Millisecond brain signals predict response to fast-acting antidepressant
Electromagnetic biomarker could minimize trial-and-error prescribing
The future prediction of pharmaceutical efficacy by means of a noninvasive imaging technique known as magnetoencephalography (MEG) may be on the horizon as researchers, using images of the brain‘s fastest signals, have discovered a predictive electromagnetic marker that reveals a patient‘s response to a fast-targeting antidepressant.
MEG detects the brain‘s millisecond electromagnetic activity and differs from functional techniques, which may involve radiation exposure and can only capture activity lasting seconds or minutes. “Such biomarkers that identify who will benefit from a new class of antidepressants could someday minimize trial-and-error prescribing and speed delivery of care for what can be a life-threatening illness,” said Carlos Zarate from National Institute of Mental Health (NMH), who along with colleagues reported their discovery in a recent issue of Biological Psychiatry.
Evidence suggests that the brain chemical glutamate acts more intimately to the source of the depression than the brain chemical serotonin. Conventional antidepressants, which work via serotonin, are known to take weeks until an affect is established. Ketamine, on the other hand, which targets glutamate, has been reported to lift depressions in just hours. Because the anterior cingulate cortex (ACC) is involved in the regulation of emotion processing, and its volume has been found to be reduced in patients with major depression, it is believed that ACC activity might foretell a response to glutamate-targeting medications.
NMH researchers used a known method of stimulating the ACC by rapidly flashing images of fearful faces whilst using the MEG scanner to capture the brain‘s split-second responses of 11 depressed patients and 11 healthy participants.
While healthy participants‘ ACC activity declined as they familiarized to the faces, depressed patients‘ ACC activity showed a contrasting trend. The stronger this increase, the more improved the symptoms within 4 h after receiving a single infusion of ketamine.
It is believed that the delay in the ACC activity could be an insight into the defective circuitry mechanism associated with glutamate. “The ACC may be slow to respond, but not completely impaired, in patients who respond to ketamine,” explained Cornwell. Although the side affects of ketamine make it unsuitable for use as an antidepressant, the new findings help narrow the search for treatment methods that function through the same way.
Sources: Salvadore G, Cornwell BR, Colon-Rosario V et al.: Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine. Biol. Psychiatry (2008) (Epub ahead of print); www.eurekalert.org/pub_releases/2008–2010/ca-adr101508.php
Biomarker warns of kidney injury in heart surgery patients
Researchers have associated kidney injury after cardiac surgery with increased levels of the blood protein neutrophil gelatinase-associated lipocalin (NGAL).
Postcardiac surgical renal failure is a well-recognized complication, which remains a leading cause of patient morbidity. At present, blood tests that warn of potential kidney problems take up to 2 days after heart surgery, thus limiting measures to decrease the associated morbidity and mortality following such a complication. However, it is claimed by University of Florida College of Medicine (UF, FL, USA) researchers that heart surgeons may soon be able to identify high-risk patients for kidney injury within an hour of surgery. They believe designing a test that could immediately identify at-risk patients could lead to treatments that prevent kidney injury altogether.
The study found an association between postsurgery kidney damage and the early presence of a protein known as NGAL in the blood. Levels of NGAL as well other inflammatory biomarkers elevated and were detected as soon as 1 h after the completion of thoracic aorta or valve surgery. UF surgical resident, Dr Tad Kim, said “The problem with kidney injury is that the markers we commonly use, like measuring the serum creatinine, often change when it is already too late in the game. It would be nice if we could see something via a simple blood or urine test that tells us earlier in the process that the kidneys are undergoing injury so we can intervene instead of waiting.”
No US FDA-approved drug at present can impede damage to the kidneys during surgery; however, two clinical trials involving UF researchers are looking into possible drugs with defensive attributes. According to the study‘s principal investigator, Dr Thomas Beaver, an experimental compound known as AP214 is being examined to see if it can reduce the levels of NGAL released after surgery.
Despite being in the early stages, it is believed that the ability to govern a test in the operating room that instantly obtains signs of renal damage and deliver drug intervention will be made possible within 3 years.
Sources: Doi K, Hu X, Yuen PS et al.: AP214, an analogue of alpha-melanocyte-stimulating hormone, ameliorates sepsis-induced acute kidney injury and mortality. Kidney Int. 73(11), 1266–1274 (2008); www.news.ufl.edu/2008/10/14/biomarker-kidney/
Study launched by NCI to determine if biomarkers can help guide treatment for lung cancer
The National Cancer Institute (NCI) has launched its first ever study to identify, using biomarkers, a protein known as EGF receptor (EGFR), believed to be responsible for tumor growth in non-small-cell lung cancer. The clinical trail Marker Validation for Erlotinib in Lung Cancer (MARVEL), also known as N0723, is in Phase III and hopes to establish the value of markers as prognostic tools.
