New Test Detects Early-Stage, Asbestos-Related Pulmonary Cancer

Researchers at NYU Langone Medical Center have investigated a novel protein test to detect early-stage, asbestos-related pulmonary cancer. The test can accurately identify proteins secreted from cancerous tumors caused by asbestos exposure.

The study was presented at the American Association for Cancer Research 102nd Annual Meeting 2011 on April 4th.

In a blinded test performed under the sponsorship of the National Cancer Institute's Early Detection Research Network Biomarker Discovery Lab, researchers detected 15 of 19 cases of stage 1 or stage 2 malignant pleural mesothelioma. The study shows the test is approximately 80 percent sensitive in identifying disease. In addition, the specificity of the test was 100 percent with no false positives.

Malignant pleural mesothelioma is an aggressive, asbestos-related pulmonary cancer that develops in the lining of the lungs. Each year, the disease causes an estimated 15,000 to 20,000 deaths worldwide. It can be fatal within 14 months following diagnosis because of the advanced stage that it is typically found.

The goal of a new diagnostic test is to find the cancer early enough to effectively treat it, according to Harvey I. Pass, MD, director of the Division of Thoracic Surgery and Thoracic Oncology at NYU Langone Medical Center and the NYU Cancer Institute.

"The only patients that seem to benefit from therapy in mesothelioma are those that are found in stage 1, and this is only 10 to 15 percent of patients," said lead researcher Dr. Pass. "Moreover, when found early, the magnitude of the operation necessary to reduce the burden of disease may be less, making the patient better able to cope if the disease recurs and the patient needs more aggressive therapy."

The research team used the "Multiplex SOMAmer Assay" by SomaLogic, Inc. to examine 170 blood samples from 90 patients diagnosed with malignant mesothelioma and 80 participants who were previously exposed to asbestos. The technology uses SOMAmers, chemically modified single-stranded DNA molecules to bind specifically to target proteins , to identify and quantify biomarkers.

According to Dr. Pass, this test measures 19 protein biomarkers for malignant pleural mesothelioma and is able to find and quantify the small amount of proteins secreted by tumor cells. Ongoing studies are refining the test and validating the results in other patient blood samples.

Scientists Aim to Kill Lung Tumors

Enzyme regulates the division of tumour cells and blood vessel growth in the cancer tissue.

Lung cancer is the leading cause of cancer death throughout the world. Standard treatment methods do not usually result in long-term recovery. In addition to the proliferation of the tumour cells, the growth of blood vessels controls tumors development. The blood vessel growth is controlled by several signalling molecules. Scientists from the Max Planck Institute for Heart and Lung Research in Bad Nauheim and Justus Liebig University Giessen have discovered a molecule that plays a key role in this process. They succeeded in reducing tumour growth in their experiments by blocking the phosphodiesterase PDE4.

Lung cancer mainly affects smokers; however the disease can also be caused by contact with carcinogenic substances like asbestos. Chemotherapy or radiotherapy often prove insufficient in treating the disease. Hence, scientists are engaged in an intensive search for ways of halting the growth of lung tumours. The blood vessels that supply the tumour with nutrients offer a potential point of attack.

New blood vessels form to ensure an adequate supply of nutrients to the growing tumour. The growing tissue is immediately penetrated by blood vessels. The growth of the blood vessels is regulated by the tumour cells using a complex signal cascade, which is triggered initially by a low oxygen content (hypoxia) in the tumour tissue. "This state, which is known as hypoxia prompts the activation of around 100 genes in the tumour cells," explains Rajkumar Savai, research group leader at the Max Planck institute. "In addition to the growth of blood vessels, hypoxia also stimulates the proliferation of lung cancer cells." Three molecules play a particularly important role in this process. The activation of the genes at the beginning of the cascade is triggered by the transcription factor HIF and a messenger molecule, cAMP, is involved again at the end of the cascade. The researchers examined the third molecule that acts as a link between these two molecules in detail.

The molecule in question is a phosphodiesterase, PDE4. The scientists from Bad Nauheim and Giessen were able to demonstrate in their study that various sections of PDE4 have binding sites for HIF.

