WASHINGTON — A new study shows that a combination of drugs can be used in targeted therapy against a common type of lung cancer.
Lung adenocarcinomas, the most common genetic subtype of lung cancer which has long defied treatment with targeted therapies, has had its growth halted by a combination of two already-in-use drugs in laboratory and animal studies, setting the stage for clinical trials of the drugs on patients, researchers at Dana-Farber Cancer Institute in Boston, Massachusetts and other scientists report in a new study.
The study, published in the journal Cancer Discovery, describes a new tack in the treatment of lung adenocarcinomas which account for about 40 percent of all lung cancers that carry mutations in the gene KRAS.
While most efforts to target KRAS directly with drugs have not proved successful, the authors of the current study took a more circuitous approach, targeting KRAS’s accomplices, the genes that carry out its instructions rather than KRAS itself, reports Science Daily.
“About 30 percent of lung adenocarcinomas have mutations in KRAS which amount to nearly 30,000 of all patients diagnosed with lung cancer each year in the United States,” says the study’s senior author, David Barbie, MD, of the Lowe Centre for Thoracic Oncology at Dana-Farber and the Broad Institute of Harvard and Massachusetts Institute of Technology.
“That represents the single biggest subset of lung cancer patients, if grouped by the mutations within their tumour cells. Unfortunately, there has not been a reliable way of striking at the genetic mechanism that causes these cells to proliferate.”
Mutations in KRAS cause cancer cells to grow and divide in a wildly disordered way. The lack of drugs able to block KRAS safely has led investigators to look for ways of stifling its effects “downstream” by interfering with the signals it sends to other genes.
“The next step will be to take these results to the clinic where the combination can be tested on lung cancer patients,” says Wong.
“We’re in the process of developing a clinical trial. Because KRAS mutations are also common in colon and pancreatic cancer, we’re hopeful that trials will be organised for these patients as well.”
An new experimental drug that has shown promise in the treatment of melanoma may potentially treat patients with a most common form of lung cancer, scientists say.
The drug has shown early potential as an effective treatment for non-small cell lung cancer, the leading cause of cancer death among men and women worldwide.
Dr Edward Garon, director of thoracic oncology at University of California, Los Angeles (UCLA), presented the preliminary results of a Phase 1B study of the new drug, called MK-3475.
The detailed interim data on safety and activity came from a cohort of 38 patients with non-small cell lung cancer who were treated previously for the disease without positive results. For the study, the patients received MK-3475 every three weeks.
Among the participants, 24 per ce
nt responded to the drug, with their tumours shrinking, and the median overall survival rate was 51 weeks.
For those who responded, the median response duration- the average amount of time their tumours remained shrunk-had not been reached at the time of this analysis, so it is at least 62 weeks.
Based on this data, a Phase 2/3 trial comparing two different doses of MK-3475 to standard chemotherapy for lung cancer has begun enrolling patients.
Some cancer cells can evade detection by the immune system by expressing a protein called PD-L1, which interacts with the protein PD-1 to prevent the immu
ne system from seeing the cancer as an invader.
MK-3475, an anti-PD-1 immunotherapy drug made by Merck, allows the immune system to properly detect the cancer and to activate T cells-the so-called “foot soldiers” of the immune system-to attack and kill cancer cells.
The most commonly reported drug-related side effects in the study were of low grade.
“These are early results, but we ar
e very encouraged by what we’ve seen so far with this drug,” Garon said.
Chinese researchers found that those who consumed raw garlic as part of their diet were 44 per cent less likely to suffer the disease.
Even when they allowed for whether people smoked – the biggest single cause of lung cancer, the scientists found garlic still seemed to reduce the dangers by around 30 per cent, the `Telegraph` reported.
Previous research has suggested that the popular herb can ward off stomach cancer and colon cancer, and a study at the University of South Australia suggested that it could reduce the risk of bowel tumours by nearly a third.
