A Theranostic Antibody-Cytokine Reagent for Diagnosis and Multipronged Therapy of Malignant Mesothelioma
Abstract
This project is directed towards the Peer Reviewed Cancer Research Program Topic Areas of Immunotherapy and Mesothelioma. We propose a novel diagnostic and therapeutic approach that has Military Relevance Focus by addressing current gaps in the efficient prognosis and treatment of malignant mesotheliomas (MM), which are disproportionately common in Military Veterans and a significant cancer risk for active duty Service members. Our main objective is to develop a novel reagent that will be able to accumulate in the tumor, enhance tumor detection, block a specific target in the tumor cells, and potentiate anti-tumor immune response. Our reagent will be an engineered protein ("immunocytokine") that will recognize a molecule named fibulin-3, which is produced by the cancer cells to promote tumor growth. Our reagent will block fibulin-3 in the tumor and at the same time will attract immune cells to attack the tumor cells. First, we will determine if our reagent can detect and block fibulin-3 in patient samples and tumor cells, which can be used to identify patients for our targeted therapy. Next, we will confirm that our reagent is specific and effective to kill mesothelioma tumors in animal models. Finally, we will modify our reagent so that it can be detected in magnetic resonance imaging (MRI) scans and will test if this approach enhances the visibility of small tumors by MRI and can be used to predict the response of MM to our therapy. Successful completion of this project will result in new "theranostic" reagents that combine therapeutic and diagnostic properties in the same molecule. Those reagents will be used to enhance early detection of mesothelioma, select patients with a specific molecular target, predict the possible response of those patients to therapy, and finally treat them with an effective, targeted therapy that will have less toxicity than conventional chemotherapy. Although our project is a basic science investigation, we expect that it will demonstrate the feasibility of using a theranostic reagent for mesothelioma, allowing us to pursue further clinical development. Tumor-targeting engineered proteins (such as antibodies and immunocytokines) are among the most promising agents for cancer therapy and a very appealing option for pharmaceutical companies seeking novel strategies against cancers. Therefore, validation of our anti-fibulin-3 reagent may attract industry support that will allow us to develop this reagent as an Investigational New Drug for mesothelioma. With appropriate support, we expect to complete preclinical testing and pursue a preliminary Food and Drug Administration application within 2 to 3 years following the successful completion of this project. We expect that our project will advance both basic and preclinical research for mesothelioma. At the basic science level, we will develop novel theranostic reagents and will further understand their properties, mechanism of action, specificity, and efficacy against MM cells. At the preclinical level, we will be able to demonstrate the feasibility of combining diagnostic and therapeutic features in the same reagent. We will also determine if this approach improves the analysis of tumor markers in vitro, detection of the tumor, tumor targeting, anti-tumor immunity, or any combination of these effects. Validation of our reagents at the basic and preclinical levels will allow us to formulate a rational approach to better identify MM patients that can be selected for targeted therapies and that will have the highest chance to benefit from those therapies, achieving long-term survival. Our research is relevant to both military Veterans and active duty Service members. Veterans have disproportionately high incidence of mesothelioma because they have been chronically overexposed to asbestos and other mineral pollutants during their time in Service, whereas active Service members continue to be at high risk for the same type of e
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810183
Entities
People
- Mariano S Viapiano
Organizations
- State University of New York Upstate Medical University
- United States Army