The researchers then tested the influence of a PDE4 blockade on the cells from ten different cell lines, which are characteristic of around 80 percent of lung cancers, in the laboratory. The rate of cell division in the cells treated with a PDE4 inhibitor was significantly lower and the HIF level also declined as a result.

The effect in the tumour bearing mice was particularly obvious. To observe this, the Max Planck researchers implanted a human tumour cell line under the skin of nude mice and treated the animals with the phosphodiesterase 4 inhibitor. Tumour growth in these animals declined by around 50 percent. "Our microscopic analysis revealed that the blood vessel growth in the tumours of the mice that had been treated with the inhibitor was significantly reduced. We also observed indicators of decelerated cell division in the tumour cells. Overall, the tumour growth was strongly curbed."

Werner Seeger, Director of the MPI and Medical Director of the JLU University Hospital Giessen, reports: "We were able to show that PDE4 plays an important regulation function in cell division in lung tumours and in the development of blood vessels in cancer. Therefore, we hope that we have found a starting point for the development of a treatment here." In the view of tumour specialist Friedrich Grimminger, Chairman of the Department of Medical Oncology in Giessen, it may be possible in future to combine the inhibition of PDE4 with traditional radiotherapy or chemotherapy. In this way, the effect of the traditional treatment measures could be reinforced and patient prognoses may improve as a result. However, further laboratory studies are required before clinical tests can be carried out.

Deaths and Major Morbidity from Asbestos-Related Diseases in Asia Likely to Surge in Next 20 Years, Experts Warn

An alarming new article in Respirology issues a serious warning of massive rises in deaths from asbestos-related lung diseases in Asia.

Dr Ken Takahashi, Acting Director of the WHO Collaborating Center for Occupational Health, and his team put together important data on asbestos use in 47 Asian countries in this landmark article. Cyprus, Israel and Japan had the highest age-adjusted mortality rates in Asia. This study published in Respirology, a journal of the Asian Pacific Society of Respirology, will serve as an important reference document for health authorities in Asian-Pacific.

Asian countries accounted for 64% of the global consumption of asbestos in the period of 2001-2007, a striking increase from 14% between 1920 and 1970. This is a result of unregulated asbestos import and use in many Asian countries.

"Despite concerns of the global ARD epidemic and Asia's growing importance in the world, data on current asbestos use and asbestos related diseases in Asia remain limited," said Dr. Ken Takahashi. This article extracted data from the WHO Mortality Database and published literature and will inform public health planning and regional health policies in Asian countries.

The WHO identifies asbestos as one of the most dangerous occupational carcinogens, declaring the need to eliminate asbestos use and associated health damages. An estimated 107,000 people worldwide die from asbestos related diseases. Asbestos is a mineral fiber commonly used for insulation in constructions. It is relatively affordable and makes it attractive in developing countries.

Asbestos related lung diseases, particularly mesothelioma, lung cancer and asbestosis (asbestos induced lung fibrosis), typically develop after decades of lag time from first exposure. Up to 2007, Asian patients accounted for 13% of the cumulative global mortality from asbestos-related pleura-pulmonary diseases. Dr. Takahashi is concerned that "the sharp increase in asbestos use in Asia will see a surge of mortality and morbidity from asbestos related diseases in this region in the decades ahead."

This article will serve as a stern warning for Asian governments who have yet to ban the use of asbestos. Healthcare providers in Asia must also begin to equip themselves the expertise and resources to manage this 'Asian asbestos tsunami.'

Promising Developments in Early Diagnosis and Treatment of Mesothelioma

New results presented at 3rd European Lung Cancer Conference in Geneva, Switzerland show important steps being made to improve the diagnosis and treatment of malignant pleural mesothelioma, an aggressive cancer of the outer lining of the lungs caused by asbestos exposure.

Micro RNAs speed diagnosis

Australian researchers have identified a small molecule that is more abundant in the blood of people with the deadly lung disease mesothelioma than in healthy people. Their findings bring scientists a step closer to being able to diagnose mesothelioma earlier than is currently possible.

At present diagnosing mesothelioma depends on the availability of a lung biopsy that contains enough tumor tissue. However suitable biopsies are not always available, which can leave doctors uncertain about the patient's diagnosis, sometimes resulting in a delay to the start of treatment. "If doctors could use a diagnostic marker based on a simple blood test to help with diagnosis, it could circumvent the problem of availability of tumor tissue and help to accelerate the diagnostic process," says Dr Michaela Kirschner from the Asbestos Diseases Research (Concord Hospital Campus) in Sydney, who reported the new findings.