Scientists at Jiangsu Provincial Centre for Disease Control and Prevention compared 1,424 lung cancer patients with 4,500 healthy adults.
They found that those who ate raw garlic at least twice a week were significantly less likely to get lung cancer, even if they smoked or were exposed to high-temperature cooking oil fumes, which is thought to be another trigger for the disease.
The key ingredient behind this effect seems to be a chemical called allicin, released when the clove is crushed or chopped, according to previous studies.
It is thought to dampen down inflammation in the body and act as an anti-oxidant, reducing damage from so-called free radicals to the body`s cells.
However, it is not clear whether cooked garlic would have the same effect.
“Garlic may potentially serve as a preventive agent for lung cancer,” researchers said.
The study was published in the journal Cancer Prevention Research.
Several new studies that may help doctors tailor lung cancer treatment to the characteristics of
individual patients and of their tumors are being presented at the 3rd European Lung Cancer
Conference in Geneva.
“A major goal of lung cancer treatment is to tailor the treatment to the individual,” says Dr Fiona Blackhall from The Christie NHS Foundation Trust in Manchester, UK. “The studies that will be presented at ELCC 2012 are important practical steps to achieving this in the clinic. Methods ranging from convenient blood-based molecular tests, detailed genetic analysis of tumors and functional imaging techniques have been applied in patient populations receiving a range of treatments. These findings provide impetus to continue developing a personalized medicine approach to lung cancer with the overall aim of selecting the most effective treatment for the individual.”
Proteins provide clues to outcomes
An international group of researchers report promising results with a test that may identify patients likely to benefit from first-line therapy with a particular drug combination.
Dr Oliver Gautschi from the Swiss Group for Clinical Cancer Research (SAKK), and collaborators from The Netherlands and the US company developing the test, conducted a retrospective analysis of two phase-II trials with a serum proteomic classifier called VeriStrat®. Their aim was to evaluate the prognostic value of the test in patients with advanced non-small cell lung cancer receiving first-line treatment with bevacizumab and erlotinib.
VeriStrat® uses mass spectrometry to measure proteins in pre-treatment blood and assigns a result that correlates with outcome from treatment with a class of drugs known as EGFR inhibitors, which includes erlotinib and gefitinib. The test was initially developed and validated in patients who had already been treated with chemotherapy, and who then received an EGFR inhibitor in second line, Dr Gautschi explains.
“We conducted this project to see if the test is also prognostic in untreated patients who received an EGFR inhibitor in the first line. Until now, this has not been clear.”
The researchers used VeriStrat® to analyze blood samples from 117 patients previously enrolled in two phase II trials and compared the results to the patients’ progression-free survival and overall survival. The analysis showed that those classified by the test as likely to have better outcomes on EGFR inhibitor therapy did indeed live longer.
“The difference in overall survival between patients classified by the test as likely to have better or worse outcomes when receiving EGFR inhibitors was clinically relevant,” Dr Gautschi said. However he noted that definitive conclusions about the use of this test in previously untreated patients requires further studies.
“There is an unmet need for reliable blood-based markers in patients with lung cancer, because lung tumors are harder to biopsy than breast tumours for example. The current study indicates that modern technologies, such as proteomics, are promising tools, which need further validation in large trials,” he said. In this context, the European Thoracic Oncology Platform (ETOP) is currently launching a prospective phase-III trial to futher validate this test in patients with lung cancer.
“Clinical trials involving robust predictive tools have potentially a great impact and can be of paramount relevance in defining the real role of personalized cancer medicine,” commented Dr Rafael Rosell from the Catalan Institute of Oncology in Badalona, Spain, Member of the ESMO Chest Tumors Faculty group. “This broad proteomic analysis can provide useful information, circumventing the problem of tumor heterogeneity that can arise when a single tumor biopsy is examined,” Dr Rosell added.
