Mesothelioma Researcher Receives Prestigious Grant from Department of Defense

Marjorie ZaudererMarjorie Zauderer, MD, is a medical oncologist at Memorial Sloan Kettering Cancer Center specializing in the care of lung cancer and mesothelioma patients, and serves as a member of the Meso Foundation’s Science Advisory Board. Recently, Dr. Zauderer was granted the Career Development Award to fund her mesothelioma research project.

Dr. Zauderer received the Career Development Award for her current research project involving the role of the BAP 1 gene (BRCA associated protein-1) in mesothelioma. Inherited mutations in the BAP1 gene have been shown to predispose patients to malignant pleural mesothelioma. “A better understanding of this gene could mean a better understanding of mesothelioma and how it develops in patients,” Zauderer states.

Dr. Zauderer began working on this project three years ago and has been gathering specimens and samples throughout this time. She predicts that enough samples will be collected within the next year or two to begin analysis that could yield significant insights and statistics. Her goal in 3 to 5 years is to have a plausible drug that has already completed phase 1 testing or is ready to begin phase 1 testing in clinical trials.

In an interview, Dr. Zauderer expressed her passion for her work, citing her many college application essays that she recently came across. “All my applications were about how I wanted to use genetics to help medicine. 20 years later, that’s actually what I do,” Zauderer states.

The Career Development Award provides funding from the Department of Defense to support a specific research project. Funding is provided to the selected project over a three year period, during which certain research components must be met and specific goals achieved. Mesothelioma is a disease of interest to the Department of Defense, as an estimated one third of mesothelioma patients either served in the Navy or worked in shipyards.

Learn more about Marjorie Zauderer at curemeso.org.

Progress in Mesothelioma Research is Possible, Requires Collaboration

Researcherby Mary Hesdorffer, NP, Executive Director, Meso Foundation

Through our peer reviewed research grant program, the Meso Foundation supports the most promising research projects in the field of mesothelioma. Cutting edge research is crucial to the lives of those affected by mesothelioma, and it is the key to finding a cure for this cancer.

The Meso Foundation’s grant program has been ongoing for 14 years. Until the Foundation was founded and the program was developed, there was little movement in the field of mesothelioma research. In fact, there was no treatment yet approved for this disease. Pharmaceutical companies and Bio Tech companies were producing new agents every year, but in order for mesothelioma to be considered for these drugs, a better understanding of the disease was needed.

This year, I am pleased to announce that pharmaceutical companies have taken a big interest in mesothelioma. Companies are hosting global and national clinical trials based upon much of the groundwork that developed from the research funded through our grant program.

To date, the Meso Foundation has funded 94 projects and awarded $9 million. The funded research has taken place in 6 different countries and has resulted in 180 published pieces. We are taking mesothelioma research to the next level.

Among the research we have funded, there has been an interest in examining patients’ responses, or lack thereof, to therapies. Tumors are unique to the individual, and we know that some patients will have a very good response to a therapy and some will not. The goal is to understand why they differ in order to filter out those who will not benefit from a prescribed treatment and refer them to more appropriate therapy.

Over the past few years, I have attended a number of mesothelioma conferences, both here and abroad. I am proud to inform you that our funded researchers are the most recognized names in the field. They have made a personal commitment to both the Meso Foundation and the scientific community to continue this work.

Our current grant cycle recently ended, and we received applications from 39 research projects. After the peer review process, our Scientific Advisory Board submitted 10 projects to be considered for funding. In the current economic climate, we cannot fund all of these grants, and it is a shame that promising research will go unfunded this year. We are a small disease with little outside interest, and to remain a viable organization and continue funding research, we depend upon philanthropy.

Please consider donating to the Meso Foundation through our year-end fundraising campaign. Visit curemeso.org/savelives to support our research grant program, among our other vital programs and patient services. Your support saves lives!