So far a number of proteins have been proposed as blood-based markers for malignant pleural mesothelioma; however none of these has so far reached the accuracy required for routine clinical use.

In the new study, Dr Kirschner and colleagues explored whether molecules known as microRNAs in blood could serve as a diagnostic marker for the disease. Studying 5 patients with malignant pleural mesothelioma and 3 healthy controls, they identified 17 microRNAs with significantly differential abundance in the two groups. They then validated these miRNAs in a series of blood samples from 15 patients and 13 controls. These studies revealed that the level of a particular microRNA known as miR-625-3p was four-fold higher in the blood of mesothelioma patients.

Measuring levels of that molecule in blood samples allowed the researchers to discriminate between MPM patients and controls with an accuracy of 82.4%.

"Detailed analyses of our two independent sample series have shown that miR-625-3p performs as well as any previously proposed protein marker for detecting mesothelioma," Dr Kirschner said. "However, like most diagnostic markers, miR-625-3p is not 100% accurate, and therefore there is a chance the assay will produce both false positives as well as false negatives. Further studies on larger sample sizes are needed to see whether the accuracy of miR-625-3p can be confirmed or even turn out to be better than currently observed."

"Should further studies prove that microRNAs in plasma are accurate enough for the diagnosis of malignant pleural mesothelioma, this will lead to the development of a diagnostic test for routine clinical use," Dr Kirschner said. "This test would then represent a relatively simple way to circumvent the problems associated with obtaining a tissue biopsy. For a patient this would mean that appropriate treatment could be instituted at an earlier stage."

High-dose radiotherapy gives good response rates

Despite a widespread belief that mesothelioma does not respond to radiotherapy, Australian researchers have found that it may have the best response rates of any single treatment for patients with disease largely confined to one side of the chest.

Between 2003 and 2011, Dr Malcolm Feigen and colleagues from Austin Health Radiation Oncology Center in Melbourne gave radiotherapy to 45[1] patients aged 45 to 74 with doses of between 45 and 60 Gy to one side of the chest over six weeks. The radiation was administered using 3D-conformal or intensity-modulated radiotherapy. None had surgery to remove their affected lung. At the beginning of treatment more than 80% of patients had the more advanced stage III or IV disease, and all had prior chemotherapy and/or surgery, except for two.

The median survival for the patients was 12.4 months from starting radiotherapy, ranging from 2 to 87 months, the researchers say. There were no life-threatening or fatal toxicities from treatment.

"Many believe mesothelioma to be radioresistant and that toxicity is prohibitive if high doses are given with the affected lung in situ," Dr Feigen and colleagues say.

"Our experience provides clear evidence that radiation is arguably the most effective single agent for mesothelioma and new technologies including intensity-modulated radiotherapy allow high doses to be delivered safely."

Blood markers identified

Swiss, Italian and US researchers report that they have tested another group of potentially useful blood markers for mesothelioma.

Dr Ferdinando Cerciello from the Swiss Federal Institute of Technology and the University Hospital Zurich and colleagues studied 56 candidate biomarker peptides that they isolated from laboratory samples of mesothelioma and tested in the blood of patients with mesothelioma, healthy donors and non-small-cell lung cancer patients.

The study "revealed potential candidate biomarkers in serum, accessible simultaneously by mass spectrometry," the authors report. At the meeting, they will report the strategy for the selection and measurement of their 56 peptides in serum as well as the results of an evaluation in 75 blood samples.

Sorafenib well tolerated

The drug sorafenib is well tolerated in patients with mesothelioma after completion of platinum containing chemotherapy, British investigators report.

In a phase II trial of sorafenib following first-line chemotherapy in 53 patients with malignant mesothelioma, 34% of patients were progression-free after six months.

Dr Sophie Papa and Dr James Spicer from Kings College London and colleagues say that the drug was well tolerated and offered a length of progression-free survival that "compares favorably" to other targeted agents in this disease.

