This proposal describes the development of a companion diagnostic agent for imaging of osteoactivin expression. The significance is to aid the patient selection for new drugs that target this receptor, in particular a new antibody-drug conjugate (ADC) that targets osteoactivin for treatment of triple negative breast cancer (TNBC). The goal is to develop a Positron Emission Tomography (PET) imaging agent that binds to osteoactivin to stratify TNBC tumors that will most likely respond to the treatment with the ADC, known as Glembatumumab-vedotin (CDX-011), and predict response to such therapy in tumor-bearing mice. My approach is to radiolabel the osteoactivin-specific naked antibody, Glembatumumab (CR011), with the positron-emitting radionuclide, 89Zr. I will optimize the chemistry to synthesize 89Zr-CR011 and use this agent to (i) assess the expression of osteoactivin in known cell lines and patient derived tumor xenografts, (ii) evaluate changes in osteoactivin expression in vivo throughout CDX-011 therapy and (iii) explore the induced upregulation of osteoactivin using chemotherapies currently used for the treatment of TNBC to enhance the potency of CDX-011. The outcome of this project will help in treatment planning for a disease previously considered to be non-targetable. My long-term goals are to become an independent investigator focusing on developing novel radiopharmaceuticals for non-invasive imaging of cancer biomarkers to help define optimal treatment strategies and to translate these new radiopharmaceuticals to clinical trials to identify patients who will likely benefit from targeed therapies. With the mentorship of Dr. Suzanne Lapi, an expert in PET imaging and development of novel radiopharmaceuticals, Dr. Cynthia Ma, an expert in the treatment of TNBC in preclinical and clinical studies, and Dr. Shunqiang Li, an expert in the development of patient-derived xenografts, I will expand my current proficiencies in biological chemistry and radiochemistry to include cancer biology, clinical oncology, and further advance my knowledge of imaging. At Washington University, I have all the resources to conduct the K99 phase of this award and my mentoring team has the combined expertise and mentoring experience to help me become an independent investigator.
Triple negative breast cancer is difficult to treat because of its aggressiveness and molecular heterogeneity. A promising antibody-drug conjugate, CDX-011, has prolonged the survival of patients with triple negative breast cancer by targeting osteoactivin, a cell-surface receptor unique to cancer cells. This proposal aims to develop a companion diagnostic agent that visualizes the expression of osteoactivin in the body to help optimize triple negative breast cancer treatment by identifying patients who may benefit from CDX-011.
|Marquez-Nostra, Bernadette V; Lee, Supum; Laforest, Richard et al. (2017) Preclinical PET imaging of glycoprotein non-metastatic melanoma B in triple negative breast cancer: feasibility of an antibody-based companion diagnostic agent. Oncotarget 8:104303-104314|