Targeting AXL Receptor Tyrosine Kinase with a Humanized Anti-AXL Monoclonal Antibody as a Novel Therapy for Ovarian Cancer
Abstract
High-grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer and accounts for most of the ovarian cancer mortality. There is an urgent need to identify novel and effective targeted therapies for patients with HGSOC. Our preliminary studies found that ~80% of HGSOCs produce a protein called AXL on the outside of cancer cells. Higher levels of this protein are significantly associated with worse clinical outcomes, such as shorter. AXL protein is a receptor tyrosine kinase that plays a critical role in regulating many important cellular processes that are also used by cancer cells to proliferate, migrate to new areas, and invade into neighboring tissues. Overproduction of AXL by cancer cells can enhance these processes and promote tumor growth and metastasis. AXL s innate feature as a cell surface protein makes it an ideal target for antibody-based therapy, like other antibody-based therapies with existing FDA approvals. Our group has studied AXL protein for more than 8 years. Our previous studies on breast cancer discovered that AXL protein is overproduced in triple-negative breast cancer (TNBC). In order to specifically target AXL, we have developed a humanized anti-AXL monoclonal antibody (hMAb173) that can induce the rapid degradation of AXL and reduce cancer cell growth and tumor formation. Due to the tremendous translational potential of hMAb173, our research on TNBC received the Breakthrough Award from the Department of Defense Breast Cancer Research Program. The knowledge and therapeutic agents that developed in our study on breast cancer can be quickly applied to HGSOC and will greatly facilitate this proposed project. In this study, we will evaluate the potential of targeting AXL with hMAb173 as a novel therapeutic agent for HGSOC. Two forms of hMAb173 will be tested, the free antibody and the same antibody conjugated to a chemotherapeutic agent (also known as an antibody-drug conjugate). We will validate the therapeutic efficacy by treating preclinical ovarian cancer patient-derived xenograft (PDX) animal models with hMAb173. We will also use a novel immunocompetent transgenic animal model to investigate the therapeutic advantage of combining hMAb173 with FDA-approved immunotherapy antibody drugs. In addition, we will use cutting-edge proteomics and transcriptomics to dissect the molecular mechanism of AXL in promoting ovarian cancer initiation and progression. Our proposed studies, if successful, will help define targeting AXL with our novel humanized antibody as a promising therapeutic agent for HGSOC. New clinical trials based on hMAb173 could result from our proposal for evaluating its efficacy in patients with HGSOC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310752
Entities
People
- Xinyan Wu
Organizations
- Mayo Clinic
- United States Army