2003

"Dendritic Cell-Based Immunotherapy of Mesothelioma"

Dr. B. Lambrecht, M.D., Ph.D.
Erasmus Medical Center
Rotterdam, The Netherlands

The potential to harness the patient's immune system underlies the growing interest in cancer immunotherapy. Immunotherapy can be made more successful if we know how exactly tumor immune responses are induced. Dendritic cells (DC) are so-called sentinel cells that patrol the body for tumors and harmful antigens. These cells present tumor antigens to the immune system and are vital for inducing T-cell responses, thereby generating tumor-specific immunity.

The use of DC immunotherapy for cancer in humans is in its earliest phases, but promising results have been seen in melanoma and some hematological cancers. Dr. Lambrecht and his team will test this approach for the first time in mesothelioma. As the preparation for beginning a clinical trial, many issues have to be addressed, such as the best way to load tumor antigen, the best source of DCs and the best way to inject cells. In this study, mesothelioma derived small vesicles (exosomes) will be used as a cell-free source to load tumor antigen on DCs. Optimal conditions for immunotherapy will be tested in vitro and in an in vivo mouse model of mesothelioma.

If the method proves both efficacious and applicable to mesothelioma, this study will be the basis for a follow-up clinical trial in humans.

"Targeted Virotherapy for Mesothelioma"

David T. Curiel, M.D., Ph.D.
University of Alabama at Birmingham

Gene therapy utilizes two alternatives: Mutation compensation corrects the gene abnormalities which allow tumor development in the first place, while molecular chemotherapy delivers toxin genes to the tumor cells. Both alternatives are quite promising, but their success has been limited by the difficulty of delivering the therapeutic gene to the target cells (cell transduction) in quantities sufficient to be therapeutic, while limiting the transduction in healthy cells.

The second method, molecular chemotherapy, usually uses as the "vector" (the method of delivering the gene) a virus which is nonreplicating. Unfortunately, this makes the transduction, which leads to the intended cell lysis (death), a terminal event for the virus or vector, thus preventing further transduction in neighboring tumor cells. Dr. Curiel, a renowned gene therapy expert, seeks to develop a conditionally replicative virus that would replicate only in transduced mesothelioma tumor cells, thus limiting its effect on normal tissue, and yet would replicate through a lytic cycle, thus producing progeny to infect neighboring tumor cells and thus multiply its effect. If successful, this study will also provide the rationale for a clinical trial.

"Gene Therapy in Mesothelioma"

Gavin J. Gordon, Ph.D.
Harvard Medical School/Brigham and Women's Hospital
Boston, MA

Clinicians at Brigham and Women's Hospital and elsewhere have developed the "tri-modal" or "multi-modal" treatment for mesothelioma -- surgical resection, chemotherapy, and radiation therapy. While this trimodal treatment dramatically improves 5-year survival in selected patients, the majority of even the most optimal patients ultimately succumb to local recurrent disease. This is consistent with the widely documented resistance of mesothelioma tumor cells to commonly used chemotherapy drugs such as cisplatin.

Discovering new drugs to overcome mesothelioma's resistance is a process which is timely, costly, and uncertain. Therefore, improving patient response to current drugs is likely to more quickly and dramatically affect mesothelioma patient survival. Dr. Gordon has recently discovered that the Inhibitor of Apoptosis Protein 1 (IAP-1) gene is largely responsible for the inherent cisplatin resistance of mesothelioma cells. Dr. Gordon seeks to develop a gene-therapy based strategy to target IAP-1 (and possibly other related proteins) in an effort to improve the efficacy of drugs currently used to treat mesothelioma.

"Radiation Sensitization Via Inhibiting Survival of Mesothelioma and its Vascular Endothelium"

Bo Lu, M.D., Ph.D.,
Vanderbilt University Medical Center
Nashville, TN

Like Dr. Gordon, Dr. Lu seeks to sensitize mesothelioma to existing treatment, in this case radiation therapy as opposed to chemotherapy. This project takes advantage of the fact that pleural mesothelioma is typically local. Metastases is relatively rare and the tumor usually progresses -- and ultimately causes death - intrathoracicly (within the chest). Thus, intrathoracic radiation could be expected to be an effective treatment strategy if a major obstacle -- radiation's toxicity to critical organs in the chest -- could be overcome.

