AXL-TARGETING ANTIBODY-DRUG CONJUGATE AS NOVEL THERAPY FOR TRIPLE-NEGATIVE BREAST CANCER

Project: Research project

Project Details

Description

Background: Triple-negative breast cancers (TNBC) represent 10%-15% of all breast cancers. Patients with TNBC are treated with systemic chemotherapy with mostly short-term benefits and associated adverse effects. There is currently no targeted therapy for TNBC. Aberrant activation of oncogenic tyrosine kinase receptors in cancer initiates a phosphorylation cascade in cells to deliver signals that ultimately translate into cell proliferation, suppression of apoptosis, invasion, and metastasis. Therefore, selective inhibition of tyrosine kinases has emerged as a novel paradigm for targeted cancer therapeutics. Our recent studies identified that AXL, a receptor protein tyrosine kinase (RTK), is selectively overexpressed and activated in highly aggressive TNBC cells. Based on this discovery, in this study we propose to create a novel humanized anti-AXL monoclonal antibody drug conjugate (ADC) as a novel therapy to treat TNBCs with AXL overexpression.Overarching Challenge: The success of the proposed study will address the overarching challenges of (i) revolutionizing treatment regimens by replacing them with ones that are more effective and less toxic and (ii) eliminating the mortality associated with metastatic breast cancer, particularly for TNBC.Objective: The objective of this proposal is to establish AXL as a novel therapeutic target for patients with TNBC. To achieve this, we will develop a novel personalized therapy with a therapeutic agent, a humanized anti-AXL antibody drug conjugate to specifically and effectively target TNBC with AXL overexpression.Specific Aims:Aim 1: To develop a humanized anti-AXL antibody-drug conjugate that targets AXL receptor tyrosine kinase on the surface of TNBC cells.Aim 2: To test the efficacy of the AXL-targeted anti-AXL antibody drug conjugate in preclinical animal models.Aim 3: To develop companion diagnostic assays for AXL expression and activation status in clinical samples to allow patient selection for therapy. Study Design: We will first synthesize the antibody drug conjugate by conjugating hMAb173 with mertansine, a highly potent microtubule inhibitor. The antibody drug conjugate will specifically target AXL overexpressing cells, internalize, and kill the targeted cells. We will also develop a PET (positron emission tomography) imaging method to non-invasively and sensitively monitor the antibody drug conjugate delivery and distribution in vivo. We will evaluate the therapeutic potential of this novel antibody drug conjugate in preclinical primograft models that are directly derived from human triple-negative breast tumors. We will also develop a highly sensitive and accurate mass spectrometry-based method to examine the AXL expression and activation for patients with TNBC.Impact: This study will (a) develop a humanized ADC as promising novel therapeutic agent precisely targeting TNBCs with high expression of AXL and (b) establish a mass spectrometry-based companion diagnostic method to examine AXL expression and activation status allowing TNBC patient enrichment for this targeted therapy. The large amount of clinical sample collections in Mayo Clinic including the breast cancer tissue bank with >30 thousand tissue specimens and >50 patient-derived xenograft models provides an excellent resource to facilitate the proposed studies. A successful completion of the studies outlined in this proposal will lay a strong foundation to translate our preclinical discoveries into a clinical investigation for women with AXL-positive TNBCs and to deliver safe and effective therapy and improve survival. Thus, our project is based on a humanized monoclonal antibody specifically targeting AXL, which is configured to provide a rapid path leading from target discovery to rational selection of patients for personalized therapy. Our studies can also impact breast cancer research more broadly by developing a new paradigm for identifying subsets of TNBC patients based on phosphoproteomic profiling to identify additional novel therapeutic targets followed by functional validation in vitro and in preclinical PDX mouse models.

StatusActive
Effective start/end date9/1/198/31/22

Funding

  • Congressionally Directed Medical Research Programs: $786,814.00

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