Message to Pharma: Large Trials in Mesothelioma are Possible

Dr. Lee Krugby Lee Krug, MD, Memorial Sloan Kettering Cancer Center

This month, a notification was sent to investigators on the DETERMINE Trial that accrual will be completed by the end of October. DETERMINE is an international, randomized trial comparing treatment with an immunotherapy drug called tremelimumab to treatment with placebo as second or third line therapy in patients with malignant mesothelioma. The trial opened in May, 2013, and in just 17 months will have enrolled 564 patients! This is a notable achievement. To put this in perspective, the last phase III of this magnitude testing vorinostat in a comparable group of patients (VANTAGE Trial) took 5 1/2 years to enroll 660 patients. There are differences between these two trials that could have accounted, in part, to the more rapid accrual. In DETERMINE, 2/3 of the patients receive the study drug, 1/3 get placebo, while in VANTAGE it was half and half. Also, immunotherapy drugs such as tremelimumab have garnered tremendous excitement in the oncology field due to their promising results in numerous cancers such as melanoma skin cancer and lung cancer. Yet, despite these differences, this accomplishment of completing a trial of this size in such a short period of time should be a wake-up call to the pharmaceutical industry. Historically, drug companies have been reluctant to undertake large trials in mesothelioma due to concerns about feasibility and slow accrual. But this trial demonstrates the potential. Patients with mesothelioma urgently need better treatments, and with only one chemotherapy regimen approved, there is a tremendous opportunity to impact the outcomes for these patients. So here is the message to pharma: Large trials in mesothelioma are possible, and the community of patients with mesothelioma is eager to participate.

Lee M. Krug, MD, is an Associate Attending Physician in the Division of Thoracic Oncology, Department of Medicine at Memorial Sloan-Kettering Cancer Center in New York, New York where he completed a fellowship and chief fellowship in medical oncology. Dr. Krug is the Director of the Mesothelioma Program at Memorial Sloan-Kettering Cancer Center. Read more about Dr. Krug’s work here.

Best of iMig 2014: Day 3

Mary at iMig***The Best of iMig 2014 updates were created by iMig and distributed to conference attendees during iMig 2014. The following is a verbatim re-post of those updates.***

The Need for Early Intervention in a Heterogeneous Disease

Early detection and treatment are essential in mesothelioma
Click here to watch Dr. Jan van Meerbeeck discuss early detection

Understanding Checkpoint Inhibition in Mesothelioma

Programmed death ligand 1 (PD-L1) expression is an independent adverse prognostic factor in malignant pleural mesothelioma (MPM) – Steven C Kao
Upregulation of PD-L1 may allow cancers to evade the host immune system. We examined the association of PD-L1 expression with clinicopathological characteristics and outcomes in patients with MPM. Archival tumour samples from consecutive MPM patients undergoing pleurectomy/decortication were used to construct tissue microarrays and immunohistochemistry was undertaken using primary antibody against PD-L1. Survival was determined by Kaplan-Meier method and compared using log-rank test. Multivariate analysis was performed using the Cox regression model.  Our analysis included 69 patients (median age 65 years; 81% male; 49% epithelial subtype).  The median overall survival (OS) was months. Ten cases exhibited PD-L1 staining (14.5%) and PD-L1 expression was associated with poor survival (median OS: 4 vs. 9.2 months, p<0.001). Adjusting for gender, age and histosubtype in multivariate analyses, PD-L1 expression remained a significant adverse prognostic indicator (HR 3.5, 95% CI: 1.6-7.8; p<0.01).  These results indicate that PD-L1 expression occurred more frequently in the non-epithelial subtypes of MPM and was independently associated with adverse prognosis.

Improving immune checkpoint blockade efficacy in mesothelioma: a systems biology approach – W. Joost Lesterhuis
Antibodies blocking immune checkpoint molecules such as CTLA-4 have been to be shown efficacious in thoracic cancers, with some patients displaying durable complete regression. However, many patients do not show this positive reactivity after treatment. It is not known what molecular events govern an effective response or what the best treatments are to combine it with.  We followed two strategies to improve checkpoint blockade efficacy in preclinical models. First, we tested various cytotoxic chemotherapeutics since recently many immunopotentiating effects for these drugs have been uncovered. Second, we characterized the molecular response to anti-CTLA-4 in a subcutaneous murine tumour model, using gene expression data from responding and non-responding tumours. We subsequently identified synergistic anti-CTLA-4/drug combinations using a computational drug repurposing approach.  We found that treatment with gemcitabine chemotherapy in combination with anti-CTLA-4 blockade resulted in the induction of a potent anti-tumour immune response; and using the systems biology approach, we identified and validated in vivo several drugs that increased the response rate to anti-CTLA-4 in a synergistic manner.