Dr. Lu aims to overcome this obstacle. Survivin is known as a "pro-survival" protein because, as a member of the Inhibitor of Apoptosis (IAP) family, it inhibits normal apoptosis or cell-death. Survivin is up-regulated in mesothelioma. Dr. Lu will seek to confirm his hypothesis that survivin creates resistance to radiation therapy in mesothelioma cells. He will then seek to inhibit survivin in mesothelioma cells, in order to selectively sensitize the mesothelioma cells to radiation therapy, allowing a dosage that is lower and less toxic to surrounding critical organs. If successful, Dr. Lu's project offers the prospect of very rapid translation to improved treatment for mesothelioma.

"Phenotypic and Genotypic Determinants to Identify Patients at High Risk for Mesothelioma"

Jill A. Ohar, M.D.
Wake Forest University Health Sciences
Winston-Salem, NC

In her study, Dr. Ohar hopes to address the problem that mesothelioma is usually diagnosed in its later stages of development. For example, it is often first misdiagnosed as congestive heart failure or pneumonia, and only after treatment attempts for these conditions have failed is the diagnosis of mesothelioma made. As a result of the late diagnosis, treatment options and effectiveness are limited.

Dr. Ohar has helped develop what is likely the nation's largest medical database of asbestos-exposed individuals. By comparing the individuals within this group who developed mesothelioma against those who did not, she hopes to develop a profile of clinical and genetic characteristics that define a population at highest risk for mesothelioma. She will analyze clinical variables such as symptoms, gender, age, education, income, age at first exposure to asbestos, latency (period after exposure until the development of asbestosis), occupational history, personal and family history of malignancy, emphysema and asthma. She will also analyze the DNA of the different individuals for the presence of susceptibility genes including detoxifying genes; N-acetyl-transferase (NAT), glutathione-S-transferase (GST)-t, mu & p and inflammation regulatory genes; and macrophage scavenger receptor 1(MSR), tumor necrosis factor (TNFa) and its receptor.

Identifying these clinical and genetic characteristics that lead to high mesothelioma risk should enable earlier detection and treatment of mesothelioma, resulting in more prolonged survival or cure.

2002

Pharmacogenetic and Pharmacogenomic Studies of Thymidylate Synthase Enhancer Region Polymorphisms in Mesothelioma and Their Therapeutic Implications in Patients Treated with Pemetrexed Sodium

Johann Sebastian de Bono, M.D., Ph.D
Muralidhar Beeram, M.D.
Institute for Drug Development
Cancer Therapy and Research Center
University of Texas at San Antonio

This cutting-edge study applies the new field of pharmacogenetics (improving chemotherapys effectiveness and lowering its toxicity by individualizing it to the patients particular genetic profile) to malignant mesothelioma. The study will examine Alimta (pemetrexed), the first anticancer drug shown to improve the survival of malignant mesothelioma patients.

Both Alimtas anticancer activity and its side-effect profile are largely due to its effect on the enzyme thymidylate synthase (TS). Interestingly, general population genetic variations cause TS levels to vary greatly among patients. The study will analyze the impact of mesothelioma patients varying TS levels on Alimtas anticancer activity and its side effects. The goal is to allow Alimta dosing to be individualized or tailored to a particular patient based on a simple blood test determining the patients TS level.

Molecular Diagnosis of Mesothelioma Using DNA Methylation Signatures"

Ite Laird-Offringa, Ph.D.
Assistant Professor of Surgery
USC/Norris Cancer Center

DNA methylation is a chemical modification of DNA that occurs in many cancers. It is one of the mechanisms by which so-called tumor-suppressor genes are inactivated in cancer cells. Recent research suggests that the pattern of DNA methylation is specific for different kinds of cancer, and therefore DNA methylation analysis is one of the most promising new areas of cancer diagnostics. The Laird-Offringa laboratory proposes to identify methylation patterns specific for mesothelioma, using state of the art technology developed at the University of Southern California.

This will have two immediate applications. First, identification of DNA regions that are specifically methylated may lead to the identification of tumor-suppressor genes that are silenced in mesothelioma. Identifying these inactivated tumor-suppressor genes is critical to understanding, and eventually being able to stop or reverse, the multistep pathway that allows the mesothelioma tumor to develop and progress.

