Targeting Ovarian Cancer Stem Cells Interactions with the Niche
Abstract
Career Goals: My primary focus is to build a solid and successful area of research in the field of ovarian cancer (OC) that will enable me to become an independent investigator. At the completion of this research project: (1) I will have a better understanding of the molecular mechanisms that enable OC stem cells to acquire resistance to traditional chemotherapy and (2) I will develop an effective antibody-based strategy that selectively targets the small population of cancer-driving cells. The results obtained during this project will lead to new publications and preliminary data for future federal grants. At the same time, the mentored environment at Northwestern University will provide advice, resources, and networking opportunities, representing a stepping-stone to support my transition toward independence. My research plan will be integrated by didactic courses, conferences, and meetings with my mentor, collaborators, and experienced investigators. Commitment to the Ovarian Cancer Academy: I am profoundly motivated toward exchanging knowledge and close collaboration among peers. In this direction, I will be honored to fully commit and participate in the Ovarian Cancer Academy. This will give me the opportunity to present the potential of my project to a network of top-notch investigators who are well established in the field, providing a contribution to unmet scientific needs in the fight against OC. Rationale for Proposed Research: OC recurrence and spread have been linked to a small population of cells called cancer stem cells, which are resistant to traditional chemotherapy. The accumulation of ascites provides a favorable environment that protect the quiescent cancer stem cells during chemotherapy and promote their growth. The focus of our research is to understand how tissue transglutaminase, an enzyme found to be active in ovarian tumors, protects stem cells and stimulates their growth. We found that this enzyme is enriched at the membrane of cancer stem cells, forming a complex with several receptors, such as integrins, that allow the stem cells to attach and grow in the peritoneal space. Additionally, we provided evidence that tissue transglutaminase binds to the cellular receptor, Frizzled 7, and that this interaction stimulates survival pathways in cancer stem cells. Here, I propose to use this discovery to design a new treatment for OC by generating an antibody that could disrupt the complex between tissue transglutaminase and Frizzled 7 and eliminate cancer residual after chemotherapy. To accomplish this proposal, I will elucidate three objectives: (1) biochemical definition of the interaction between tissue transglutaminase and Frizzled receptors leading to beta-catenin activation in OC; (2) define the mechanism by which tissue transglutaminase interaction with Frizzled7 regulates beta-catenin transcriptional activity in OC cells and tumors promoting stemness; and (3) develop novel strategies to target the tissue transglutaminase complex with Frizzled7 blocking beta-catenin activity in OC. Applicability of the Research: The development of novel strategies targeting cancer stem cells is highly relevant, as these cells are responsible for tumor recurrence after chemotherapy and the fatality of OC. The project has the potential of bringing a new therapy and a new target to the forefront for patients diagnosed with early and advanced disease and have a combination of surgery and chemotherapy. Contributions to Advancing the Knowledge of Ovarian Cancer: This innovative study will address a new conceptual discovery with potential future therapeutic applications aimed to interfere with the establishment of a supportive environment for the chemo-resistant cancer stem cells. The newly discovered complex is proposed as a novel regulator of OC stem cells and as a new target to block tumor relapse after chemotherapy. Impact on Military Service Members: OC is the deadliest gynecological
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910008
Entities
People
- Salvatore Condello
Organizations
- Indiana University
- United States Army