Image-Guided Bidirectional EphB4 Agonist-Based Therapy for Ovarian Cancer
Abstract
Ovarian cancer affects more than 22,000 women in the United States each year. Despite progress in surgery and chemotherapy, the disease still proves lethal to most patients. Most ovarian cancers have a positive response to initial chemotherapy, but over 70% of ovarian cancer patients ultimately develop metastasis, which inevitably becomes resistant to the existing chemotherapy drugs. These patients then succumb to the disease. Evaluation of multiple chemotherapeutic agents in several combinations and schedules has not yielded a significant overall improvement in outcome over the last 20 years. Clearly, new, effective therapies are urgently needed. High-grade serous ovarian cancer (HGSC), the most aggressive subtype of ovarian cancer, accounts for two- thirds of all ovarian cancer deaths. In most cases of HGSC, the level of the protein EphB4 is high. EphB4 in ovarian cancer cells interacts with another protein, EFNB2. The interaction between EphB4 and EFNB2 has both a positive impact and a negative impact in terms of tumor control. The positive impact is that interaction between the two proteins can suppress the proliferation and metastasis of ovarian cancer cells. The negative impact is that interaction between the two proteins can stimulate angiogenesis (formation and growth of new blood vessels), which supports tumor growth. EphB4-based therapy has raised more attention clinically and has been tested as monotherapy or in combination with immunocheckpoints such as pembrolizumab in several solid cancers, including small cell lung cancer and advanced bladder cancer in phase II trials. Recently, in a series of experiments designed to identify potential new drugs, we discovered a small molecule, which we called BIDEN-AP, that simultaneously promotes the positive impact and suppresses the negative impact of interaction between EphB4 and EFNB2. In mouse models of human cancer, BIDEN-AP suppressed tumor growth and metastasis. Furthermore, in mouse models of human cancer, BIDEN-AP also inhibited a process called epithelial-mesenchymal transition (EMT), which contributes to metastasis. In this proposal, we hypothesize that BIDEN-AP-based agents inhibit EMT and angiogenesis, suppress tumor growth, and overcome acquired resistance to anti-angiogenic therapies in HGSC. We further hypothesize that molecules based on BIDEN-AP can be used in combination with noninvasive medical imaging techniques to determine EphB4 expression status in HGSC tumors and tumor-associated blood vessel cells. The ability to determine EphB4 expression status in this way would help physicians select patients most likely to benefit from BIDEN-AP-based agents and monitor the response to treatment with such agents. On this ground, the proposed work is a direct response to address two of the FY22 W81XWH-22-OCRP-IIRA Areas of Encouragement: (a) Develop novel therapeutic strategies for treatment and (b) prevention and Improve precision medicine. To test this hypothesis, we will pursue three specific aims: (1) determine the effects of BIDEN-AP-based agents on inhibiting EMT and angiogenesis; (2) investigate the mechanisms of action for BIDEN-AP-based agents suppressing tumor growth and overcoming acquired resistance to anti-angiogenic therapy; and (3) determine the pharmacokinetics and pharmacodynamics of BIDEN-AP-based agents using positron emission tomography/computed tomography. We expect the proposed work to show that BIDEN-AP has strong potential to improve the clinical outcomes of patients with ovarian cancer that is not responding to current therapies and to show that noninvasive medical imaging is a useful tool for both determining EphB4 expression level prior to therapy and re-assessing EphB4 expression status after treatment. Such a tool will greatly facilitate selection of patients for personalized therapy and monitoring of response to molecularly targeted therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310501
Entities
People
- Chun Li
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army