Abstract TMEM-118: ROLES OF T-LAK CELL-ORIGINATED KINASE (TOPK) AND THE MICROENVIRONMENT IN DRIVING OVARIAN CANCER PROGRESSION

Abstract

Abstract Ovarian cancer (OvCa) therapy is confounded by late detection and a lack of effective therapeutics. After debulking surgery, most patients initially respond to platinum-based chemotherapeutics, however their tumors inevitably develop resistance and recur. Developing new treatments for OvCa will depend on a thorough understanding of OvCa biology. We recently identified T-LAK cell-originated kinase (TOPK), a serine-threonine kinase, as highly expressed in OvCa. A member of the cancer/testis antigen (CTA) family, TOPK is induced by mutant TP53 and is expressed in early, in situ serous tubal intraepithelial carcinoma lesions. Targeting TOPK with a small-molecule inhibitor in a mouse model of OvCa led to significant reductions in tumor burden. To better understand the interplay between TOPK and the tumor and stroma in ovarian cancer progression, we performed compartment-resolved, quantitative shotgun proteomics on microdissected tumor and stromal samples across a hypothetical progression series of ovarian cancer from in situ STIC to omental metastases. With a highly-sensitive platform, we were able to accurately quantify proteins across the progression series and confirmed expression of known tumor and stromal markers in the data set. Interestingly, we observed a conserved stromal response associated with metastasis. This signature included both genes known to play a role in cancer-associated fibroblasts, as well as proteins with no previously described roles in the tumor stroma. Many components of the signature are also representative of the previously described “mesenchymal” subgroup of ovarian cancer. In vitro and in vivo functional assays have confirmed essential roles for several of these proteins in regulating the cancer-associated fibroblast phenotype. This work establishes TOPK as a potential therapeutic target for ovarian cancer and emphasizes the importance of compartment resolved studies in understanding the individual roles of the tumor and stroma in ovarian cancer progression. Citation Format: Mark A. Eckert, Fabian Coscia, Shawn Pan, Chun-Yi Chiang, Stephanie McGregor, Ricardo Lastra, S. Diane Yamada, Matthias Mann, and Ernst Lengyel. ROLES OF T-LAK CELL-ORIGINATED KINASE (TOPK) AND THE MICROENVIRONMENT IN DRIVING OVARIAN CANCER PROGRESSION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-118.