"Mesothelioma, one of the most important occupational diseases, is attracting more and more attention nowadays," noted Prof Paul Baas from the Department of Thoracic Oncology at The Netherlands Cancer Institute, member of the ESMO Chest Tumors Faculty Group. "New developments in the diagnostics and treatment of this disease are really important, including those presented during the ELCC 2012 meeting: improvements in the diagnosis by simply measuring biomarkers in peripheral blood samples will identify patients who may be candidates for new studies or financial reimbursement by their employers. The developments in molecular biology allow us now to detect circulating fragments of (micro)RNA and peptides that may play an important role. Furthermore the understanding that radiation therapy and targeted agents can be given to these patients will lead to new, promising, studies."

Possible Vaccine for Mesothelioma Proven Safe

Researchers have demonstrated the safety of a potential vaccine against mesothelioma, a rare cancer associated primarily with asbestos exposure. The vaccine, which infuses a patient's own dendritic cells (DC) with antigen from the patient's tumor, was able to induce a T-cell response against mesothelioma tumors.

"[This] is the first human study on DC-based immunotherapy in patients with mesothelioma," wrote Joachim G Aerts M.D., Ph.D., a pulmonary physician at Erasmus Medical Center in the Netherlands.

The findings have been published online ahead of print publication in the American Thoracic Society'sAmerican Journal of Respiratory and Critical Care Medicine.

The U.S. and other developed countries have prohibited the use of asbestos for decades, but the time between asbestos exposure and diagnosis of mesothelioma can be up to 50 years. The incidence of mesothelioma, therefore, is still on the rise and expected to continue to increase until 2020. Once diagnosed, mesothelioma has a median survival time of 12 months. The standard chemotherapeutic treatment only improves survival time by about three months.

The anticipated increase in the incidence of mesothelioma, together with the paucity of treatment options, has spurred considerable interest in the development of new therapies. Immunotherapy, which uses the body's own immune system to target and destroy cancer cells, has been shown to have some promise.

"The possibility to harness the potency and specificity of the immune system underlies the growing interest in cancer immunotherapy," said Dr. Aerts. "One such approach uses the patient's own DC to present tumor-associated antigens and thereby generate tumor-specific immunity."

Building upon their previous research which demonstrated that DC vaccinations induced anti-tumor immunity and conferred a survival benefit in mice, Dr. Aerts and colleagues sought to test the clinical relevance of their finding. After recruiting 10 human patients recently diagnosed with malignant pleural mesothelioma of the epithelial subtype, they cultured immature DC from their blood and exposed the DC to the antigen produced by the patients' tumors. The DC were also exposed to keyhole limpet hemocyanin (KLH), which was used as a surrogate marker to show an immune response. The DC were then matured and injected back into the patients in three doses over a two-week interval.

Serum samples from all patients showed a significant increase of pre- versus post-vaccine antibodies to KLH. In the four patients whose tumor material was sufficient for testing, there was clear induction of cytotoxicity against their own tumors after vaccination. Three patients showed signs of tumor regression, though this could not be conclusively or directly attributed to the vaccine.

Encouragingly, while eight of the patients developed flu-like symptoms in response to the vaccinations, the symptoms normalized after one day in all but one of the patients. There were no signs of autoimmune diseases in the patients provoked by the vaccination, nor other serious side effects.

"The major problem in mesothelioma is that the immunosuppressive environment caused by the tumor will negatively influence our therapy so we are now working on a method to lower this immunosuppressive environment," said Dr. Aerts. "We hope that by further development of our method it will be possible to increase survival in patients with mesothelioma and eventually vaccinate persons who have been in contact with asbestos to prevent them from getting asbestos related diseases."

Mouse Model For Mesothelioma Reproduces Human Disease

Scientists have established a mouse model for human malignant mesothelioma  that will provide valuable insight into cancer development and progression along with new directions for design of therapeutic strategies. The research, published by Cell Press in the March issue of Cancer Cell, may eventually lead to a substantially improved outlook for patients with this devastating disease.