Second, methylation patterns can be used as signatures to identify mesothelioma. Mesothelioma-specific methylation patterns could be invaluable tools for the accurate diagnosis of mesothelioma, in particular in cases where the distinction between mesothelioma and other conditions (such as adenocarcinoma of the lung) is difficult. In the future, mesothelioma-specific methylation patterns could be developed into tools for early detection (by testing the blood or other bodily fluids of a patient for the tell-tale methylation patterns), as prognostic indicators (based on analysis of correlations of methylation patterns with patient characteristics, such as response to therapy and overall survival), and as a measurement of patient response to therapy (based on decrease or increase of the patterns following treatment).

2001

"Validation of Prognostic Markers in Mesothelioma"

Raphael Bueno, M.D.
Assistant Professor of Surgery
Division of Thoracic Surgery
Harvard Medical School and Brigham and Womens Hospital
Boston, Massachusetts

Dr. Bueno and his research partners have discovered in initial experiments that mesotheliomas can be classified into three different categories based on the pattern of expression of a small number of genes. It turns out that the survival of patients after therapy for mesothelioma varies based on which subclass they belong to. The work Dr. Bueno and his team will perform through the MARF grant is directed at validating this predictive test in a larger number of patients. This improved means of classifying patients will hopefully allow physicians and patients to select treatment strategies for mesothelioma more rationally.

"Computerized Analysis of Mesothelioma on Thoracic Computed Tomography Scans"

Samuel G. Armato III, Ph.D.
Assistant Professor
Department of Radiology
The University of Chicago
Chicago, IL 60637

To evaluate tumor response to therapy in mesothelioma patients, doctors must perform tedious and subjective manual measurements of tumor thickness for the many images acquired during a CT scan. Through this project, Dr. Armato will develop an automated, computerized system that will objectively provide doctors with quantitative measurements of mesothelioma tumor volume. Such measurements should contribute to better understanding and evaluating the effects and benefits of different mesothelioma therapies.

National Mesothelioma Data/Tissue Bank Pilot Project (Special MARF Initiated Project)

Dr. Robert Cameron
Chief of Thoracic Surgery
UCLA Medical School

2000

"Identification of a 1p22 Tumor Suppressor Locus Frequently Deleted in Malignant Mesothelioma''

Joseph R. Testa, Ph.D.,
Director, Human Genetics Program
Fox Chase Cancer Center
Philadelphia, PA

Dr. Testa is studying a chromosomal site, 1p22, which is deleted in 75% of all mesotheliomas, and which is suspected to harbor tumor suppressor genes. The Human Genome Project has recently discovered the actual gene candidates that normally reside in this region. Dr. Testa, therefore, will study each of the candidates to determine which one is altered at the DNA level in mesotheliomas, so as to cause the loss of the tumor suppressor function. By identifying the altered or missing tumor suppressor gene through support from the MARF grant, Dr. Testa would be in an ideal position to seek support from the National Institute of Health for a large study to identify the gene's specific tumor suppressing function. A way to replace the gene, or duplicate its function, could then be developed.

"A Study of Biologic Markers of Angiogenesis during a Phase II Trial of the VEGF Receptor Inhibitor SU5416 in Malignant Mesothelioma''

Hedy Kindler, MD,
Assistant Professor of Medicine, Hematology/Oncology
University of Chicago
Chicago, IL

Dr. Kindler is studying the biologic correlates of blood vessel formation in mesothelioma patients being treated with SU5416. SU5416 is a blood vessel inhibitor, or anti-angiogenesis drug. Anti-angiogenesis drugs such as Endostatin have recently received scientific and public attention as a promising new way to fight cancer. Among anti-angiogenesis drugs, SU5416 shows perhaps the most promise for fighting mesothelioma. It specifically targets the growth factor VEGF, and mesothelioma patients have higher circulating levels of VEGF than patients of any other solid tumor. The prestigious National Cancer Institute is already funding a SU5416 clinical trial at the University of Chicago; and by funding Dr. Kindler's work MARF will build upon and extend the information obtained from this trial.