2007 Mesothelioma Research Grant Awards

Mitchell Ho, PhD - Craig Kozicki Memorial Grant
National Cancer Institute, NIH

Title: Targeting Mesothelin by Human Antibodies for Mesothelioma Treatment

Description: Mesothelin and CA125 are highly expressed in most malignant mesotheliomas. Their interaction plays an important role in peritoneal tumorigenesis. We aim to generate a panel of human monoclonal antibodies that will effectively neutralize human and mouse mesothelins, blocking the mesothelin-CA125 interaction in vitro and inhibiting tumor growth in a peritoneal mesothelioma mouse model.

Robert Kratzke, MD - Christopher Stoeckler Memorial Grant

University of Minnesota

Title: Targeting Cap-Mediated Translation for Mesothelioma Therapy

Description: The cellular processes that regulate the synthesis of proteins are disrupted in mesothelioma resulting in the unregulated production of cancer related proteins. The restoration of this process to its normal state results in the inhibition of mesothelioma. We are developing a new class of chemotherapy drugs that restore regulation of protein synthesis and reverse mesothelioma. This study will test the capability of this new class of treatments to halt mesothelioma and increase chemotherapeutic sensitivity.

Ravi Salgia, MD, PhD - Jeffrey P. Hayes Memorial Grant

University of Chicago

Title: Protein Kinase C as a Novel Therapeutic Target in Mesothelioma

Description: Malignant mesothelioma is a cancer of the pleura, which has a poor prognosis and few therapeutic options. Our research focuses on identifying drugs that may significantly improve quality of life as well as patient survival. Protein kinase C is a molecule known to cause cells to be more invasive and to divide faster, and we have shown that this molecule is present in human mesothelioma. We propose to target this molecule in mesothelioma cells with a promising new drug, enzastaurin, which specifically acts upon it. Our plan is to test the biology and response of tumor cells to drugs in isolation and in a microscopic worm model (C. Elegans). C. elegans is a novel model system which is able to produce answers to our scientific questions in a much shorter time span and at lower cost. Our aim is to translate our findings into useful new insights for the treatment of this devastating disease.

Ramasamy Jagadeeswaran, MD

University of Chicago

Title: Paxillin is a Potential Molecular Therapeutic Target in Malignant Pleural Mesothelioma (MPM)

Description:  Targeting paxillin is likely to be more effective than targeting a single receptor tyrosine kinase. Importantly, we believe paxillin will ultimately become a potential therapeutic target and the studies proposed in this award will give us a novel target against this devastating illness. The proposed work will certainly define the role of paxillin mutations and amplification in mesothelioma and aid in the development of novel therapeutics, and thus highly innovative.

David I. Goldman, MD
Albert Einstein Collge of Medicine of Yeshiva University

Title: The Role of the Proton-Coupled Folate Transporter (PCFT) as a Determinant of the Activity of Pemetrexed in Mesothelioma

Description:  This proposal is based upon the recent discovery in this laboratory of a novel transport system (PCFT), present in most human cancers, that drives pemetrexed into tumor cells. The aims of this proposal are to assess the extent to which PCFT and other transporters are present in human mesothelioma specimens and to determine the impact of PCFT relative to other transporters on the antitumor activity of pemetrexed when PCFT is generically engineered into mesothelioma cell lines.

Alain Borczuk
, MD
Columbia University Medical Center

Title: Poor Prognosis Gene Expression Signatures Suggest Molecular Pathways of Mesothelioma Progression and Potential Therapeutic Targets.

Description: Abdominal malignant mesothelioma (AMM) is a subtype of mesothelioma that involves intra-abdominal surfaces. Several factors are associated with increased chance of therapeutic success and prolonged survival. Using gene expression profiling, our prior work identified factors in AMM that were predictive of poor prognosis that have been confirmed by other groups in the more common pleural mesothelioma. We have subsequently determined a 31-gene signature that segregates AMM into favorable prognosis and poor prognosis subgroups. The proposal seeks to validate this signature on an independent test group of AMM and pleural mesothelioma and to further study pathways of aggressive AMM. The function of one of the genes (called EZH2) found to be increased in the poor prognosis AMM suggests a therapeutic strategy in patients with aggressive AMM.

Sergey Ivanov, PhD
NYU School of Medicine

Title: ROMA for the Identification of Genes Associated with Early Stages and Progression of Asbestos-Induced Pleural Malignant Mesothelioma

Description: We studied the genetic history of asbestos-induced mesothelioma using a novel technology (ROMA) and computational approaches. The critical chromosomal regions and hundreds of genes contained within were identified as a result. We are planning now to separate mesothelioma-associated genes from “by-standers” through global analysis of gene activity (expression array study). The genes selected by both methods will then be thoroughly tested in functional assays to identify therapeutically important targets.

Adi Gazdar, MBBS
University of Texas Southwestern Medical Center

Title: Establishment of Immortalized Mesothelial Cell Lines: A Unique Resource for the Study of Mesothelioma

Description: Mesothelioma research has been hampered by the lack of suitable laboratory systems to study the development of mesothelioma. Normal mesothelial cells survive for relatively short periods of time and are not suitable for studying the lengthy tumor process which takes several years. We have developed a simple method to immortalize normal mesothelial cells while retaining their basic genomic properties. We will initiate several such cultures and distribute them freely to the scientific community. These reagents will be unique and invaluable for the study of mesothelioma development

Marc de Perrot, MD
University of Toronto

Title: Development of a Novel Therapeutic Strategy with Pemetrexed and Regulatory T cell Depletion for Malignant Pleural Mesothelioma: A Translational Research Project

Description: Immunotherapy is a promising option for the treatment of mesothelioma. Our preliminary data in a mice model of intrapleural mesothelioma suggests that the combination of chemotherapy and immunotherapy with depletion of regulatory T cells can have a synergistic impact on outcome. These results may offer new therapeutic avenues in the treatment of this devastating tumor.

Carmen J. Marsit, PhD
Brown University

Title: Array-Based miRNA Expression and Methylation Profiling of Normal and Tumorigenic Pleural Mesothelium

 Description: This research hopes to discover novel, specific, diagnostic and prognostic biomarkers of disease and will greatly enhance an ongoing study. In addition, this project aims to describe new markers of disease that may translate to novel treatments, more personalized medicine, and improved patient outcomes.

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