Dr. B.N.M. Lambrecht
Department of Pulmonary Medicine
Erasmus Medical Center
Rotterdam, The Netherlands

In a phase 1 clinical trial focused on immune therapy, Doctor B.N.M. Lambrecht of the Erasmus Medical Center plans to evaluate dendritic cells as a therapeutic adjuvant for treating malignant mesothelioma in humans. Dendritic cells, also called veiled or reticular cells, are antigen-presenting cells that circulate in the blood and lymph to alert the immune system to foreign intruders. This grant follows up on previous successes with immunotherapy studies in mice that were very effective. Dendritic cells proved capable of generating an immune response when presenting mesothelioma tumor antigens to the immune system. The current study intends to test the feasibility and safety of using tumor lysate-loaded dendritic cells to activate the immune response.

Rapid Screening of DNA Methylation Markers for Accurate Molecular Diagnosis of Mesothelioma

Dr. Ite Laird-Offringa
Departments of Surgery and Biochemistry & Molecular Biochemistry
University of Southern California
Los Angeles, CA, 90089

Hot on the heels of other meso-specific serum biomarker announcements in late 2004 and early 2005, researchers at USC under the direction of Dr. Ite Laird-Offringa were given a grant to continue the search for diagnostic markers for mesothelioma. Previous research relied upon a marker-by-marker search for mesothelioma specific indicators. USC plans to accelerate the search 70 fold by using DNA microarray chips to pre-screen roughly 7000 serum markers using the MethyLight analytical system. Tissue samples would be examined to quickly focus in on specific molecular markers found more often in mesothelioma tumor specimens. These would then be used to develop additional serum tests specific to mesothelioma that will aid early diagnosis of the cancer.

Inhibiting bcl-xl in Mesothelioma by Small-Molecule BCL-2/BCL-XL Antagonists

Professor Xiaobo Cao
Departments of Surgery/ Research and Education
Scott White Memorial Hospital
The Texas A&M University
Temple Texas 76504

The molecular understanding of the human genome has allowed researchers to undertake much more precise and tactical interventions against mesothelioma. Professor Xiaobo Cao of Texas A&M University, and his team, received a grant to investigate a specific gene family BCL-2, known to over-express a protein BCL-XL which blocks cell death (apoptosis) in mesothelioma tumors. Researchers wish to evaluate a BCL-2/BCL-XL antagonist, a compound that blocks the actions of the over-expressed protein, to see if it will cause tumor cell death and sensitize mesothelioma cells to the effects of existing chemotherapy agents. If valid, such an approach will offer superior specificity to mesothelioma and greater effectiveness in treatment. BCL-XL antagonists have great clinical potential to become chemo-sensitization agents and apoptosis inducers. Molecular studies of this nature were virtually impossible ten years ago and represent the leading edge of scientific research today.

Histone Deacetylase (HDAC) in Malignant Mesothelioma

Dr. Sunil Sharma
Nevada Cancer Institute
Las Vegas, NV 89135

A Nevada Cancer Institute team under the direction of Dr. Sunil Sharma will continue its investigation of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor. SAHA and other HDLC inhibitors have demonstrated effectiveness against a broad spectrum of cancer activity and provide a promising new approach to therapy. Tumor resistance to HDAC inhibitors will be studied in an effort to identify combination therapies with drugs like mTOR inhibitors and nutrient uptake inhibitors that can increase tumor response to treatment. Dr. Sharma intends to generate a mesothelioma cell line resistant to SAHA and other drugs like valproic acid and then compare them to parent cell lines using molecular analysis to identify markers of resistance. These markers will then become targets for therapy.

Genetically engineered human mesothelioma cells

Dr. Tan A. Ince
Whitehead Institute
Laboratory of Robert A. Weinberg
Massachusetts Institute of Technology
Cambridge, MA 02142

Dr. Tan Ince of the Robert A. Weinberg laboratory at MIT was given a grant to pursue a method of isolating and identifying specific therapeutic targets in mesothelioma tumor cells. Therapeutic targets are specific locations in the cellular DNA which are expressing proteins that inhibit cell death (apoptosis) and cause rapid cell division. Normally, mesothelioma cells take decades to appear in patient populations. They are the product of mutations in oncogenes and tumor suppressing genes, including hundreds of point mutations, small deletions from the genes and DNA translocations, not all of which are necessarily related to tumor development. Consequently identifying which of these many mutations is responsible for the development of mesothelioma is extremely hard to do. The sheer number of changes makes the analysis complex and separating those markers related directly to cancer growth from benign mutations can be difficult.

