Suppressor Promotes Tumor Development in Gynecologic Cancers
1) Employ a system biology approach using multiple genome-wide methods including ChIP-seq, Faire-seq, ATAC-seq and RNA-seq to comprehensively assess ARID1A-induced chromatin configurations that affect DNA damage repair and DNA synthesis. 2) Demonstrate the transcriptome regulated by ARID1A containing SWI/SNF complex during tumor initiation and progression. 3) Apply genetically engineered mouse models to elucidate the functional roles of ARID1A in collaboration with other cancer pathways in developing uterine and ovarian cancer. 4) Study the synthetic lethality of ARID1A inactivation.
Identify and Characterize Mullerian Progenitor Cells and Reveal Their Roles in Genesis of Uterine and Tubal Cancers
1) Discover somatic progenitor cells that generate the Mullerian duct epithelium using primary culture and genetically engineered mouse models. 2) Characterize these progenitor cells and the effects of micro-environmentalfactors in developing endometrium and fallopian tube epithelium. 3) Understand the molecular events that transform progenitor cells into neoplastic cells. 4) Determine whether the endometrium-committed progenitor cells are able to form endometriotic lesions in a newly developed mouse model.
Spleen Tyrosine Kinase (SYK) Inhibitor Sensitizes Paclitaxel Cytotoxicity in Ovarian Cancers
1) Determine the mechanisms how activation of SYK signaling antagonizes paclitaxel's effects (stabilizing microtubule followed by inducing apoptosis) by identifying its downstream substrates including those involved in cytoskeleton dynamics, death prevention program and oncogenic signaling. 2) Initiate Phase Ib/II clinical trial to determine the safety and possible clinical benefit of SYK inhibitor in advanced ovarian cancer patients. 3) Identify biomarkers that are associated with better clinical response to SYK inhibitor.