(Special MARF Initiated Project)

Dr. Robert Cameron
Chief of Thoracic Surgery
UCLA Medical School

(Special MARF Initiated Project)

Dr. Harvey Pass
Karmanos Cancer Institute

SMRP Serum Levels in Asbestos-Exposed Libby Montana Area Residents

Dr. Brad Black
Center for Asbestos Related Diseases
Libby, MT

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 Libby, Montana will be performing these critical studies.

Tragically, Libby is the site of the W.R. Grace mine that spread asbestos-contaminated vermiculite throughout the town, and shipped it all over the country. Hundreds of Libby residents have died of asbestos diseases. The CARD provides clinical services to Libby residents who need diagnosis and coordination of care for any asbestos related disease. It has collected multiple serum samples from individuals exposed to asbestos and is a unique, ideal setting for the important work of defining SMRP levels in asbestos exposed populations. This research will help the people of Libby, following the awful tragedy that occurred there. By participating in this research, they in turn will be helping mesothelioma patients around the world.

Pemetrexed: Cellular Pharmacology and Mechanisms of Resistance in Mesothelioma; Role of Methylathioadenosine Phosphorylase

(The Mesothelioma Applied Research Foundation Alvin Rehbeck Memorial Grant*)

Dr. I. David Goldman
Albert Einstein Cancer Center
Bronx, NY

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.

Dr. Goldman is one of the leading researchers in how tumors acquire resistance to specific drugs such as Alimta. Studies in tumors other than mesothelioma indicate that drug resistance can occur when either (1) the drug is actively transported out of the tumor cells, or (2) compensatory pathways are activated so DNA synthesis can continue even in the presence of the drug. One such compensatory pathway utilizes an enzyme called MTAP (methylthioadenoside phosphorylase). When present, MTAP serves as a back-up mechanism which cells use to continue DNA synthesis and therefore to continue division and growth.

Dr. Goldman and his colleagues will investigate specifically in mesothelioma small molecule inhibitors that have recently been developed for MTAP. He will seek to confirm that Alimta treatment in combination with these MTAP inhibitors will overcome mesothelioma tumors resistance to Alimta and improve mesothelioma patients response to treatment. These important combination studies will yield results that can be rapidly translated into the clinic for improved patient therapy.

*MARFs grant to Dr. Goldman is funded entirely by a $100,000 gift to MARF from the children of Alvin Rehbeck in his memory.

Immunotherapy With Soluble, Multimeric CD40L and Other TNFSF Ligands

Dr. Richard Kornbluth
Veterans Medical Research Foundaton
San Diego, CA

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.

Using an immunomodulator protein known as CD40 Ligand (CD40L) to stimulate the immune cells has been reported to eradicate mesotheliomas in mice, but a form of CD40L that can be effectively delivered to human mesothelioma tumors has not been found. Dr. Kornbluth will use a new technology to formulate CD40L in a special structure, so that it can be more powerfully delivered to the tumor and better activate the immune cells. Dr. Kornbluth will test this new formulation in mice in order to determine whether a clinical trial in mesothelioma patients is appropriate.

MARFs reviewers were excited by the innovative nature of Dr. Kornbluths research, and its potential to trigger a clinical trial for the benefit of mesothelioma patients. Dr. Kornbluths work also underscores the important role the VA can take in overcoming the disease. Mesothelioma is a service-related disease, and dedicated, outstanding researchers including those working with the VA like Dr. Kornbluth are making progress. The VA should join with MARF in a serious commitment to fund this research.

Studies of c-Met in Mesothelioma

Dr. Ravi Salgia
The University of Chicago
Chicago, IL

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.

Pre-Clinical Studies of a Novel Therapeutic Strategy for Malignant Mesothelioma

Dr. Bernadette Scott
Monash University
Clayton Victoria, Australia

Dr. Scotts 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. This innovative work has the potential to open new areas within the field of mesothelioma research.

Malignant Mesothelioma and Thalidomide; A Translational Research Project

Dr. Paul Baas
Netherlands Cancer Institute
Amsterdam, Netherlands

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.

Development of Novel Therapeutic Strategies for Malignant Pleural Mesothelioma: Targeting the IGF System

Dr. Cecilia Camacho-Hbner
St. Bartholomews Hospital, William Harvey Research Institute, University of London
London, England

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.

Defining and Targeting Mesothelioma-Specific Internalizing Cell Surface Receptors for Novel Therapeutics

Dr. Bin Liu
University of California San Francisco
San Francisco, CA

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.

Epigenetic Changes in Mesothelioma

Dr. Gregory Otterson
The Ohio State University Research Foundation
Columbus, OH

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.