Mesothelioma, lung cancer, pneumonia, asbestos, acute, bronchitis, pain, skin

Mesothelioma, lung cancer, pneumonia, asbestos, acute, bronchitis, pain, skin

chitika

Sunday 29 September 2013

Novel Blood-Based Protein Signature Determined for Rare, Aggressive Lung Cancer

Malignant mesothelioma is a rare, aggressive form of lung cancer that can develop after prolonged exposure to asbestos. Because early diagnosis is difficult, most patients face a poor prognosis and have few options for treatment. In the study, authors compared proteins in the blood of asbestos-exposed individuals without the disease to blood proteins in asbestos-exposed mesothelioma patients to identify 13 proteins that are linked to the disease, including in the early stages.

According to the researchers, the discovery of the new blood-based proteins linked to the disease could help to develop better, less invasive diagnostic tests to detect the disease at earlier stages.

"By measuring changes in blood concentration of a series of proteins we can potentially catch mesothelioma at an earlier stage," said Ostroff, Clinical Research Director at Soma Logic. "Our efforts are now focused on further development of this approach, and how best to get it rapidly into clinical use for the sake of individuals who can benefit from earlier detection of this devastating disease."

High Levels of Blood-Based Protein Specific to Mesothelioma

"This gene produces a protein, fibulin-3, that is present in levels four to five times higher in the plasma of patients with mesothelioma compared to levels in asbestos-exposed patients or patients with several other conditions that cause tumors in the chest," said lead investigator Harvey I. Pass, MD, the Stephen E. Banner Professor of Thoracic Oncology, vice chair of research for the Department of Cardiothoracic Surgery and division chief of General Thoracic Surgery at NYU Langone Medical Center. "We didn't know anything about this protein's role in mesothelioma before this study, but it may be an extremely useful tool for monitoring patients under treatment and possibly even diagnosing the development of mesothelioma at early stages. This marker is as exciting as any bio-marker in mesothelioma today and warrants further research and validation by the scientific community."

The study appears in the October 11 issue of the New England Journal of Medicine.

Malignant mesothelioma is a rare but aggressive thoracic cancer that can develop several decades after exposure to asbestos. Diagnosis is often delayed until patients begin to show symptoms, including shortness of breath, cough, chest pain and, in advanced stages, weight loss and night sweats.

Often, patients with mesothelioma seek treatment when the shortness of breath becomes a noticeable problem. At that point, an x-ray typically reveals fluid in the chest, but many doctors fail to inquire about asbestos exposure upon receiving this report. Rather, doctors initially associate fluid in the chest with pneumonia or other inflammatory conditions, further delaying diagnosis, Dr. Pass explained.

Despite advances in chemotherapy, radiation therapy, and surgical management for malignant mesothelioma, the median survival for patients diagnosed with mesothelioma remains 12 months.

"There is a great need for something -- some marker or test -- that will heighten the alarm that a patient presenting with new onset chest fluid could have mesothelioma," Dr. Pass said. "Our findings indicate that a simple blood test may lead physicians to ask questions about asbestos exposure and consider whether the medical history and symptoms are compatible with mesothelioma."

Dr. Pass and his team are dedicated to finding diagnostic bio-markers -- genes, proteins or other molecules -- that are not only different in people with mesothelioma compared with cancer-free individuals who have been exposed to asbestos, but also different when compared to individuals with a variety of conditions that could cause fluid in the chest other than mesothelioma.

Fibulin-3 is a protein that floats around outside cells, coating the cells and free floating in blood plasma and extracellular fluid. For the current study, the research team compared levels of fibulin-3 in two separate cohorts of patients who were exposed to asbestos through their jobs: a group of iron workers and other asbestos-exposed individuals in Detroit, and a group of insulators in New York. Both cohorts included individuals who had been exposed to asbestos but did not develop mesothelioma, as well as individuals with a confirmed mesothelioma diagnosis. The researchers found that fibulin-3 expression was markedly elevated in the plasma of the patients with mesothelioma compared with the plasma of patients without mesothelioma. But the researchers wondered if maybe the elevated fibulin-3 levels were associated with other conditions, in addition to mesothelioma, that are associated with the development of chest tumors.

To test how specific the over-expression of fibulin-3 is to mesothelioma, they compared levels of the protein in the plasma of patients with mesothelioma to the plasma levels of the protein in patients afflicted by a variety of different types of cancer resulting in tumors in the chest -- individuals without mesothelioma, but with conditions that "look like mesothelioma," Dr. Pass said. They found that fibulin-3 also discriminated between non-mesothelioma patients with different kinds of chest-tumor cancers and patients with mesothelioma, confirming high specificity for mesothelioma and not for conditions that "look" like mesothelioma.

To validate their results, the researchers then performed a blinded study with another cohort of patients from Toronto, Canada for whom plasma fibulin-3 was measured, but the researchers had no knowledge of whether the individuals had mesothelioma or not. Based on the fibulin-3 levels, the researchers were able to differentiate the mesothelioma from the non-mesothelioma with high accuracy.