A total of 85–90% of all lung cancers are manifestations of non-small-cell lung carcinoma (NSCLC), a lethal disease that is difficult to treat if belatedly diagnosed. The therapeutic benefits of using biomarkers are now being assessed in an extensive clinical trial launched by the NCI.
Superfluous gene coding, which can activate tumor growth, is believed to be due to the presence of EGFR, the levels of which increases in some cancers. It is anticipated that a biomarker identifying EGFR will allow the facilitation of drugs that prohibit the stimulation of tumor growth.
This trial is a pioneering alliance between NCI, the FDA, and the Centers for Medicare and Medicaid Services. It was formed in 2006 and is known as the Oncology Biomarkers Qualification Initiative (OBQI). The study is now known as MARVEL and will endeavor to ultimately allow treatment to be given based on the presence or absence of EGFR activation.
Erlotinib (Tarceva®, Genentech) and pemetrexed (Alimta®, Eli Lilly), approved treatments for advanced NSCLC, will be given after standard chemotherapy to EGFR-positive and -negative patients of the 1200 tested for the status of this biomarker.
It is theorized that EGFR-positive lung cancer patients will be better suited to erlotinib, whereas preferential treatment will be observed between pemetrexed and EGFR-negative lung cancer patients. This is because erlotinib specifically targets EGFR, unlike pemetrexed, which inhibits the formation of precursor purine and pyrimidine nucleotides, thus preventing the formation of DNA and RNA, which are required for cell growth and survival.The incorporation of genetic studies for both drugs will be utilized to further identify patients with different sensitivity and toxicity profiles to these therapies.
Studies addressing the most important factors that influence responsiveness to erlotinib are yet to be performed. Such factors include a history of smoking, Asian ethnicity, female gender and whether the resulting cancer cells are classified as adenocarcinomas (as opposed to squamous or other types of cell).
The North Central Cancer Treatment Group (NCCTG) and other NCI-sponsored clinical trial groups will lead this Phase III study. Patients will be recruited over a 4 year period and their EGFR status will be tested. A total of 950 out of the 1200 patients will be randomly assigned to the treatment protocol and after a minimum of 1–2 years of follow-up, the NCCTG expect to determine the value of markers as predictive and prognostic tools.
It is hoped that better agents will get to cancer patients much faster. NCI director John Niederhuber asserts that “the MARVEL trial is of major importance because it could define, based on a single test, the best therapy for this disease. The future of moving highly targeted agents from the lab to the clinic will be heavily dependent on biomarkers for patient selection.”
Sources: ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT00738881?id=N0723&rank=1#desc; NIH News: www.nih.gov/news/health/oct2008/nci-02.htm
Society of Nuclear Medicine unveils a bridge to clinical trial development for imaging biomarkers
In response to the need for greater lucidity and modernity in the application of biomarker imagery in clinical research and clinical practice, the Molecular Imaging Clinical Trials Network (MICTN) has been introduced by the Society of Nuclear Medicine (SNM), an organization that promotes the science, technology and practical application of nuclear medicine.
There is an overall consensus that incorporating imaging biomarkers with drug development will see an extensive decrease in factors such as regulatory costs, complexity and time, all of which appear to hinder the advancement of efficient and novel drugs.
The MICTN aims to integrate imaging biomarkers into Phase I, II and III of pharmaceutical clinical trials and the past president of SNM, Alexander JB McEwan, believes “the network will stimulate the development of additional novel imaging biomarkers”.
A unique model has been designed for investigational imaging biomarkers into multicenter clinical trials and will incorporate drug development, molecular imaging, radiolabeled probe development and manufacturing and regulatory issues.
Investigational new drugs for biomarkers of interest and homogeneous imaging protocols across qualified multicenter clinical trial sites will be established in order to educate the imaging community in the phantom program, the multicenter clinical trials and registry participation. Deliberations have already begun with pharmaceutical developers interested in near-term clinical trials using F-18 FLT and the network is anticipated to be fully functional in the first quarter of 2009.
According to the President of SNM Robert W Atcher, “SNM is taking the lead to establish FDA-friendly imaging biomarkers via approved INDs. The FDA, pharmaceutical companies and the SNM community have all been extremely cooperative in designing the Molecular Imaging Clinical Trials Network because it is about building bridges and moving the field forward.”
Source: EurekAlert! www.eurekalert.org/pub_releases/2008–2010/sonm-sua100708.php
Promising method to delay the progression of blood cell cancer
The prospect of personalized care for the common blood cell cancer, chronic lymphoid leukemia (CLL), has taken a step forward thanks to researchers at Mayo Clinic, USA. The team has found that the need for conventional chemotherapy in patients with early-stage, high-risk, CLL may be delayed by an extra 2 years if predictive biomarkers and two targeted treatments are used.