Stem Cell-directed Therapy: Synergy of a Novel Combination

The Cancer Stem Cell Inhibitors VS-6063 (Defactinib) and VS-5584 Exhibit Synergistic Anticancer Activity in Preclinical Models of Mesothelioma

Dr. Mitch Keegan discusses new findings indicating synergistic effects of defactinib (VS 6063), a FAK inhibitor, and VS-5584, a potent and selective small molecule inhibitor of PI3K and mTORC1 and mTORC2, in an animal model of mesothelioma.
Click here to watch Dr. Keegan 

Social Advocacy Remains Critical for Protection against Asbestos

The Critical Role Scientists and Health Professionals Can Play to Prevent Asbestos-Related Harm: Recent Examples and Lessons Learned – Kathleen Ruff
Evidence of harm caused by asbestos has been available for many decades. Yet the asbestos industry continues to place almost 2 million tons of asbestos every year in buildings and infrastructure in developing countries. For a century, Canada was a leading asbestos producer, exporter and propagandist. Scientists can play a key part in preventing a continuing epidemic of asbestos-related diseases. They have scientific credibility to challenge the industry’s misinformation and to demand evidence-based public health policy.

Together with human rights advocates and victims groups, scientists challenged Canada’s asbestos policy. They recognized that, when scientific evidence is distorted so as to endanger health, silence is not neutrality, it is complicity. They exposed the industry’s misinformation; they challenged the double standard whereby vulnerable populations overseas were being exposed to harm; they held policy makers, particularly those with a duty to protect health, accountable; they intervened in the public policy process; they shared their expertise with the larger public thus countering the lobbying efforts of vested interests.

In a few short years, the asbestos industry lost political and public support. Consequently, in 2011, the Quebec government shut down the industry by cancelling a crucial loan.

Our experience in Canada shows how scientists and health professionals can cooperate to achieve a critically important outcome. Scientists have a responsibility to defend the integrity of science and public health policy. As the Canadian asbestos issue demonstrates, when scientists fulfill that responsibility, they can have significant impact in preventing harm.

Community Perspectives on Compensation for Asbestos-Related Diseases, including Mesothelioma, in South Africa

Current compensation systems are based on individual claims and therefore cannot address the social costs of the asbestos industry. Much remains to be done to address retrenchment, poverty, environmental contamination, gender concerns and the burden of asbestos-related disease.
Click here to watch Sophia Kisting discuss compensation for asbestos-related diseases 

A Perspective of the Importance of Science and Social Activism in Asbestos-related Disease

The asbestos industry continues to make claims clearly contrary to the wealth of data documenting the dangers associated with exposure. It is critical that scientists and clinicians be aware of these claims and take a central role in debunking them.
Click here to watch Kathleen Ruff comment on the role of scientists 

Staging and Surgery in Mesothelioma

IMIG/IASLC Staging

A reliable staging system for malignant pleural mesothelioma has been very elusive. The IMIG/IASLC, TNM Staging System has become a worldwide standard, but has limitations.
Click here to watch Dr. Jeremy Steele discuss IMIG IASLC 

North American Multicenter Feasibility Trial of Volumetric CT for the Clinical Staging of MPM

Volumetric assessment of malignant pleural mesothelioma is feasible at a research level. Translation to clinical practice may need improvement in quantitative assessment of malignant pleural mesothelioma and overcoming some of the technological limitations.
Click here to watch Dr. Ritu Gill discuss volumetric 

The Best of iMig 2014 – Comments from the Incoming President

Professor Dean Fennell, the incoming President of iMig, summarizes his views on the “Best of iMig”
Click here to watch Prof. Dean Fennell summarize the highlights 

The Best of iMig 2014 – a Final Word
iMig 2014 brought together nearly 300 scientists, clinicians, and patient advocates from around the world to Cape Town for 4 exciting days that included nearly 350 platform and poster presentations. The meeting provided a forum for sharing information about new technologies, the latest basic and clinical research findings, and how we can join together to help patients with this disease and educate all about the dangers of asbestos exposure.

This international conference was a great success and continues the work of iMig aimed at understanding and ultimately preventing and defeating mesothelioma.

To learn more about iMig 2014, read Best of iMig 2014: Day 1 and Best of iMig 2014: Day 2.

“Best of iMig 2014” has been supported by the unrestricted sponsorship of Versastem, Inc.

