Targeting the IGFBP2-Src Signaling Axis to Block Metastatic Spread and Tumor-Mesothelial Crosstalk
Abstract
Hypothesis and Rationale for the Proposed Project: Ovarian cancer is the second most lethal gynecologic malignancy in the USA. The majority of ovarian cancer patients (70%) present with metastatic disease and have a poor 5-year survival (29%). Metastatic ovarian cancer spreads to multiple organs in the peritoneal cavity. Treatment includes a combination of chemotherapy and surgery. The surgical debulking status is one of the most important prognostic indicators, with the extent of irresectable disease inversely correlated with patient outcomes. These irresectable tumor implants are formed by attachment and growth on mesothelial cells that line organ surfaces, leading in many cases to invasion into the host tissue. Therefore, it is critical to identify new therapeutic targets to block metastatic progression and biomarkers to personalize therapies. Our short-term goals are: (1) to understand the biology behind cancer-mesothelial interactions that promote metastatic progression in chemotherapy-resistant tumors and (2) to assess the therapeutic potential of targeting cancer-mesothelial signaling in combination with chemotherapy to halt metastatic outgrowth. We recently discovered that human patient-derived xenograft models of ovarian cancer with high expression of insulin growth factor binding protein 2 (IGFBP2) exhibit greater metastatic potential and reprogram mesothelial cells towards a pro-metastatic state. In this proposal, we will determine how IGFBP2 secreted by chemotherapy-resistant cancer cells promotes metastatic dissemination. We will also evaluate the therapeutic potential of combination chemotherapies targeting IGFBP2-induced signaling in mesothelial cells to eliminate metastatic tumor growth in patient samples and animal models. Applicability of Research: These research studies could ultimately benefit ovarian cancer patients who present with chemotherapy resistance and have high expression of the IGFPB2 protein (43% patients). Given that Src inhibitors are FDA-approved and a subset of ovarian cancer patients exhibit improved survival, the findings obtained from this proposal have the capacity to inform development of biomarkers and the design of new personalized treatment strategies. Specifically, these inhibitors will be tested using a panel of patient samples to discover predictive biomarkers of therapy benefit. If preclinical success of predicting efficacy in individual patient samples is shown, it will be possible to implement our microfluidic model as a companion screening tool in clinical trials led by our collaborator at the University of Pittsburgh (Dr. Buckanovich). Importantly, the bioengineered model that we will employ in our studies has three unique features: (1) testing of a large number of treatment combinations, (2) spatial control of tumor:mesothelial cellular neighborhoods to provide novel insights into cell-cell signaling, and (3) real-time monitoring of cell growth and therapy response. Hence, the unique features of this bioengineered technology model provide multiple opportunities to screen and design rational combination therapies with distinct effects on different cells in the ovarian tumor microenvironment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310207
Entities
People
- Ioannis K Zervantonakis
Organizations
- United States Army