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2014 Mesothelioma Research Grant Awards

Principal Investigator: Ravi Salgia, MD, PhD
Institution: University of Chicago
Title of Project: EPHA2 as A Novel Therapeutic Target in Malignant Pleural Mesothelioma
Description: EPHA2 protein is a receptor of the ephrin-A1 ligand, and its over-expression has been reported in many cancers where it is linked to growth and the metastatic potential of tumors. The EPH receptor family represents the largest group of receptor tyrosine kinases (TK) and is important in embryonic development, cell migration, vascular development and tissue border formation. Preliminary data from this laboratory has shown that over-expression of EPHA2 occurs in MPM cell lines and patient tumors with mutations in the ligand binding domain and TK domain and amplification in some cases. MPM cell lines with EPHA2 mutations grow faster and are more resistant to cisplatin. Based upon these findings and using a battery of MPM lines and tissue arrays, this project will determine the expression, amplification and mutation status of EPHA2 and attempt to correlate these data with clinical parameters such as age, gender, histologic subtype, ethnicity, asbestos exposure, and survival. These approaches will yield useful prognostic information in MPM. In addition, studies will elucidate the biological and biochemical functions of wild- type and mutated EPHA2 (viability, migration, signaling pathways using PamGene kinase profiling, etc.),and explore the effects of inhibition of EPHA2 in MPM lines. In addition, the response of these lines to cytotoxic chemotherapies (doxazosin, cisplatin) and nanoparticles loaded with these agents and EPHA2 siRNA will be explored.

The studies proposed may impact the therapy and overall survival for patients with MPM and have the potential to enable several clinical advantages. A clinical database will be developed that will be available to other researchers. Finally, the ultimate goal of this research is to extend these pre-clinical studies to fruition by implementing clinical trials exploiting EPHA2 inhibition. This goal will be facilitated by the expertise of Dr. Salgia in developing a large bioinformatics database for thoracic oncology and his previous design and implementation of clinical trials.

Principal Investigator: Tanguy Seiwert, MD
Institution: University of Chicago
Title of Project: The T-cell inflamed immune microenvironment in Malignant Mesothelioma
Description: Mesotheliomas are frequently infiltrated with immune cells and immune responses to proteins specifically expressed on mesotheliomas have been described in patients. The inability of the immune response to rid the body of cancer suggests the presence of complex mechanisms by which the tumor escapes this immune response.

Dr. Tanguy Seiwert and colleagues at the University of Chicago propose to study in greater detail the strong immune response observed in many malignant mesotheliomas with the ultimate goal of harnessing and modulating this response in a favorable way i.e. to fight the cancer. The investigators have previously shown that approximately a third of mesotheliomas have a T cell inflamed phenotype indicative of a strong immune response.

Their planned approach involves 1. characterization of immune markers in the tumor microenvironement of old tumor samples by immunohistochemistry and fresh tumor samples by flow cytometry and 2. Sequencing of T cell receptors and tumors to identify the specificity of immune responses. Further the proposed study will enroll patients in a clinical trial of pembrolizumab, (anti-PD1 antibody) an antibody which targets one of the mechanisms employed by the tumor to escape the immune response. Functional studies of immune cells derived from patients before and after treatment with pembrolizumab will also be carried out. A major strength of the study is the strong translational component with assessment of a number of immune parameters on samples from patients enrolled in the clinical trial.

The proposed study if successful will change the landscape of mesothelioma treatment. Drugs targeting the immune checkpoints have altered the care of patients with a number of other cancers including melanoma and non-small cell lung cancer. Among the challenges that lay ahead include identifying patients who are likely to benefit from this treatment.

Principal Investigator: Travis Young, PhD
Ken Bendix Memorial Grant
Institution: California Institute for Biomedical Research
Title of Project: Controllable CAR-T Therapy for Mesothelioma
Description: Dr. Travis Young, a postdoctoral fellow at the California Institute for Biomedical Research, submitted a proposal entitled “Controllable CAR-T Therapy for Mesothelioma”. He has significant experience and expertise in protein chemistry and immunology. His work aims to engineer a patient’s own immune cells so that they target mesothelioma cells for attack by the immune system. The specific aims of his project are to demonstrate the redirection of controllable CAR-Ts to FAP and mesothelin-positive cancer cell lines, understand the optimal targeting paradigm for mesothelin and FAP controllable CAR-T cells, and demonstrate the efficacy and understand the optimal dosing paradigm in mouse xenograft models. One highly novel element of Dr. Young’s approach is the inclusion of a tightly regulated antibody-based “switch”. This allows great control of CAR-T cell activity so that safety and efficacy can be well balanced, a previous barrier in developing highly effective CAR-T cell therapy.

Currently, among many ongoing clinical trials, some exciting durable and complete responses to this type of therapy have been achieved in other diseases. By targeting FAP and mesothelin, which are common tumor associated antigens in mesothelioma, there is great potential to develop these CAR-T cells into a new therapy for mesothelioma. If these experiments are successful, potential clinical trials could be designed to test these agents in patients with mesothelioma.

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