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.***

Best of iMig 2014: Day 1

CocktailReception***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.***

In the opening plenary session of iMig 2014, Dr. Jim te Water Naudé and Dr. Steven Mutsaers welcomed close to 300 healthcare professionals to Cape Town, South Africa.

It’s an impressive number of attendees for this somewhat remote but beautiful venue and given iMig’s membership of around 500 members. The assembled group comprises the finest minds in mesothelioma related research, treatment, and advocacy from around the world. It’s quickly evinced as a heavily scientific affair with a fun spirit as Dr. te Water Naudé jokingly threatens to use a vuvuzela horn on speakers who defy their time restrictions.

The initial plenary session focused on several areas of interest to the broad range of delegates traveling to iMig. The opening plenary speakers’ presentations are outlined below as are several key presentations chosen by iMig peers as the “Best of iMig 2014”.

Dr. Constantine Alifrangis Speaks on Next Generation Sequencing in Mesothelioma 
Click here to watch Dr. Alifrangis’s Presentation
Dr. Constantine Alifrangis focused on the study of cancer genomes and how it might be used to identify new treatments and individualize care for patients with mesothelioma. These approaches have identified specific genomic alterations in mesothelioma associated with unexpected drug sensitivities in mesothelioma. As for other cancers, study of cancer genomes in mesothelioma has the potential to guide development of novel therapies for this disease. Click here to hear and see more about this work.

Dr. Ravi Salgia presents “From Chaos to Mitochondrial Functionality” 
Click here to watch Dr. Salgia’s Presentation
Dr. Salgia summarized efforts from his group to bring mathematical modeling to the study of malignant mesothelioma and how the rules of this theory can be applied to consideration of mutations associated with mesothelioma, suggesting that DNA acts much likes fractals. He emphasized that the fractal dimensionality of mesothelioma cells is dramatically different from that of normal cells and that mitochondrial networks in mesothelioma can also be modeled with fractal analysis. Click here to learn more about this new approach to understanding mesothelioma and the biology of other cancer cells.

Dr. Robert Weinberg speaks on Cancer Stem Cell Targeting Therapies 
Click here to watch Dr. Weinberg’s Presentation
Dr. Weinberg focused on the importance of cancer stem cells in mesothelioma. The concept of a stem cell origin of cancer was first described over fifty years ago as a small subset of cells capable of re-initiating a clonal tumor, and there is evidence for both a stem cell origin of mesothelioma, and a stem cell population in the mesothelioma tumor microenvironment. These cells play an essential role in the invasion-metastasis cascade, they are risk to conventional chemotherapy,and are believed to underlie resistance and relapse in mesothelioma. Click here for a summary of the latest information on cancer stem cells in mesothelioma.

Laurie Kazan-Allen Presents on The Global Asbestos Landscape 
Click here to hear Ms. Kazan-Allen’s Presentation
Ms. Kazan-Allen emphasized that the battle with mesothelioma is being fought on two fronts: countries where asbestos has been banned and those in which consumption remains legal. In 2014 the asbestos dialogue has become a mainstream discourse encompassing fundamental matters such as human rights, public health, social justice and economic sustainability. Decisions about asbestos use must now be driven by political, social and environmental considerations, not just economics. Click here for a detailed discussion of these critical issues and the “asbestos war”.

Improving outcomes in mesothelioma: an international approach to meeting nurses’ educational needs
Click here for Liz’s Commentary
Effective management of patients with mesothelioma requires large cadres of well-trained nurses in parts of the world in which the incidence of disease is high. The United Kingdom has >2,500 cases of mesothelioma diagnosed each year and nursing education is critical for optimizing care for these individuals. The Royal Marsden School of Cancer Nursing and Rehabilitation in cooperation with Mesothelioma UK has developed an accredited interactive on-line accredited mesothelioma course to help meet this need. The course can be taken by undergraduates and graduate students.

The content of this course is tailored to meet the needs of international students and the curriculum includes two introductory, nine didactic, and three practically focused weeks of training. Content delivered by expert faculty includes global asbestos consumption, signs and symptoms of mesothelioma, diagnosis, treatment, symptom management, and medico legal issues. Patient and carers perspectives and end-of-life issues are also addressed in detail. The course content is focused on the diagnosis/treatment journey of the patient with mesothelioma.

