Dr. Bin Liu, University of California San Francisco

We have previously identified a panel o monoclonal antibodies from a phage display library that bind to mesothelioma cells in situ in actual cases and mediate efficient intracellular delivery of small molecule drugs to mesothelioma cells. This proposal aims to establish the molecular identify of the corresponding mesothelioma antigens.

Dr. Deborah Altomare, Fox Chase Cancer Center

Malignant mesothelioma (MM) is highly resistant to conventional therapies. Activated proteins that are part of growth factor stimulated signaling pathways, such as those composed of PI3K/AKT/mTOR and PAK/Raf/MEK/ERK, are likely to contribute to a high rate of tumor cell growth, progression and resistance to treatment. Therapeutic effectiveness may be improved by combining drugs that promote MM cell death. Dr. Deborah Altomare of Fox Chase Cancer Center will employ human MM cells and a mouse model of asbestos-induced carcinogenesis that mimics many of the features of human MM as preclinical models to test drug combinations targeting activated AKT and PAK//ERK pathways. Her hypothesis is that effectiveness of MM therapy may be improved through combinations of anticancer agents that work together to increase cell death. The specific aims of this proposal are: 1) Determine whether pharmacologic targeting of the AKT and PAK/ERK signaling pathways alone or in combination, induce growth arrest or cell death in human MM cells. We will use a novel phosphatidylinositol 3-kinase (PI3K) inhibitor and the pharmaceutical Sorafenib (Nexavar). Moreover, we will examine whether these agents increase the effectiveness of the therapeutic drug Alimta in human MM cells. 2) Determine in a preclinical animal model whether treatments targeting AKT and PAK/ERK signaling can repress MM tumor progression. Overall, insights derived from these studies are expected to provide important clues for the design of effective new combination therapies targeting pathways in MM tumors, and findings may translate into the design of new clinical trials to improve MM patient survival.

Dr. Alla Ivanova, New York University, School of Medicine

The long-term goal of my project is to understand the mechanism(s) of the mesothelioma innate drug sensitivity in order to develop new therapeutic tools for sensitizing tumor cells to specific drugs prior to drug treatment. This approach will help to enhance cytotoxicity and significantly augment the eradicating effect of anti-cancer drugs.

Dr. Brooke Mossman, University of Vermont & State Agricultural College

New treatment strategies for mesothelioma are desperately needed. We will test novel particles containing two cancer chemotherapeutic drugs on human mesothelioma cells in culture and implanted onto mice, data necessary for their approval to treat patients with mesothelioma.

Dr. Courtney Broaddus, University of California, San Francisco

Anti-tumor antibodies offer the exciting potential of delivering therapy specifically to tumors while minimizing toxicity to normal tissues. Indeed, therapeutic antibodies have entered clinical practice for a few cancers. With the benefit of earlier MARF support, Dr. Bin Liu and I have developed several tumor-specific antibodies to mesothelioma. These antibodies were developed and then selected by a novel molecular technique called phage display for their ability to bind to and be internalized by human mesothelioma cells. These antibodies react with both epithelial and sarcomatous human mesothelioma cells and fail to react with normal human mesothelial cells.

Here, we propose to investigate these antibodies for their ability to target mesothelioma cell lines and human mesothelioma tumor fragments in vitro and in vivo in mice in order to determine their potential clinical usefulness for diagnosis and/or therapy. First we plan to select those antibodies that are most specific for the tumor cells grown in 3D, where the cells may present surface markers in a fashion similar to that in vivo. Then, we will move to test the 1-2 most promising antibodies on actual human tumor fragments grown in culture and then implanted into the peritoneal space of nude mice. The antibody will be radiolabeled, injected intravenously and then imaged for its ability to target the implanted human tumors with a mouse tomographic imaging instrument that combines photon detection with computed tomography (SPECT/CT). With the support provided by this funding, we plan to pursue the clinical applicability of these unique antibodies for diagnosis and future therapy.

Dr. Stephen Levin, Mount Sinai School of Medicine

A database containing results of clinical examinations performed on 2907 asbestos insulators in 1982-83 will be made analyzable and their frozen serum specimens will be organized and catalogued in Year 1. In Year 2, the death experience of this group will be updated to enable use of their serum specimens to validate blood markers of mesothelioma.

Dr. Lee Krug, Memorial Sloan-Kettering Cancer Center

WT-1 is a gene involved in the development of cancer and is frequently found in mesothelioma tumors. In this study, we plan to give a vaccine against WT-1 to paitents with mesothelioma to see if it causes an immune response.

Dr. Faris Farassati, University of Minnesota Medical School

Mesoththelin is an antigen which is expressed in significantly elevated levels in mesothelioma patients and has been used for diagnosis of this malignancy. It has also been used for targeting antibodies against mesothelioma cells. On the other hand, direct destruction of mesothelin and its consequences on the viability of mesothelioma cells has never been investigated. In this proposal, we asked a simple question: what if we inhibit the synthesis of mesothelin in mesothelioma cells. Interestingly, once we successfully inhibited the expression of this molecule by using a novel gene therapy method names as siRNA (short interfering RNA), we observed that viability and invasiveness of human mesothelioma cells was significangly reduced. On such basis we introduced our design for making an anti-mesothelin lentivirus which is capable of attacking mesothelioma cells an dinhibiting the production of mesothelin in them by producing siRNA against mesothelin. We expect that this virus will specifically taget/destory mesothelioma cells and leave the normal cells untouched since normal cells either do not express mesothelin or express it at very low levels. We are planning to test the efficiency of the virus as a novel therapeutic tool for mesothelioma in-vitro (petri dishes) and in-vivo (animal model).

Dr. Guang-Hui Xiao, Fox Chase Cancer Center

Malignant mesothelioma (MM) is resistant to conventional therapies. The experiments outlined in this proposal will evaluate the therapeutic potential of adenovirus-mediated expression of NK4 in MM cell lines and its antitumor ef{icacy in an animal model of MM.
These investigations could provide a promising new modality for the treatment of MM.

Dr. Anil Wali, Wayne State University/Karmanos Cancer Institute

This hypothesis driven project will have major impact on new interventional approaches and treatment. It will also identify clinical/molecular determinants for prognosis of this deadly disease. This study will generate new data and concepts that will further advance our knowledge for the optimization of therapeutic regimens for mesothelioma.