In addition, the researchers discovered that post-surgery levels of fibulin-3 were drastically decreased compared to pre-surgery levels in mesothelioma patients in whom the mesothelioma was removed. In selected cases of recurrence, the fibulin-3 level rose, hinting that the marker may be useful for monitoring treatment effects.

"This marker is as good, if not better, in terms of sensitivity and specificity than other known markers for mesothelioma, and its level in mesothelioma chest fluid appears to have prognostic implications," Dr. Pass said. "Moving forward, an international effort to validate these findings is needed, as well as an effort to understand whether this marker can diagnose mesothelioma prior to the development of symptoms in high-risk individuals. This needs to be performed prospectively in a well-defined high-risk for mesothelioma cohort."

Mesothelioma Drug Slows Disease Progression in Patients With an Inactive NF2 Gene

Mesothelioma, which is usually caused by exposure to asbestos, has few treatment options and patients usually die within 9-17 months of diagnosis. Previous research has shown that the gene NF2, which produces a protein called Merlin, is frequently inactivated in approximately 50% of mesothelioma. Merlin negatively regulates another protein called focal adhesion kinase (FAK) in mesothelioma, and so when NF2 and merlin are inactivated, the activity of FAK is increased and mesothelioma cells become invasive and start to spread. When NF2 and Merlin activity is restored, FAK activity and cell invasion are decreased.

Professor Jean-Charles Soria, Professor of Medicine and Medical Oncology at South Paris University and head of early drug development at the Institute Gustave Rossy in Paris (France), said: "This suggested that if we could inhibit FAK in mesothelioma patients, it might slow or stop the spread of the disease. Pre-clinical work has shown that an agent, currently known as GSK2256098, is a potent and specific inhibitor of FAK. Early in the clinical study presented November 9, a patient with mesothelioma, who had progressed quickly on prior therapies, had prolonged stable disease while on GSK2256098, which is suggestive of clinical activity."

Prof Soria and colleagues at nine centers in France, Australia and the United Kingdom recruited 29 mesothelioma patients to the phase I study of GSK2256098, starting in July 2010. The study is continuing.

The mesothelioma patients took the drug orally in capsule form twice a day at doses ranging from 300 -1500 mg, with the majority (22) taking 1000 mg a day. There were no complete or partial responses; 14 patients had stable disease, nine had progressive disease, three had non-measurable disease, and three left the study before evaluation of response. Overall, patients had an average of 17 weeks before the disease progressed.

However, in patients in whom Merlin was inactivated, the average time before the disease progressed was 24 weeks, compared to 11 weeks in patients with active Merlin and nearly 11 weeks in patients in whom the activity of Merlin was unknown.

Adverse side-effects were mainly low grade and tolerable.

"These findings are important but preliminary," said Prof Soria. "They show that merlin is a potential bio-marker in mesothelioma that may enable us to identify a subset of patients who could benefit from GSK2256098 and have longer, progression-free survival. Mesothelioma is a deadly disease without many treatment options, and therefore identification of novel and effective therapies is needed."

The researchers will accumulate and analyses further data, and larger clinical trials will be needed to confirm these findings. In addition, other cancers such as melanoma and meningioma (tum-ours of the membranes around the central nervous system) show loss of NF2 and merlin function, and so researchers are also investigating whether the findings from this trial may be relevant to other cancers.

Professor Stefan Sleijfer, the scientific chair of the EORTC-NCI-AACR Symposium, from Erasmus University Medical Center (The Netherlands), commented: "This study strongly suggests that inactivation of Merlin may act as a marker to identify patients who may benefit from this compound. Furthermore, better insight into the role of merlin in mesothelioma may lead to novel targets of treatment. This is highly needed given the detrimental prognosis of patients suffering from mesothelioma."

[1] EORTC [European Organization for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].

[2] Abstract no: 610. Poster session, Phase I trials, 09.00 hrs, 9 November.

[3] The study is funded by GlaxoSmithKline.

Potential New Target to Treat Malignant Pleural Mesothelioma

In the September issue of the International Association for the Study of Lung Cancer's journal, the Journal of Thoracic Oncology (JTO), researchers conclude that Ephrin (EPH) B2 seems to play an important role in malignant pleural mesothelioma cell lines and tumors.

Using expression arrays, researchers from the New York University Langone Medical Center looked at EPHB2 in 34 malignant pleural mesothelioma tumors , and found it significantly elevated in tumor tissue compared with matched normal peritoneum. They found EPHB2 over-expressed in all malignant pleural mesothelioma cell lines, but not in benign mesothelioma cells. EPHB2 is also significantly elevated in malignant pleural mesothelioma tumor tissue compared with matched normal peritoneum.