Normally, chemotherapy is needed approximately 2 years after cancer diagnosis in people with this kind of high-risk CLL, but the use of the biomarkers and early treatment saw some patients not needing chemotherapy until 4 years after cancer diagnosis.
This Phase II study used two monoclonal antibodies, alemtuzumab and rituximab, to test for the safety and efficacy of early treatment in 30 patients with high-risk CLL. These two antibodies are already used widely in treating patients with advanced-stage CLL. Eligibility criteria for this study included no previous treatment, no National Cancer Institute-Working Group 1996 criteria for treatment, and the patient had to have at least one marker of high-risk disease (17p13, 11q22-), or a combination of unmutated IgVH and CD38+/ZAP70+.
The study lasted 31 days and the 30 patients enrolled in the study received subcutaneous alemtuzumab, with initial dose escalation followed by 30 mg three-times weekly, and four doses of 375 mg/m intravenous rituximab per week. A total of 90% of patients responded to the treatment, with 37% having complete responses. The researchers concluded that the therapy regimen used was a safe and effective early treatment for patients with high-risk CLL.
The study‘s lead investigator, Clive Zent, said, “This is the first publication of a study on CLL in which patients were selected for early treatment of their disease based on molecular prognostic markers, and it is also the first one to test a combination of targeted therapies in a group of patients who would not ordinarily be treated yet.”
“The standard of care for these patients is to watch and wait until patients develop more advanced disease and then to treat them with chemotherapy and monoclonal antibodies. We believe this new approach is better for patients because it identifies those who will develop aggressive CLL sooner rather than later and helps delay the need for more toxic treatments,” he continued. “While this is a novel concept in the field of CLL treatment, we think it moves us toward the day when we can treat all patients uniquely, based on the characteristics of their individual cancer.”
The rate of progression varies among patients, as Zent explains, “We know that roughly one-third of patients will need treatment within two years of diagnosis, one-third will need treatment at some point in the future, and the remaining one-third of patients will never need treatment and will not die of their disease. Because, in the past, we could never predict which patients would have more aggressive disease, we have had to watch everyone, and that requires repeated blood tests and physical exams.”
It remains to be determined whether this strategy will have any significant effect on morbidity and mortality but, as Zent concluded, “Using these tools and treatments, we hope to be able to substantially delay CLL progression in patients who are at risk. We don‘t know yet that this strategy will decrease mortality in patients, because that can only be proven in a Phase III randomized clinical trial. But these good results now set the stage for such a study.”
Source: Zent CS, Call TG, Shanafelt TD et al.: Early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab Cancer 113(8), 2110–2118 (2008).
Novel heart failure biomarker identified
Cardiologists at Emory University School of Medicine (GA, USA) have uncovered a new biomarker that can predict an individual‘s risk of heart failure. The biomarker in question is resistin, a hormone produced by fat cells.
Using findings from the Health Aging and Body Composition (ABC) study, which started in 1998 and followed 3000 elderly people in the Pittsburgh and Memphis areas over 7 years, the team of scientists found that for every 10 ng/ml increase in resistin levels in blood the risk of new onset heart failure increased by 38%. These results mean that resistin is likely to be a stronger predictor of heart failure risk that the previously identified inflammatory markers, such as C-reactive protein. The precise function of resistin is not known but it is thought to be associated with inflammation and insulin resistance.
Director of heart failure research at Emory University School of Medicine, Javed Butler, said “This is one of the strongest predictors of new-onset heart failure we‘ve been able to find, and it holds up even when you control for other biomarkers and risk factors, including high blood pressure and diabetes.”
Butler concludes, “Considering the increasing number of people who are obese or have diabetes, very many of them are going to be at some level of risk for heart failure later in life. The value of a marker such as resistin may be in accurately identifying among this large population of at-risk individuals who is at the highest risk and then targeting interventions to those people.”
The findings were presented at the American Heart Association Scientific Sessions conference in New Orleans (LA, USA) on 12 November 2008.
Source: Woodruff Health Sciences Center, Emory University (GA, USA). www.whsc.emory.edu/press_releases2.cfm?announcement_id_seq=16524
Researchers find new biomarkers for Barrett‘s esophagus
Biomarkers have been discovered by researchers at Rhode Island Hospital‘s Molecular Pathology Core Facility and the Division of Gastroenterology (RI, USA) for Barrett‘s esophagus (BE), which may help identify patients who are likely to progress to esophageal adenocarcinoma (EAC), the most common form of esophageal cancer.