Micro RNA marks response to chemoprevention
Dr Celine Mascaux from the University of Colorado and collaborators report that the micro RNA miR-34c is a potential biomarker for histological response in lung cancer chemoprevention studies.
Chemoprevention is a way of preventing the development of cancer using medicines or other agents, including the prevention of cancer in at-risk individuals such as smokers.
Currently, the best intermediate endpoint for studies of chemoprevention is a histological grading of cells in the airways of the lungs. However, as Dr Mascaux’s group notes, “more quantitative biomarkers of response would be desirable.”
Dr Mascaux and colleagues analyzed the expression of selected micro RNAs as potential surrogate biomarkers in a lung cancer chemoprevention trial that compared a drug called iloprost to placebo in 125 former or current smokers.
In a recent study, oral iloprost has shown promise to prevent the development of lung cancer in high-risk people.
After analyzing 14 different micro RNAs from 496 lung biopsies, they found that change in the expression of a particular micro RNA — miR-34c — in follow-up biopsies was inversely correlated with histological response.
Changes in the expression of this micro RNA may therefore be a quantitative biomarker of response in lung chemoprevention studies, they say.
RRM predicts shorter survival
Dr Giovanna Dal Bello and colleagues report that expression levels of ribonucleotide reductase subunit 2 (RRM2) predict shorter survival in patients whose non-small cell lung cancer had been surgically removed. In 82 patients, the Italian group found that RRM2 was an independent prognostic marker of shorter survival.
“The difference in overall survival between patients with high or low RRM2 levels was clinically relevant,” said Dr Dal Bello from the National Institute for Cancer Research in Genoa, Italy. “In particular, mean survival time of patients with high RRM2 levels was 36.5 months compared to 46.1 months for those with low RRM2 levels.”
“This is the first study that identifies RRM2 expression as a negative prognostic factor in resected stage I-III NSCLC,” they report.
“RRM2 was identified as an unfavorable prognostic marker in our study population and this is in agreement with its crucial role in supplying deoxyribonucleotides for DNA synthesis and repair and with the finding that cells overexpressing RRM2 exhibit enhanced cellular invasiveness,” Dr Dal Bello explained.
Because of the high and rapid recurrence rate of lung cancer, prognostic markers to identify patients with higher risk of relapse represent a high unmet medical need. “The prognostic role of RRM2 can help to identify patients at higher risk of relapse who may benefit from adjuvant chemotherapy,” she noted.
Epigenetic clues distinguish tumor types
Dr David Shames from a San Francisco, California–based biotechnology company and colleagues report that epithelial-like lung tumors, which have a better prognosis and exhibit greater sensitivity to inhibitors of the EGFR pathway, can be distinguished from mesenchymal-like tumors on the basis of global DNA methylation patterns.
DNA methylation is an important form of ‘epigenetic’ modification, which affects the expression of genes within cells.
Using cancer cell lines and surgically resected non-small cell lung cancer tumors, the researchers showed that patterns of DNA methylation can divide non-small cell lung cancer into two phenotypically distinct subtypes.
Their work also provides proof of principle, they say, that “differences in DNA methylation can be used as a platform for predictive biomarker discovery and development.”
A promising biomarker of response to radiotherapy
In a further report, Dr Ioannis Trigonis from the Wolfson Molecular Imaging Centre and The Christie Hospital in Manchester, UK, describes the findings from an assessment of F-18 fluorothymidine (FLT), a tracer molecule used in PET scanning to measure tumor cell proliferation.
Dr Trigonis’ group studied 14 patients with NSCLC who had a total of 31 dynamic FLT PET-CT scans before and within 1-2 weeks after the start of radical radiotherapy. They found that radiotherapy induced early significant decreases in tumor FLT uptake that varied across patients.
Their results indicate the potential of FLT PET to identify how well patients are responding to radiotherapy and guide therapeutic approaches, they say. More results will be presented at the meeting.
Provided by European Society for Medical Oncology