***The Best of iMig 2014 updates were created by iMig and distributed to conference attendees during iMig 2014. The following is a verbatim re-post of those updates.***

Best of iMig 2014: Day 2

Dr. Hassan Receives Wagner Award***The Best of iMig 2014 updates were created by iMig and distributed to conference attendees during iMig 2014. The following is a verbatim re-post of those updates.***

2014 Wagner Medalist Announced

Dr. Raffit Hassan discusses immunologic interventions in mesothelioma
Click here to watch Dr. Raffit Hassan

The 2014 winner of the Wagner Medal was Raffit Hassan. Dr. Hassan was trained in Kashmir and the United States and is currently Head, Thoracic and Solid Tumor Immunotherapy Section, Center for Cancer Research at the National Cancer Institute.  Dr. Hassan has played pivotal role in validating the tumor differentiation antigen mesothelin as a target for cancer therapy and development of mesothelin targeted immunotherapy. This work has laid the foundation for several mesothelin directed agents that he is evaluating in the clinic for treatment of mesothelioma, lung and pancreatic cancer. Dr. Hassan has published extensively in pleural mesothelioma and was recently given the Pioneer Award by the Mesothelioma Foundation.  His award lecture was focused on mesothelin-targeted therapies for the treatment of mesothelioma.

Asbestos Exposure – A Long and Troubling History

Asbestos Blues: A History of Asbestos Mining in South Africa – Jock McCulloch
Australia and South Africa are the only countries to have mined crocidolite or blue asbestos. Crocidolite was mined in the Northern Cape for one hundred years and at Wittenoom in Western Australia from 1944 until 1966. Mining has left a pandemic of asbestos disease in the Northern Cape and although production levels were modest, Wittenoom has become the site of Australia’s worst occupational health disaster. The mines of the Northern Cape also supplied the first conclusive evidence linking asbestos to mesothelioma, but discovery had no impact on the global consumption of asbestos.

Corruption is a serious problem in communities burdened by asbestos-related disease and this has justifiably bred profound mistrust of outsiders involved in asbestos compensation, research, or litigation. This corruption has involved both suppression and destruction of knowledge and this has been one of the most effective strategies employed by the asbestos industry.  The history of suppression of information documenting the dangers of asbestos exposure dates back to the 1930’s when the work of George Slade demonstrating the health effects of asbestos exposure in miners was suppressed and ultimately destroyed.  These actions contributed to the absence of any regulation at all of asbestos mining in South Africa until 1955.  In the United States, the asbestos industry actually paid researchers to claim that asbestos was not significantly associated with mesothelioma.  Corruption of science slows regulatory legislation and limits the success of litigation aimed at compensating victims.

Occasional Exposure to Asbestos: What is the Risk? – Sjaak Burgers
The question “What is the risk of occasional asbestos exposure?” has a scientific, a political and a social answer, which are all interrelated.

Data from populations with a low, occasional asbestos exposure is scarce. A search in Western Australia uncovered asbestos exposure, sufficient to cause mesothelioma in almost all cases. Whether the risk for mesothelioma and lung cancer increases linearly or has a particular threshold is still not completely clear, but the weight of evidence supports the view that even occasional asbestos exposure is related to increased risk for mesothelioma and lung cancer.  Observations supporting the view that even minimal asbestos exposure carries significant risk have provided the basis for political discussions on reimbursement for asbestos victims. These data have been used by the World Health Organization and national policy makers to set the Maximal Tolerated Risk and the Negligible Risk Level for asbestos exposure in the working environment and at home.

In the Netherlands, the same risk estimates are part of the guideline “Occasional Asbestos Exposure”. This guideline covers the laws and regulations on asbestos, and focuses on reliable quantification of the exposition, and uses the risk estimates to educate the victims about the health risks. It has proven to be helpful to ease the panic that usually accompanies the discovery of asbestos in the neighborhood.

New Molecules and New Therapies – Advancing Mesothelioma Care

Keynote, Dean Fennell presents on treatment developments for mesothelioma
Click here to watch Dean Fennell

Paul Bass summarizes evidence from studies showing specific targeting of cancer stem called by defactinib, a novel inhibitor of FAK
Click here to watch Paul Baas

Role of Focal Adhesion Kinase (FAK) Inhibition in Mesothelioma – Ravi Salfia
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays an important role in signal transduction pathways that are initiated at sites of integrin-mediated cell adhesions and by growth factor receptors. It is a key regulator of survival, proliferation, migration and invasion, all of which are all involved in the development and progression of cancer.  FAK has also been implicated in the phosphorylation of several focal adhesion associated proteins, including paxillin.  Overexpression and/or increased activity of FAK is common in a wide variety of human cancers and a large and growing body of literature has provided strong evidence that FAK has important roles in tumor formation and metastasis.

