The use of histone deacetylase (HDAC) inhibitors to sensitize patients to cancer therapies, particularly patients with hormonally positive breast cancer with resistance to drugs like tamoxifen, were among the advances discussed in November at the Molecular Targets and Cancer Therapeutics Conference, sponsored by the American Association for Cancer Research (AACR). In a randomized controlled phase 2 study of metastatic breast cancer patients, for instance, postmenopausal women with positive disease achieved double the progression-free survival with use of entinostat combined with exemestane versus exemestane alone, Researchers examined blood samples in a subset analysis of 49 patients to evaluate whether changes in circulating blood cells reflected the activity of the HDAC inhibitor and found that biological activity of the drug, which could be associated with clinical benefit, was apparent as soon as 8 days after administration. Entinostat is the first drug for metastatic breast cancer to show that clinical outcome can be predicted shortly after administration.1 More than 750 abstracts in oral and poster sessions were presented at the AACR Molecular Targets meeting. Abstracts delved into subjects such as the molecular drivers of metastasis, immunotherapy, cancer stem cells, tumor metabolism and epigenetics, and drug development for targeted therapies. In one of the most highlighted studies of the meeting, researchers reported that amplification of anaplastic lymphoma kinase (ALK), which has been reported in other cancers such as non-small cell lung cancers, may be a primary driver of the rapid metastasis experienced by patients with inflammatory breast cancer. If validated, the use of anaplastic lymphoma kinase (ALK) inhibitors may be a new treatment approach for patients with this lethal form of breast cancer, says Kenneth Anderson, MD, co-chair of the meeting and editor-in-chief of Clinical Cancer Research.2 Other studies explored the subject of antifolate resistance in non-small cell lung cancer and how best to predict such resistance. In one study, researchers treated human NSCLC cell lines (KRAS wild type, KRAS mutant nonamplified, and KRAS mutant amplified) with the antifolates methotrexate or pemetrexed. Results showed that KRAS wild-type and KRAS mutant amplified cells were relatively resistant to antifolate treatment. In contrast, antifolates inhibited growth in KRAS mutant nonamplified cell lines. The researchers also reported dramatic and prolonged responses to pemetrexed therapy in patients with KRAS mutant NSCLC. Thus, it's important for oncologists to test for KRAS mutation as well as KRAS amplification in order to assess the potential efficacy of antifolates, the researchers concluded.3 “Many of the studies presented here show the power of mechanistic-based science to elucidate new diagnostic biomarkers or targeted treatment options with either a single agent or combined therapy,” says Dr. Anderson. The U.S. Food and Drug Administration (FDA) is funding centers at the University of Maryland and Georgetown University aimed at improved review of the safety and efficacy of drugs and medical products. The Centers of Excellence in Regulatory Science and Innovation (CERSI) were each funded with a $1 million grant and may receive more funds over the next 3 years. It currently costs $1 billion and takes about 10 years to develop a new drug, according to James Polli, PhD, the Shangraw/Noxell Endowed Chair in pharmaceutical sciences at the University of Maryland and co-principal investigator for the University of Maryland CERSI. “We plan to sponsor educational lectures and daylong events that will feature the best academic scientists and provide FDA reviewers with a broad exposure to current research,” he says. According to Dr. Polli, FDA reviewers need improved training in preclinical science. “When regulators can ensure that the science is better for products such as predictive tests, there will be less need for oversight and more opportunities for accurate risk evaluation,” he says. Instructors at the University of Maryland will train FDA reviewers in how to use clinical data to assess the possible side effects of new drugs and drug-drug interactions. “The problem the FDA faces is that it's often hard for reviewers to get additional training in new research since their time is limited and so are the resources of the FDA,” Dr. Pollli says. The Georgetown CERSI will be working on one project to assess ways to use bioinformatics to enhance medical product development and another to examine data sharing. “The FDA has access to vast amounts of data that can be mined to answer important biomedical and public health questions but it's important to determine how data can best be utilized while protecting the intellectual property rights of pharmaceutical companies and stakeholders such as researchers, universities, and the public,” says Ira Shoulson, MD, professor of neurology, pharmacology, and human science at Georgetown and the university's CERSI principal investigator and director. The U.S. Department of Defense has awarded