2011 Mesothelioma Research Grant Awards

Tao Dao, MD, PhD
Memorial Sloan Kettering Cancer Center
TCR-like mAb specific for WT1 peptide/MHC complexes on mesothelioma

WT1 has become an attractive target in mesothelioma. Antibody therapy is a way to target proteins but WT1 is not expressed on the outside of the cell thus making the use of monoclonal antibodies an effective way in which to target WT1. To target WT1 using an immunological approach this proposal will use peptides that are presented by HLA-A2 molecules (human leukocyte antigen A-2 which are antigens that help the immune system detect foreign invaders) as a carrier to target and kill mesothelioma cells.

This proposal is to test the therapeutic activity of the mAb in animal models of human mesothelioma with a goal of translating it into human trials. If successful, this approach promises to be a new therapy for mesothelioma and would also open a door for a wide range of cancers that highly express WT1 or other intracellular oncoproteins.

 

Assunta DeRienzo
Brigham and Women's Hospital
Identification of Novel Mutations in Malignant Pleural Mesothelioma using Deep Whole-Genome Sequencing

This project aims to explore the whole-genome data of ten MPM tumors and matched normal for the identification of both therapeutic targets in individual genes, specific pathways and predictive biomarkers. Novel molecular mechanisms will be revealed.

This proposal will attempt to combine all genomic data to obtain insight to the molecular mechanism of MPM, by identifying recurrent mutated genes, associating them to defective pathways, and defining different subgroups of MPM patients. (defining the association of defective genes, and how they impact the properties of cells which become malignant and correlate the finding with the clinical course of the 10 patients whose tumors are being studied). 

 

Marc Ladanyi - Ron Simkins Memorial Grant
Memorial Sloan-Kettering Cancer Center
Frequent inactivation of BAP1 in mesothelioma: biology and new therapeutic opportunities

Dr. Ladanyi and his group analyzed the genome of 53 malignant mesothelioma tumors and have reported that BAP1 inactivation or loss occurs in approximately 42% of mesotheliomas. The role of BAP1 in malignant mesothelioma has yet to be clarified and may prove to be of interest in both the pathogenesis of mesothelioma, cell proliferation or even cell death. The proposal will look at three sets of experiments to characterize how the loss of BAP1 may cause mesothelioma to become more vulnerable to either existing or novel targeted therapy approaches.

 

Liang-Chuan S Wang
Perelman School of Medicine at the University of Pennsylvania
The Role of the IFN response in Chemosensitivity of Mesothelioma to Pemetrexed

This project will investigate how the IFN (interferon gama an important protein in our immune system) pathway is involved in regulating the response of mesothelioma cells to chemotherapy-induced cell death. A better understanding of this protective mechanism can further assist in determining optimal treatment strategies and potentially augmenting effects of chemotherapy. Despite numerous new chemotherapeutic agents being developed over the last two decades, the median survival after receiving these drugs remains around 12-15 months. Recently, our group has found a protective mechanism used by mesothelioma cells to resist chemotherapy. If we understand and harness this properly, it may be possible to optimize the current treatment strategy to improve clinical outcomes.

 

Nadia Zaffaroni
Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
Identification and validation of miRNAs as novel biomarkers and therapeutic targets in diffuse malignant peritoneal mesothelioma

miRNAs, until recently, were thought to be useful as messengers between cells but we now realize that they play a unique role in manipulating gene function.

The main aims of the project are: i) the identification of dysregulated miRNAs in Diffuse Malignant peritoneal mesothelioma (DMPM) to discover specific miRNAs acting as key players in disease incidence and progression. In addition, through the prediction and validation of the targets of such miRNAs, we propose to shed light on the biological mechanisms and regulatory events through which they lead to mesothelial carcinogenesis (changing cells from benign to malignant); ii) the identification of up-regulated miRNAs in blood of DMPM patients, which could represent new biomarkers for monitoring DMPM patients following treatment and, possibly, anticipating the clinical diagnosis of recurrence (similar to prostate where we follow PSA); iii) the identification of miRNAs significantly associated to patient prognosis, which could be used in combination with conventional clinico-pathological variables for the selection of patients who will benefit from this specific treatment (helping to understand who best benefits from a particular therapy) iv) the functional validation of specific miRNAs as possible novel therapeutic targets or tools in DMPM, through the analysis of the consequences of modulation of their expression on the phenotype of human DMPM experimental models in vitro and in vivo (both cell and animal models).


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