Researchers believe, "targeting EPHB2 might provide a novel therapy to improve the prognosis in people suffering from malignant pleural mesothelioma. Further investigation in vitro using specific inhibitors of EPHB2 is required to determine the importance of EPHB2 and its interactions with other members of the receptor kinase and their ligands to prove its role as a marker of progression or worse prognosis for malignant pleural mesothelioma.

Mesothelioma: A Targeted Approach to Asbestos-Related Cancer

Malignant mesothelioma (MMs) is a rare form of cancer, most commonly caused by exposure to asbestos. It tends to be diagnosed decades after exposure occurs, so is rarely caught early. Current treatments, including surgery and chemotherapy, have limited efficacy and unpleasant side effects.

Traditional chemotherapeutic drugs work by destroying cells that divide quickly. As such, they're indiscriminate killers, destroying healthy dividing cells such as those in the bone marrow, digestive tract and hair follicles, as well as cancer cells. The result is an unwelcome mix of side-effects including a weakened immune system, gastrointestinal problems and hair loss. Targeted therapies, which are designed to kill cancer cells and leave healthy tissue unharmed, are highly sought after.

The new targeted therapy is a silica micro particle, coated in antibodies that recognize a protein produced by the tumour cells in large amounts. When the micro-particles are injected into a mouse model of the cancer, the antibody helps the micro-particles bind to the tumour cells, where they are then able to release their hidden inner cargo -- the chemotherapy drug rubicund.

The new therapy is more effective and less toxic than rubicund alone, Brooke T. Mossman and colleagues report. Tum ours shrank, the cancer cells proliferated less, and the animals were able more or less to maintain their weight and health throughout the treatment. Overall, the data suggest that targeted therapy may prove better than chemotherapy alone.

Using this targeting approach, the authors were able to reduce the dose of rubicund used four-fold thus almost eliminating side effects and toxicity. And because the treatment appears to reduce the number of proliferating tum-our cells, it may prove useful early on, when pre-malignant or malignant MM cells are first observed, but before disease has been confirmed by histology.

Mesothelioma: Two Groundbreaking Trials Into Treatments for Asbestos-Related Cancer

Professor Dean Fennel, of the University's Department of Cancer Studies and Molecular Medicine, is leading two groundbreaking trials into mesothelioma -- a form of lung cancer strongly linked with exposure to asbestos.

Mesothelioma most commonly starts in the inner lining of the chest wall, causing it to thicken, reducing lung capacity -- which in turn puts a strain on other organs including the heart.

Since the 1960s, it has been known that the disease can be triggered by the inhalation of asbestos fibers.

Despite the UK's ban on asbestos issued in 1985, the number of deaths caused by the disease each year has grown from 153 in 1968 to 2,321 in 2009 -- the highest incidence in the world.

This number is set to continue to rise sharply over the next 20 years, with a peak coming in 2020.

Two studies involving the University of Leicester aim to test new potential treatments which could improve survival and quality of life for mesothelioma patients.

Meso2, a study funded by Syn ta Pharmaceuticals, aims to test the effectiveness of a drug called planetesimals in preventing mesothelioma tumors.

Planetesimals inhibits the action of a protein in cells called heat shock protein 90 (HSP90) -- which is required for the stabilization and proper functioning of many proteins required for tum our growth.

The trial will involve around 140 patients across the UK, and is being led by Professor Fennel.

Professor Fennel said: "We think this is a new way of being able to target mesothelioma. Laboratory tests show planetesimals is extremely active in mesothelioma -- and combined with chemotherapy, this treatment could shrink cancers down and improve symptoms for patients."

The second trial is part of a global trial named COMMAND (Control of Mesothelioma with Maintenance Actinides) sponsored by pharmaceutical company Vera stem, which will investigate a new drug called actinides.

The researchers believe the drug could help to inhibit focal adhesion kinase (FAK), which is critical for the cancer stem cells' development into tumors.

The drug could potentially reduce the need for repeated chemotherapy treatment by killing cancer stem cells remaining following front-line therapy.

The trial will involve around 350-400 mesothelioma patients worldwide -- and the University of Leicester is leading the study for the UK, which was the first country to open the trial worldwide.

Professor Fennel, who sits on the steering committee for the trial, said: "Cancer stem cells can cause cancer to return after chemotherapy, and the FAK protein seems to be something that cancer stem cells require. If you inhibit FAK protein, you may be able to target the cancer more effectively.

"We hope that both of these trials will be positive studies for mesothelioma patients."

Mesothelioma

Mesothelioma is an uncommon form of cancer, usually associated with previous exposure to asbestos.

In this disease, malignant (cancerous) cells develop in the mesothelioma, a protective lining that covers most of the body's internal organs.

Most people who develop mesothelioma have worked on jobs where they inhaled asbestos particles, or have been exposed to asbestos dust and fiber in other ways, such as by washing the clothes of a family member who worked with asbestos, or by home renovation using asbestos cement products.