Boston University Medical School a $13.6 million grant to lead 2 multi-site studies aimed at finding ways to detect lung cancer noninvasively and to distinguish those smokers at highest risk for developing lung tumors. Although the National Lung Screening Trial showed that there were fewer fatalities among smokers and former smokers screened with low dose helical CT, using such screening for all smokers is cost-prohibitive, says Avrum Spira, MD, a pulmonary and critical care physician at Boston University Medical Center, who is leading the Department of Defense lung cancer research effort. Only 10 to 20% of smokers and former smokers actually develop lung cancer, leading researchers to ask which smokers and former smokers should receive imaging tests, particularly expensive ones, such as CT scans. To help answer this question, Boston University researchers will collaborate with military hospitals and Veteran's Affairs medical centers to investigate lung cancer risk among a large number of patients. The consortium for the lung cancer studies, called the Detecting Early Lung Cancer Among Military Personnel (DECAMP) Consortium, is the largest consortium of researchers in the U.S. dedicated to identifying noninvasive ways to detect early-stage lung cancer. Lung cancer is of special concern to the Department of Defense because military and military veterans have higher rates of smoking than the national average. They're also exposed to toxins during military action that can put them at elevated risk for lung cancer, Dr. Spira says. Researchers will investigate ways that molecular biomarkers, both genomic and proteomic, could be used to predict risk of lung cancer and to distinguish between smokers and former smokers with benign nodules in the lung versus patients with cancerous ones. In the first study, 500 military personnel with suspect lung nodules will undergo blood tests and bronchoscopy for samples that might yield molecular clues to the presence of cancer in the lungs versus those that might indicate benign nodules, and then will be followed until biopsy is completed. “One of the exciting aspects of this research is that although the cells we'll be collecting are far away from the lung, they are all bathed in the toxins in cigarette smoke that eventually cause genetic and genomic alterations as well as lung cancer,” Dr. Spira says. “Epithelial cells derived from bronchoscopy might act like a canary in a cold mine, telling you about the presence of lung cancer,” Dr. Spira said. In a second study, researchers will follow 1,000 smokers and former smokers at high risk for development of lung cancer because of the amount of cigarettes they smoked or the duration of their smoking habit. Presence of lung nodules or lung cancer will be assessed over a 5-year period. “If we can find molecular markers that cause smokers to be at elevated risk for lung cancer, then we can follow them more closely with imaging studies, and find cancer at an earlier stage. And we could potentially offer them treatment that might prevent lung cancer,” Dr. Spira said. A number of compounds to prevent lung cancer are now being tested in early clinical trials, including the prostacyclin, iloprost. Research advances in sequencing technologies that make it possible to scan entire human genomes more cost-effectively are fueling a research initiative by the National Institute of Neurological Disorders and Stroke (NINDS). Duke's Center for Human Genome Variation won the first grant in the NINDS initiative, called the Center Without Walls on Human Genetics. The Center will be using the $25 million grant, awarded over the course of 5 years, to sequence and analyze the entire genomes of 4,000 epilepsy patients. “Improved understanding of the genetic basis of epilepsy will shed light on the underlying pathophysiology that leads to epilepsy disorders,” says Erin Heinzen, PhD, co-principal investigator and assistant professor in Duke's Center for Human Genome Variation. “This knowledge will likely lead to the development of medications or treatments that can specifically treat the cause of seizures in patients,” Dr. Heinzen says. Although Duke will be leading the effort, investigators from other universities in the United States, Canada, and Australia will be contributing genomic and detailed clinical information on patients with epilepsy. Genetic studies of epilepsy indicate that many different genes are disrupted in order to cause the condition. “This high level of heterogeneity means that we will likely need very large sample sizes to identify epilepsy susceptibility genes, which can only be obtained by collaborating with other institutions studying epilepsy,” Dr. Heinzen says. When exactly might this research work affect treatment?“The timing of how long it may take for gene discoveries to be translated into clinically useful information or drug therapies is uncertain,” Dr. Heinzen says. “But it's clear that gene discovery will improve our understanding of epilepsy and over time this will improve patient care.” CTS
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