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2013 Mesothelioma Research Grant Awards

Principal Investigator: Marc De Perrot, MD
Institution: University Health Network
Title of Project: Optimizing the radiation approach to mesothelioma with immunotherapy
Description: The treatment of malignant pleural mesothelioma (MPM) is notoriously difficult. A tri-modality approach combining chemotherapy with extrapleural pneumonectomy (EPP) and radiation has provided limited overall benefit. However, hemithoracic radiation has provided excellent local control suggesting that MPM are radiosensitive. Based on our clinical experience, we developed a new protocol with a short accelerated radiation regimen of 5 days followed by EPP the following week. Over 40 patients have been recruited over the past 5 years in this protocol and the 3-year survival reached 84% in patients with epithelial subtype. Hypofractionated radiation provides better immune activation against tumor than standard radiation and could be an ideal therapy to combine with immunotherapy. Data from our mouse mesothelioma model and other models have shown that CTLA-4 blockade can improve the distant response to radiation through an abscopal effect. This effect is improved by activating the immune response against the primary tumor that can then reject a second tumor challenge. The goal of the grant is to clarify the mechanisms of activation of the immune system after hypofractionated local radiation regimen with/without CTLA-4 inhibitor. This study could rapidly translate into new clinical trials to optimize systemic immunity against local tumor in combination with radiation and prevent recurrence and metastasis.

Principal Investigator: Christian Ottensmeier 
The Lance S. Ruble, Janelle Bedel and Ferraro Law Firm Grant
Institution: University of Southampton
Title of Project: Evaluating the effect of immunity on outcomes of patients with mesothelioma
Description: Mesothelioma is a cancer of the lining of the lung, usually caused by inhalation of asbestos fibres. Mesothelioma accounts for 1% of all cancers. For most patients, treatment is not effective and even with the best standard of care, the average life expectancy from initial diagnosis is 4-12 months. In many cancers there is a strong link between the frequency of immune cells found in the cancer and clinical outcome. In the last few years, a number of cancer therapies that target the immune system have been developed and are being used to treat patients. These are now recognized as the treatments most likely to help achieve long term cancer control. Our centre has been at the forefront in the development of new immune based therapies and we have substantial experience in testing new treatments in the clinic. This study aims to gain a better understanding of the effect of immune cells in mesothelioma and identify specific immune signatures that may be useful as markers to predict clinical outcome and identify pathways that can be targeted to treat patients. This will be done by analyzing archived tissue samples from patients who are known to have had mesothelioma and by prospectively collecting blood, pleural (lining of the lung) fluid and when possible pleural biopsies from patients both with and without a suspected diagnosis of mesothelioma for comparison. This knowledge will enable new treatments for mesothelioma to be developed.

Principal Investigator: Tao Dao, MD, PhD
Institution: Memorial Sloan-Kettering Cancer Center
Title of Project: Specific immunotherapy for mesothelioma by use of a bi-specific TCR-like antibody
Description: Malignant mesothelioma is an incurable cancer and the incidence of the disease is steadily increasing worldwide. Despite the multimodal treatment options, the prognosis is extremely poor and new and more effective therapies are urgently needed.Immunotherapy could be a promising new treatment, which generally include two major approaches. One is to activate tumor-specific T lymphocytes, that kill only tumor cells. The other approach is to use tumor-specific monoclonal antibodies (mAb), that engage immune-effectors cells to kill the tumor. The mAb therapy has been proven to be the most successful form of cancer immunotherapy to the date. WT1, is a tumor-specific protein, highly expressed in mesothelioma and is one of the most studied and validated target for T cell-based immunotherapy. However, there had been no therapeutic mAb against the protein. The reason is that WT1 is found within the cells, and conventional mAbs only recognize the protein on the cell surface. However, intracellular proteins can be processed and presented as peptides by human leukocyte antigen (HLA) on the cell surface as a complex, to be recognized by T cells or mAbs. We have successfully generated the first, fully human, high affinity mAb, ESK1, specific for such a complex. ESK1 shows potent killing against mesothelioma cells both in vitro and in an animal model. This proposal is to test a new and more potent form of ESK1, with a goal of translating it into human trials.

Principal Investigator: Usha Pendurthi, PhD
Institution: The University of Texas Health Science Center at Tyler
Title of Project: Endothelial Cell Protein C Receptor Attenuates Mesothelioma Progression
Description: Malignant mesothelioma is an aggressive cancer of the mesothelium, a thin membrane that covers and provides protection to our vital internal organs. The main culprit for the development of mesothelioma is the inhalation of asbestos. As the result of a long latency period (20 to 60 years) and widespread exposure of asbestos in the past decades, the incidence of malignant pleural mesothelioma (MPM) is expected to continue into the near future. MPM is an exceedingly difficult disease to treat with no effective therapy available. An improvement in the knowledge of the disease will allow for the development of new and target-specific therapeutic agents. Preliminary studies conducted in mice in our lab show that if we introduce the expression of a specific protein in to tumor cells that is commonly present on normal mesothelium but lost its expression in cancer cells, the tumors stopped growing completely (this protein is a part of natural anticoagulant pathway, known as endothelial cell protein C receptor or EPCR). This new finding suggests that EPCR acts as a tumor suppressor. The gene expression profiling of EPCR expressing tumor cells and tumor cells lacking EPCR revealed that EPCR reduced the expression of cancer promoting genes while increasing the expression cancer suppressive genes. We plan to utilize this new information to identify the mechanism by which EPCR suppresses tumor growth and to determine the therapeutic potential of this protein.

Principal Investigator: Elisa Giovannetti, MD, PhD
The Law Offices of Peter G. Angelos Greant
Institution: VU University Medical Center
Title of Project: Novel lactate dehydrogenase inhibitors for the treatment of mesothelioma.
Description: MPM is a severely hypoxic malignancy and hypoxia acts as a driving force in proliferation, invasion and chemoresistance. A major consequence of intra-tumoral hypoxia is the metabolic switch from oxidative phosphorylation to increased anaerobic glycolysis, which is required for tumor proliferation at low levels of oxygen and nutrients. As a result of these changes, cancer cells take up glucose and increase the concentration of lactate through lactate dehydrogenase A (LDH-A), which is a key factor in hypoxic adaptation and has been associated to tumor cells viability. Therefore, the present study is aimed at investigating the therapeutic potential of the inhibition of LDH-A to overcome MPM aggressive behaviour and chemoresistance.  To address this aim, we recently developed a series of novel N-hydroxyindole-based inhibitors, which displayed a good anti-proliferative activity against different tumor cells, including MPM cells. To further evaluate their potential novel therapeutics in MPM, we will evaluate their effects on cell growth, invasion, gene expression and kinase activity using appropriate experimental models, including normal, and malignant pleural mesothelioma cells, spheroids, and bioluminescent in vivo MPM models, in normoxic and hypoxic conditions.  As such this project will help to accelerate new drug discovery and have an associated legacy with respect to supporting future trials development in MPM.