Recently, it has become possible to create cancer cells in vitro by introducing a limited number of defined genetic changes into human cell cultures. This approach was used to create a mesothelioma model starting with healthy mesothelial cells. When injected into immunocompromised mice the result was rapid development of mesothelioma in various vital organs like the liver and diaphragm. This has enabled researchers to identify a specific target gene as a possible oncogene, making it possible to test specific chemotherapies against this target. The experiments are intended to identify other therapeutic targets for treatment as well by repeating the process of comparing the genetic profiles of cancer-causing and non cancer-causing mesothelial cells.

Identifying critical activators of PI3K/Akt signaling pathway in mesothelioma

Professor Pasi Jnne
Department of Medical Oncology
Dana-Farber Cancer Institute
Boston, MA 02115

Dr. Pasi A. Jnne of the Dana Farber Cancer Institute in Boston was approved for a grant to study molecular pathways affecting mesothelioma. Genes express themselves by using signaling pathways which are locations on the surface of the gene where critical cellular processes are carried out. PI3K/Akt is a pathway associated with cell survival, growth and proliferation. This pathway regulates cell growth and survival and when improperly activated can lead to over-expression of the regulating proteins. This can cause a wide variety of tumors by encouraging cell proliferation and stopping programmed cell death (apoptosis). The PI3K is one of the most frequently mutated pathways in human cancers.

Using mass spectrometry and other methods, proteins involved with PI3K expression will be identified. This study hopes to reveal the mechanisms by which the PI3K pathway is regulated and thereby lead to the development of PI3K antagonists that can block this pathway. This will allow down-regulation (suppression) of the gene and lead to decreased growth of mesothelioma tumor cells.

Angio-immuno Agents and Their Effects in Malignant Mesothelioma

Dr. Delia Nelson
School of Biomedical Sciences
Curtin University
Perth, Western Australia, 6105

Dr. Delia Nelson of the Curtin University School of Biomedical Sciences in Perth Australia received a grant to follow up on successes in using immunotherapy to cure mesothelioma tumors in mice. There is evidence to indicate that the immune system does identify and respond to mesothelioma but the response is insufficient to arrest the disease. Immune mediated destruction of the tumor requires a powerful, local, intra-tumoral inflammatory response, something which may be possible with the correct angio-immuno agents, but has been little studied to date.

Dr. Nelsons team has tested specific agents that enhanced anti-tumor response and which altered tumor-associated blood vessels. This led to cures in 80% of mice with large mesothelioma tumors. The intention of the MARF study is to further identify agents which alter the tumor microenvironment such that tumors will regress. Changes in tumor blood vessels and in tumor infiltrating cells will be evaluated after intra-tumoral application of the angio-immuno agents. In addition, combination therapies will be tried which incorporate anti-vascular agents with the immune stimulating agents. Growth rates of the treated tumors will be measured and the effectiveness of the combination therapies will be assessed to show the potential for the treatment of human mesothelioma tumors and to provide data for subsequent clinical trials.

"Discovery and Validation of Novel Serological Biomarkers in Mesothelioma"

Dr. Anil Vachani
Abramson Research Center
University of Pennsylvania
Philadelphia, PA

Dr. Anil Vachani of the University of Pennsylvania was also awarded a grant to pursue the promising biomarker field. In addition to early diagnosis, the benefits of serum biomarkers for mesothelioma include using molecular assays to predict clinical outcome and providing a way of monitoring for recurrence in survivors. In this project, Dr. Vachanis team will take advantage of exciting new proteomics technologies that they, and their collaborators, have developed to discover novel diagnostic biomarkers of mesothelioma.
 Recent advances in critical commercially-available proteomics tools and mass spectrometry (MS) instrumentation, together with a powerful multi-dimensional separation strategy developed by Dr. Speicher, make systematic searches for new, more reliable biomarkers of diseases feasible for the first time. They will then identify candidate human mesothelioma biomarkers in an SCID mouse/xenograft model system using a novel multi-dimensional protein profiling method.

"Novel Pharmacological Targets for Malignant Mesothelioma"

Professor Giovanni Gaudino
University of Piedmonte
Novara Italy

Piedmont Universitys Dr. Giovanni Guadino will investigate novel pharmacological mesothelioma therapy targets. Scientists have learned that asbestos exposure induces apoptosis in healthy mesothelial cells and these damaged cells can be rescued by Receptor Tyrosine Kinases (RTKs). The progressive resistance of cells to apoptosis over time may represent part of a multi-step process leading to neoplastic transformation of human mesothelial cells (HMC) and the formation of mesothelioma.
Downstream signaling pathways, responsible for cell survival and transformation of mesothelial cells, will be evaluated. Since RTKs have been implicated in making cells resistant to genotoxic therapies, this may be one of the reasons for chemo resistance in malignant mesothelioma. The investigators hope to identify new agents able to interfere with RTKs and their downstream signaling in order to induce cytotoxicity and restore tumor cell chemo sensitivity.