Stable & Picomolar-Affinity Peptides Targeting Ephb4 to Prevent Metastasis in Triple-Negative Breast Cancer

Texas Southern University, Houston TX

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Abstract

ABSTRACT: Project 1 Stable & Picomolar-Affinity Peptides Targeting EphB4 to Prevent Metastasis in Triple-Negative Breast Cancer Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. It is associated with fatal metastatic spread. The 5-year survival rate of TNBC patients is only 10-15% once the disease spreads to distant organs. TNBC occurs more frequently and has worse survival outcomes in African American (AA) women. Currently, there are no targeted therapeutics to effectively prevent metastasis in TNBC. Chemotherapy, with its associated severe toxicity, remains the primary treatment option. EphB4 is a member of the largest family of receptor tyrosine kinases that are overexpressed in several cancers associated with health variations including TNBC, colorectal cancer, and ovarian cancer. Trans-interaction between EphB4 and its membrane-bound ligand ephrin B2 (EFNB2) mediates bi-directional signaling: 1) forward EFNB2→EphB4 signaling suppresses proliferative and metastatic properties of tumor cells; 2) reverse EphB4→EFNB2 signaling stimulates angiogenic properties of tumor endothelium thereby promoting metastasis. Previously, Li’s team at MD Anderson Cancer Center (MDACC) discovered a bi-directional Ephrin agonist peptide, B4-007, that simultaneously 1) activates forward EFNB2→EphB4 signaling in breast cancer cells and ovarian cancer cells, and 2) inhibits reverse EphB4→EFNB2 signaling in tumor-associated endothelial cells. Preliminary studies from Liang’s team at Texas Southern University (TSU) have identified unique sites in the B4-007 peptides susceptible to protease degradation in mouse plasma. Based on these data and computational modeling, we have designed and validated 2nd-generation EphB4-targeted peptides and peptoids (G2-ETP) with two-fold increased binding affinity compared to the parent B4-007 (KD~3 nM) and improved stability in mouse and human plasma. Our aims are 1) to synthesize, characterize, and identify G2-ETP with picomolar binding affinity (KD~100 pM) to EphB4; 2) to investigate pharmacokinetics (PK), metabolic clearance, tissue distribution, and non-GLP acute toxicity; and 3) to evaluate antitumor and anti-metastatic efficacy, pharmacodynamic (PD), and PK/PD correlations. To achieve these aims, we will employ range of biomedical techniques, along with healthy mouse models, cancer cell xenograft models, and genetically engineered mouse models to conduct a comprehensive novel peptide drug discovery and development project. This project will engage with the CBMHR Administrative Core for support and oversight, leverage the Research Capacity Core to conduct various experiments, and disseminate the research findings through the Community Engagement Core to reach different communities. Successful execution of this research will further elevate TSU’s prestige in the biomedical research fields, as well as contribute to the advancement of treatment and prevention of metastasis in TNBC patients.