To date, the course has been delivered 5 times to a total of 56 healthcare professionals have completed the course including several international students from Australia, South Africa, Japan, Ireland, and the United States. The course received a Quality in Health Care award in 2012. Two former course participants have gone on to develop similar educational programs in their own countries.

Courses similar to that described in this summary have been established in Australia and Japan.

Nursing collaborations, such as this online educational program, can help fill important gaps in meeting the health care needs of those affected by asbestos- related disease.

Clinicopathological features of patients with malignant mesothelioma in a multicenter, retrospective study – Dr. Manlio Mancoboni 
Dr. Mencoboni and his colleagues have focused on understanding factors that predict outcomes for patients with mesothelioma. They carried out a retrospective analysis of 235 patients with mesothelioma who were treated at 4 centers in Italy. These patients were typical of the larger population with mesothelioma: 76.6% were males and they were generally elderly with a median age of 69.6 years. Tumor histology was epitheliod in 82.6% and sarcomatoid in 4% of the cohort.

The treatment histories for these patients were also typical of those for patients with mesothelioma. Surgery was carried out in 20.4% of patients and radiotherapy was performed in 39.6%. In addition, 9.3% of patients underwent trimodal treatment. First-line chemotherapy was administered to 98.3% of the patients in the study cohort and 78% receive pemetrexed-based chemotherapy was administered to 78%. Overall, 68% of patients received second-line chemotherapy and 27% received third-line treatment.

The overall median survival for the patients study was 22.0 months and 19% survived for >36 months. Prognostic factors for survival were identified with univariate and multivariate analyses. Factors significantly associated with survival in univariate analysis were younger age, better performance scores, receipt of radiotherapy or surgery, epithelioid histology, and best response to first-line chemotherapy.

Multivariate analysis confirmed significant independent influences for younger age, surgery, sarcomatoid morphology (shorter survival), and first-line chemotherapeutic treatment (shorter survival vs best supportive care, but only for patients with a poor response to this treatment). 

Neoadjuvant Therapy and Surgery- Dr. Raphael Bueno 
Standard therapy for malignant pleural mesothelioma (MPM) has not advanced significantly in the past 10 years and new approaches to treatment are needed. Results from genomic studies indicate that mesothelioma is not a “disease of mutations” and those associated with disease are well known. These studies have shown that MPM is associated with changes in copy number, most often recurrent loss. Biological agents are being developed that can have significant activity in specific cancers based on mutation or other aberrant patterns and several have demonstrated significant activity in animal models and early phase clinical studies. There is an urgent need to rapidly evaluate these agents and identify biomarkers predictive of clinical responses. An attractive cohort for studies of this type is pre-operative with lower disease burden, availability of tumor for biomarker analysis, and the potential for standardization of prognostic markers. This approach is currently being taken with defactinib, a potent inhibitor of focal adhesion kinase in a biomarker-driven study with safety and pharmacokinetics with as secondary end points. Patients enrolled in this study have histologically confirmed MPM that is not metastatic or unresectable and are eligible to undergo excisional surgery such as extrapleural pneumonectomy or pleurectomy/decortication or any other mesothelioma surgery. Additional agents that might be evaluated in this should have:

  • Rational targets predictive of efficacy in MPM based on preclinical studies
  • Demonstrated activity in phase 1 trials
  • No toxicities that may complicate surgery (e.g., pneumonitis)
  • No requirement for significant delay in surgery
  • Comprehensive biomarker analysis
  • No significant impact on local hospital approach to patient management

Carrying out multicenter studies of this type will permit rapid evaluation of novel therapies and advance improvement of clinical outcomes for patients with MPM.

Tremelimumab at an optimized dosing schedule in second-line mesothelioma patients: a phase 2 single-arm study – Dr. Luana Calabro 
Dr. Calabro reported results from the MESOT-TREM-2012 study, a second-line, single arm, phase 2 clinical study with tremelimumab, a fully human anti-CTLA-4 monoclonal antibody, as monotherapy in patients with unresectable malignant mesothelioma.

In this trial, 29 patients with malignant mesothelioma patients progressing on a first-line platinum-based regimen received tremelimumab at 10 mg/kg on day 1, every 4 weeks for 6 cycles, then every 12 weeks until progressive disease or severe toxicity. Primary endpoint was objective response rate (ORR); and secondary endpoints included disease control rate (DCR), overall survival (OS), and safety. Tumor assessment per immune-related RECIST was done at screening and every 12 weeks.

