2004 Mesothelioma Research Grant Awards
Title: Comparison Of Adjuvant Treatments For Mesothelioma, Including Hyperthermia, COX-2 Inhibition, Cpil-4 Toxin Therapy, And Standard Chemotherapy (Special Initiated Project) Title: Soluble Mesothelin/MPF Related Protien (SMR) Levels in Mesothelioma: A MARF Collaborative Study for Definition of Biomarker Classification and Use in Therapy Monitoring (Special Initiated Project) Brad Black, MD Description: One of the most exciting recent developments in mesothelioma research is the promising new biomarker, SMRP (Serum Mesothelin Related Protein). With a simple blood or urine test, this marker can distinguish mesothelioma from other malignancies, and from inflammatory conditions such as asbestosis. Even more promising is that the concentration of SMRP rises with increasing burden of mesothelioma and falls with successful treatment. All of these factors point to SMRP as a powerful tool for early detection and diagnosis of mesothelioma, as well as for monitoring response to treatment and recurrence. In order to develop this tool and make it standard in the detection, diagnosis and treatment of mesothelioma, important studies still must be performed. Normal ranges of SMRP must be defined in non-asbestos exposed individuals, and in asbestos-exposed but non-cancer bearing individuals. These normal values can then be compared to the concentration of SMRP in mesothelioma patients. Dr. Black and his colleagues at the Center for Asbestos Related Diseases (CARD) in David I. Goldman, MD – Description: Alimta (Pemetrexed) is now well known as the first agent with significant activity in combination with cisplatin in the treatment of advanced mesothelioma, and the only FDA approved treatment for mesothelioma. Alimta decreases cell growth by blocking the actions of folic acid. Specifically, Alimta inhibits the activities of two enzymes: Thymidylate Synthase (TS) and Glycinamide Ribonucleotide Transformylase (GARFT), which cells use to copy their DNA so they can divide and grow (DNA synthesis). While all this is known, little is known about the mechanisms of acquired resistance to Alimta and why mesothelioma tumors stop responding to Alimta treatment. Richard Kornbluth, MD Description: Dr. Richard Kornbluth and his colleagues at the Veterans Medical Research Foundation in San Diego will seek to develop a novel method of immunotherapy, using the patients own immune system to eradicate the mesothelioma tumor. The immune system contains killer T-cells which normally recognize and destroy the cells of a growing tumor. In mesothelioma patients however, these immune cells are not properly activated, resulting in increased and un-regulated growth of the tumor. Description: Mesothelioma tumors often express high levels of c-Met, a receptor tyrosine kinase (RTK) involved in tumor cell growth, motility, and blood vasculature. The c-Met receptor binds to a protein called Hepatocyte Growth Factor (HGF), which is also over-expressed in many mesothelioma tumor samples. In normal cells, c-Met activation is dependant on HGF, but in mesothelioma tumors c-Met is always activated and therefore increases tumor growth. Much attention has recently been focused on RTKs as potential new targets for cancer therapeutics. Given that c-Met and its ligand HGF are often over-expressed in mesothelioma tumors, small molecule inhibitors to c-Met could yield promise as a novel mesothelioma treatment. Dr. Salgia will test a specific small molecule inhibitor to c-Met (SU11274) which Pfizer has developed. Dr. Salgia will examine how c-Met inhibitors alter mesothelioma cell growth and response to chemotherapies. As part of his research, Dr. Salgia will further investigate the molecular mechanisms of c-Met activation and identify specific mutations in the c-Met gene in mesothelioma tumor samples and cell lines. Description: Dr. Scott’s studies will address how a patients immune system can be manipulated to increase the effectiveness of mesothelioma treatment. Her work focuses on immune cells called macrophages. Macrophages identify cells within the body that are foreign (such as a tumor cells), and they also have properties which help tumors grow. Dr. Scott will be examining how depletion of macrophages will affect mesothelioma tumor growth in mouse models with the hope of translating the work into humans. Paul Baas, MD, PhD Description: This study is designed to further characterize Dr. Baas conditional knockout mice that grow pleural tumors focussing at mRNA by expression-array. Data and tumor samples from patients in the large randomized Dutch trial on maintenance therapy with Thalidomide will be used as a comparator. Cecilia Camacho-Hubner, MD Description: Malignant pleural mesothelioma is presently incurable, despite aggressive treatment with chemotherapy and prolonged radiotherapy. Thus, it continues to present a therapeutic challenge. Studies have shown that families of growth factors, such as the insulin-like growth factor system (IGFs), are crucial in solid tumor cell growth and survival. Therefore, the aim of this project is to inhibit IGF biological actions in mesothelioma cells in vitro. Dr. Camacho-Hbner anticipates that the proposed studies will generate valuable new data, shed more light on the physiological roles of the IGF system in the growth of mesotheliomas, and advance the knowledge of the therapeutic potential of inhibiting IGF actions in malignant pleural mesothelioma. Bin Liu, PhD Description: Dr. Liu has devised an effective, antibody-based approach to identify tumor-specific cell surface alterations. Dr. Liu proposes to apply this approach to the development of novel therapy against mesothelioma. Confidence in this study is significantly enhanced by his recent findings: (1) several tumor-targeting phage antibodies, previously isolated from selections on prostate and ovarian cancer cells, specifically recognize mesothelioma cells but not non-malignant primary mesothelial cells, or epithelial cells derived from normal prostate and breast. This result indicates that mesothelioma possesses a unique, identifiable cell surface antigenic profile. (2) Nanoparticles encapsulating small molecules can be delivered specifically to the interior of mesothelioma cells. This indicates that mesothelioma cells possess an active internalization mechanism that can be explored for the development of targeted therapy. Gregory Otterson, MD Description: There has been no systematic exploration of DNA methylation in malignant mesothelioma. Methylation of the DNA of certain tumor suppressor genes leads to these growth suppressing genes not being expressed, and is a frequent alteration in cancer. In this project, Dr. Otterson will perform a systematic methylation analysis of mesothelioma to identify new tumor suppressor genes and oncogenes involved in mesothelioma. Furthermore, Dr. Otterson will study the effects of inhibition of methylation on mesothelioma cells. Ultimately, Dr. Otterson anticipates that these findings will lead to novel therapeutic treatment strategies.
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