Inhibition or modulation of FAK would appear to be a potential way to treat multiple cancers, including mesothelioma. However, since FAK is a strong mediator of survival signaling, tumor cells with high levels of FAK could be more resistant against classic anti-cancer therapy. There are now multiple agents that specifically target FAK and inhibit this kinase.  Studies of FAK inhibitors in vitro and in animal models of different cancers have shown that these agents effectively decrease tumor growth, decrease invasion and metastasis, and inhibit pancreatic tumor microenvironment components, such as tumor associated fibroblasts and macrophages.  FAK inhibition also promotes apoptosis and modulates the activity of nuclear factor E2-related factor 2 (Nrf2).  The effects of FAK inhibition on Nrf2 activity may be particularly important since the Nrf2 signal pathway may function to protect cancer cells from against drug-induced cell death. Clinical trials with FAK inhibitors in patients with mesothelioma are now in progress.

Raphael Bueno presents the design of the phase II study of the new FAK inhibitor, defactinib for the treatment of patients with mesothelioma
Click here to watch Raphael Bueno

Establishing Tissue Banks to Support Mesothelioma Research

MESOBANK: A Clinicobiological Database for Epidemiological and Translational Research for Mesothelioma – Françoise Galateau-Sallé
The French Ministry of Health and the National Cancer Institute have funded the Clinico-biological database for epidemiological and translational research since 2011. The goal of this project was to collect structured data on follow-up and outcomes in order to structure a collection of samples of high quality for use in basic and translational research, to develop inter-institutional systems and to establish quality management policies.

The collaborative effort of the French Multicentic National Register network MESONAT and of the Center of Excellence MESOPATH made it possible to extend these efforts to mesothelioma by the creation of MESOBANK, a virtual and exhaustive repository of national data and samples pertaining to mesothelioma. The MESOBANK database was interconnected with that of the National Referent Center on pleural malignant mesothelioma and rare peritoneal tumors, supported by the French National Cancer Institute and is was also was closely networked with the National Program for Monitoring of Mesothelioma, the French MESONAT network and with the International Excellence Center.

The MESOBANK has gathered 7,725 mesothelioma samples (with >10,000 paraffin embedded blocks and 1,489 frozen tissue samples) from patients with certified diagnoses of mesothelioma. Assessment of these tissues has included systematic analysis of 10 immunohistochemical markers, and p16 deletion by FISH, allowing studies of sensitivity of markers for the diagnosis and prognosis of mesothelioma with a high statistical power. MESOBANK can provide support for new basic genomic and pharmacogenomic research programs to foster a better understanding of the molecular basis of mesothelioma and improved early detection and management of this disease.

MesobanK UK – An International Bioresource of Mesothelioma Tissue – Robert Rintoul
Availability of quality assured, fully annotated mesothelioma tissue collected to rigorous standard operating procedures (SOPs) to facilitate basic and translational research, is very limited. MesobanK in the United Kingdom (UK) was funded by the British Lung Foundation and Mick Knighton Mesothelioma Research Fund to provide researchers with access to a wide range of samples from patients with this disease.

The overall objectives of MesobanK are to:

  • Construct a tissue microarray (TMA) from 1000 cases of mesothelioma linked to a clinical data set.
  • Collect 300 cases of fresh mesothelioma tissue, whole blood, serum, and plasma linked to a clinical data set with follow up data from the National Cancer Registration Service.
  • Develop 20 new fully annotated mesothelioma cell lines.

MesobanK abides by all relevant United Kingdom and European Union legislation regarding the collection of tissue and data. The project is overseen by a Steering Committee and an independent Scientific Advisory Board reviews applications for samples, which are prioritized for access based solely on scientific merit.

To date, 500 of the 1000 mesothelioma case designated cases for TMA have been acquired from UK pathology departments and the TMA construction is underway. Several new cell lines are also being characterized. Quality assurance and control are being undertaken to ensure suitability for research use.

MesobanK will also act as a repository for samples collected within clinical trials.

Dr. L Mutti speaks on novel strategies and critical biomarkers for mesothelioma
Click here to watch Dr. Mutti 

To learn more about iMig 2014, read Best of iMig 2014: Day 1 and Best of iMig 2014: Day 3.

“Best of iMig 2014” has been supported by the unrestricted sponsorship of Versastem, Inc.

***The Best of iMig 2014 updates were created by iMig and distributed to conference attendees during iMig 2014. The following is a verbatim re-post of those updates.***