Patients enrolled had a median age of 65 years; 11 had stage III and 18 had stage IV disease. Eastern Cooperative Oncology Group performance status was 0-1 or 2 in 23 and 6 patients, respectively. Twenty-one patients had epithelioid histotype, 6 biphasic, 1 sarcomatoid, and 1 undefined. Patients received a median 6 doses of tremelimumab (range 1-11) and were followed for a median of 16.5 months.

Study results indicated 4 partial responses and 11 patients had stable disease resulting in a DCR of 51.7%. Study results also indicated a delayed response to tremelimumab treatment in some patients. The median OS was 11.5 months. Grade 1-2 and 3-4 treatment-related adverse events occurred in 89.6% and 6.8% of patients, respectively. The most common treatment-related adverse events were gastrointestinal, dermatologic and fever. Adverse events generally resolved with steroid treatment.

To learn more about the conference, read Best of iMig 2014: Day 2 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.***

Wednesday Update from iMig Conference

Mary Hesdorffer, NP, the executive director of the Meso Foundation is in attendance at the International Mesothelioma Interest Group (iMig) conference in Cape Town, South Africa. Mary has sent the following photo updates from Wednesday at the conference.

Cocktail Reception

The entertainment at the cocktail reception.

Dario Barbone, PhD

Dario Barbone, PhD, shared that he will be submitting a grant for consideration to the NCI next week. He credits the Meso Foundation’s grant for providing the funding that permitted him to carry out experiments from which the resulting data can be used in applying for larger grants. We will continue to update you on the careers of these young scientists who are the future of mesothelioma research.

Joe Friedberg and Melissa Culligan

Joe Friedberg, MD, and Melissa Culligan, BSN, RN, are in attendance.

Melissa Culligan

Melissa Culligan, BSN, RN, was the only nurse invited to present in the surgical session. Congratulations for a thoughtful presentation.

David Schrump, MD

David Schrump, MD, head of the Thoracic and Gastrointestinal Oncology Branch at the National Cancer Institute, seen during the poster discussion session.

Mary Hesdorffer to Present at iMig Conference This Week

Mary Speaking at 2013 SymposiumMary Hesdorffer, MS, APRN-BC, the executive director of the Meso Foundation, will be presenting at the 12th International Mesothelioma Interest Group (iMig) Conference in Cape Town, South Africa this week. iMig is an international group of scientists and clinicians working to understand, cure, and prevent mesothelioma. iMig presents an important conference that brings together mesothelioma professionals from around the world to discuss the current state of research and advancements in the field.

Mary is chairing a nursing panel and she will give two presentations at the conference. The first presentation, titled “The Voice of the Meso Community in the United States,” will discuss how the Meso Foundation, with the help of community members, advocated for $9.3 million in federal research funding directed to mesothelioma research since 2008. Mary’s second presentation is title “Promoting Entry into Clinical Trials and Improving Access to Specialist Treatment and Care.”

Mary is a nurse practitioner with over 16 years of experience in mesothelioma treatment. She is an expert in clinical trials for mesothelioma and her work has been published in a variety of scientific journals. Mary serves as the executive director of the Mesothelioma Applied Research Foundation.

Chicago Conference Photos Now Available

Panel at Chicago ConferenceThe 2014 Chicago Regional Conference on Malignant Mesothelioma was held on Friday, October 10 at the Palmer House Hilton in Chicago, Illinois. The conference was a collaborative effort between the Mesothelioma Applied Research Foundation and The University of Chicago Medicine.

Topics of discussion were presented by area experts in the field of mesothelioma and geared towards patients, caregivers, family members, and general health practitioners. These topics included imaging, genetics, surgery, chemotherapy, novel treatments, stem cells, immunotherapy, and resources for patients and families.

The conference was chaired by Mary Hesdorffer, MS, APRN-BC, the executive director of the Meso Foundation, and Hedy Lee Kindler, MD, a Professor of Medicine at the University of Chicago and Director of the mesothelioma and Gastrointestinal Oncology Programs at the University of Chicago Medicine.

All of the Meso Foundation’s photos from the Chicago conference are now available on the Foundation’s Facebook page.