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2012 Mesothelioma Research Grant Awards

Hegmans, Joost - Larry Davis Memorial Grant
Erasmus MC
Macrophage recruitment/polarization as a prognostic and therapeutic target

Tumor-associated macrophages are a potential target in malignant mesothelioma (MM). These potent immune cells are present in variable amounts in MM tissue (up to 60% of tumor mass) and are associated with tumor progression and bad prognosis in other cancer types. We plan to investigate if macrophages can serve as a prognostic factor in mesothelioma and if targeting or modulating of these cells could improve current treatments.


Cheung, Mitchell - The Anderson Family Grant
The Research Institute of Fox Chase Cancer Center
BAP1 Mesothelioma Mouse Models and Personalized Therapeutics

We recently reported two families with hereditary mutations in the BAP1 tumor suppressor gene that are predisposed to the development of malignant mesothelioma (MM) and other cancers (Nature Genetics 43:1022-5, 2011). While both families showed a high incidence of MM, other tumors seen in the two families differed. For example, eye melanomas were seen in one family but not in the other, possibly related to the different location of the BAP1 mutation seen in each family. We have generated two novel mouse models that mimic the BAP1 mutations seen in these two families. We will determine if the mutant mice develop spontaneous tumors, including MM, and if the two mouse models develop a different overall spectrum of tumor types. We will also determine if mutant mice develop MMs more quickly and more aggressively than genetically normal mice following exposure to asbestos. Besides inherited alterations in BAP1, acquired (“somatic”) BAP1 mutations contribute to tumor formation in a sizable proportion (20-60%) of MM patients. Thus, we propose additional experiments to take advantage of mutant BAP1 by finding ways to selectively kill cells having this genetic change. This information would potentially provide rationale for “personalizing” the therapy of a given MM patient based on BAP1 mutation status of their tumor. Germane to this, we will test if a specific class or combination of anti-tumor drugs kills BAP1 mutant MM cells more readily than in those lacking this alteration.

Barbone, Dario - Belluck & Fox Grant
The Regents of the University of California, San Francisco
Role of ANXA4, ASS1 & MVP Genes in Mesothelioma 3D Multicellular Resistance

Cancers fail to respond to clinical treatments such as chemotherapy because they possess a high resistance to apoptotic cell death. Discovering how cancers resist cell death could lead directly to steps that could bypass these survival defenses and help treatments to be more effective. When cells are studied in the laboratory, they are usually studied in flat 2D monolayers, where many mechanisms of resistance can be studied. However, solid tumors, such as malignant mesothelioma, grow as 3D masses. When tumor cells grow into 3D structures, they can acquire an additional level of resistance, described as multi-cellular resistance. We believe that the study of the resistance acquired by cells in 3D may be valuable in improving clinical treatments. Indeed, acquisition by tumor cells of multi-cellular resistance may explain many instances in which treatments that are found to be effective in laboratories fail to work in the clinic. In this study, we will investigate how three genes, ANXA4, ASS1 and MVP, which we have correlated to multicellular resistance, underlie this clinically-relevant chemoresistance. We have found two candidate drugs that can reduce their expression levels and restore chemosensitivity of spheroids and we aim to validate them as adjunct to chemotherapy. These studies will not only clarify the role of these genes in mesothelioma and provide therapeutic insights but also advance the use of spheroids as a more realistic model for studying tumor biology.

Giancotti, Filippo - The Law Offices of Peter G. Angelos Grant
Memorial Sloan-Kettering Cancer Center
Preclinical Efficacy of a TOR/PI-3K inhibitor in Malignant Mesothelioma

Inactivation of the tumor suppressor Merlin/NF2 occurs in a large fraction of malignant mesothelioma (MM). We have shown that loss of Merlin leads to hyperactivation of TOR signaling in MM line. Our Preliminary Studies suggest the dual PI-3K/TOR kinase inhibitor GDC-0980 produces a strong inhibition of proliferation in MM cells carrying NF2 mutations. We propose to test the efficacy of GDC-0980 in MM lines carrying or not NF2 mutations. If successful, these experiments will provide a strong rationale for the development of large, biomarker-driven clinical trials of GDC-0980.

Kim, Il-Jin - The Bankhead Family Fund of the Kazan, McClain, Abrams, Fernandez, Lyons, Greenwood, Oberman, Satterley & Bosl Foundation Grant
The Regents of the University of California, San Francisco
Fusion genes as therapeutic targets in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a very aggressive and one of the worst human cancers. A median survival still remains at around 15% in MPM patients and no personalized targeted therapy is currently available. Several chromosomal alterations and deletions have been identified in MPM, such as deletion/inactivation of CDKN2A, NF2, and BAP1. Most of these mutations and deletions are inactivating events. Thus, it is important to identify oncogenic drivers causing MPM to develop therapeutic molecular targets. We have done copy number analysis of three of the most commonly deleted genes (CDKN2A, NF2, and BAP1) in around 60 MPM samples and have identified triple-negative (TN) MPM patients having no deletion in any of the three genes. In our preliminary studies, these TN MPM patients showed different genetic expression and deletion patterns than other samples with deletions. Novel fusion and tumor-specific isoform candidates were identified in TN MPM patients using genome wide microarray analysis. Thus, we hypothesize that these TN MPM patients have different genetic characteristics and novel oncogenic fusions may contribute to MPM development. We have two aims in this project. First, we will perform a transcriptome (RNA)-seq to identify our novel fusion and isoform candidates in TN MPM. Second, the identified fusions and tumor-specific isoform will be validated with RT-PCR and 5’-RACE methods. The success of this project may lead to the development of novel therapeutic target.

CRAB/IASLC proposal - Judith L. Lagana Memorial Grant
Proposal for a Pilot Study on the Use of Tumor Volume Measurement from CT Scans for the Clinical Staging of Malignant Pleural Mesothelioma (MPM)

This project would establish a standardized method for clinicians to conduct volumetric CT scans and to use that volumetric data for enhancing the staging and classification of newly diagnosed MPM. This is expected to allow for improved assessment of disease stage and to optimize the treatment decisions. The accurate diagnosis of MPM is critical in determining the most effective treatment for patients. This study will be used to determine the feasibility of developing a multicenter network to use volumetric CT scans as a uniform measurement of clinical T stage in newly diagnosed MPM.