Malignant mesothelioma  is an aggressive cancer originating from the mesothelial lining of the pleural cavity. Malignant mesothelioma  is associated with asbestos exposure and is characterized by a long latency period between exposure and disease onset. Chemotherapy can sometimes lead to improvement of overall survival but there is no cure for malignant mesothelioma and patients often succumb from the disease within a year of diagnosis. "There is an urgent need for experimental models of malignant mesothelioma  that can be used to not only study the onset and progression of the disease, but also to serve as a model to select new combination therapies and targeted agents," says study leader, Dr. Anton Berns, from The Netherlands Cancer Institute.

In humans, malignant mesothelioma  has been associated with genetic lesions that result in the loss of Neurofibromatosis type 2 (NF2) and genetic lesions affecting RB and P53 pathways. Dr. Berns' team investigated whether a range of conditional single or compound mutations in the Nf2, p53 and Rb pathways within the mesothelial lining of the thoracic cavity would cause malignant mesothelioma in mice.

The researchers found that the vast majority of mice with conditional Nf2;Ink4a/Arf and Nf2;p53 mutations developed MM after a short latency period. The mouse malignant mesothelioma  tumors, which could be followed noninvasively through the use of bioluminescence imaging, closely resembled human MM. Interestingly, Nf2;Ink4a/Arf knockout mice had a more invasive cancer when compared with Nf2;p53 knockout mice. The researchers went on to show that the loss of Ink4a makes a substantial contribution to the poor clinical outcome of murine malignant mesothelioma .

These results describe an excellent model system for investigating the molecular mechanisms that underlie malignant mesothelioma . "Our mouse models should be suitable to further dissect pathways critically important in mesothelioma development and progression and serve as invaluable tools to test new intervention strategies," concludes Dr. Berns. "We have also derived a series of cell lines that reproduce the disease when grafted into the thoracic cavity. These may also facilitate design of better MM therapies."

The researchers include Johan Jongsma, Erwin van Montfort, Marc Vooijs, John Zevenhoven, Paul Krimpenfort, Martin van der Valk, Marc van de Vijver, and Anton Berns, of The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Journal reference: Berns et al.: "A Conditional Mouse Model for Malignant Mesothelioma". Cancer Cell, Vol 13, 261-271, 11 March 2008.

Renal Cancer Drug Temsirolimus Shows Promise Against Mesothelioma

 A drug commonly used to treat kidney cancer may increase the effectiveness of chemotherapy for mesothelioma, according to a study published in the May issue of the Journal of Thoracic Oncology.

Temsirolimus, a kinase inhibitor, blocks the action of mammalian target of rapamycin (mTOR), a protein that regulates cell growth, which can slow tumor growth. It's used to treat advanced renal cell carcinoma.

But researchers in Austria have found that temsirolimus also may slow the growth of malignant pleural mesothelioma cells. Mesothelioma, a cancer that is usually caused by exposure to asbestos and may not appear until 30 to 50 years after exposure, frequently resists chemotherapy and radiation treatment.

The researchers found that temsirolimus strongly blocked mTOR-mediated signals and had a cytostatic, or growth-stopping, effect on all mesothelioma cells. However, mesothelioma cells that were resistant to cisplatin, a widely used chemotherapy drug, showed hypersensitivity against temsirolimus.

That suggests that mTOR inhibitors like temsirolimus might be a promising treatment strategy either in combination with chemotherapy or as second-line treatment after chemotherapy failure.

"Malignant mesothelioma is a severe human malignancy characterized by a very bad prognosis, with a mean patient survival time of less than one year," said Professor Walter Berger, PhD, of the Institute of Cancer Research at the Medical University of Vienna. "This unacceptable situation is mainly caused by late diagnosis combined with a distinct resistance to all forms of systemic therapy available so far. Mesothelioma is frequently caused by asbestos exposure and unfortunately -- based on the long latency period -- the incidence peak lies, despite the ban on asbestos, still ahead. Consequently, novel therapeutic options for this devastative disease are urgently needed.

"In our preclinical study, published in the JTO, we were able to demonstrate that inhibition of the major oncogene mTOR is active against human mesothelioma especially after development of chemotherapy resistance both in vitro and in vivo," Berger said. "These results suggest the initiation of clinical trials involving mTOR inhibitors as a novel anti-mesothelioma strategy."

The study was supported by the Medical Scientific Fund of the Mayor of the City of Vienna, Initiative Krebsforschung of the Medical University Vienna, and a Wyeth/Pfizer research grant.