At present, patients with BE, a common precancerous condition of the lower esophagus, need to be screened by endoscopy and frequently biopsied in order to detect premalignant changes at the microscopic level. BE progresses to EAC in a series of steps from low-grade dysplasia (LGD), which is the earliest morphological sign of precancer, to high-grade dysplasia (HGD). Approximately 50% of patients who have HGD will go on to develop EAC.
According to lead author Murray Resnick, “Identification of biomarkers capable of distinguishing the grade of BE-associated dysplasia, as well as identifying patients who are most likely to progress to cancer, would be extremely valuable tools for both surgical pathologists and gastroentorologists.”
The gold standard for identifying HGD is currently morphological analysis of esophageal biopsies by light microscopy. Results then guide a treatment plan. However, distinguishing between LGD and HGD using just light microscopy can be challenging for pathologists to detect.
Resnick explains, “As pathologists, our primary goal was to identify candidate biomarker proteins suitable for the generation of specific antibodies that could detect these proteins using immunohistochemical diagnostic techniques that are readily available in all pathology departments”. From this line of thought, the researchers started trying to identify biomarkers that could differentiate between LGD and HGD.
The researchers were able to identify a number of potential biomarkers by using state-of-the-art molecular techniques, such as laser capture microdissection followed by gene-expression analysis. “Using this process, it is the first study of its kind to differentiate genes expressed in HGD versus other grades of BE-associated dysplasia. While additional studies on a larger series of cases is required, this study provides promise for our future ability to identify which patients have the potential to develop esophageal adenocarcinoma and to provide an appropriate treatment plan”, Resnick concludes.
Source: Sabo E, Meitner PA, Tavares R et al.: Expression analysis of Barrett”s esophagus-associated high-grade dysplasia in laser capture microdissected archival tissue. Clin. Cancer Res. 14(20), 644–648 (2008).
NIAID awards contracts to search for protein markers of disease
In an attempt to launch Clinical Proteomic Centers for Infectious Diseases and Biodefense, two 5-year contracts, estimated to be up to US$23.8 million combined, have been granted by The National Institute of Allergy and Infectious Diseases (NIAID).
By analyzing human blood and other tissue samples from previously completed and ongoing clinical trials, the NIAID-funded centers will search for proteins produced by either pathogenic agents or the immune system.
Dengue fever and brucellosis will be the first diseases considered and once their characteristics have been discovered, aspirant biomarkers will be made unreservedly accessible to the widespread research community for advanced expansion.
At no charge to the applicants, the NIAID-funded centers will also promote researchers from other infectious disease institutions to submit clinical samples, which will be reviewed for the presence of potential biomarker proteins.
“Identifying specific biomarkers that are present in infected people – but absent in uninfected people – would give researchers new leads in understanding how microbes cause disease and how the body reacts to those microbes,” says Maureen Beanan, a program officer in NIAID‘s Division of Microbiology and Infectious Diseases.
Source: NIH news: NIAID Awards contracts to search for protein markers of disease. www3.niaid.nih.gov/news/newsreleases/2008/proteomics.htm
Injured liver tissue regeneration a possibility
In a breakthrough discovery, scientists at the University of Pennsylvania School of Medicine (PA, USA) have found a novel marker that can identify rare adult liver stem cells. The identification of liver stem cells has remained elusive to scientists until now, and the stem cells‘ ability to regenerate injured liver tissue has the exciting potential use for cell-replacement therapy.
Led by Linda Greenbaum, the group of researchers have shown in two mice models that cells expressing the protein marker, FoxL1, are able to differentiate into both liver cells and cells that line the bile duct. It is hoped that the finding of this marker will allow for the isolation and expansion of these stem cells in the future. If this occurs, it may be possible to help patients whose livers can no longer repair their own tissue.
Greenbaum explain, “In a healthy liver, proliferation of mature liver and bile-duct lining cells is sufficient to maintain the necessary size and function of the organ. This even works when the liver is confronted with mild and acute injury, but the situation changes when injury to the liver is chronic and severe.”
A ‘back-up system‘ is used in chronic liver injury, which stimulates stem cells to proliferate and differentiate into new liver cells. In this study, the researchers found that these stem cells can be identified and potentially isolated from other liver cells because they uniquely express Foxl1. The researchers propose to use this marker to isolate the Foxl1-bearing stem cells and transplant them back into damaged livers to restore function. Greenbaum says, “At this point, we haven‘t identified the molecular targets that are regulated by Foxl1 in the liver stem cell.”
Other factors that need to be worked out include what signals activate the expression of Fox l1 and how exactly it is related to liver function. “This work has significant implications for cell-replacement therapies of chronic liver disease in the future,” concludes Greenbaum.
Sources: University of Pennsylvania: School of Medicine. www.uphs.upenn.edu/news/News_Releases/2008/11/liver-stem-cell-marker.html; Sackett SD, Li Z, Reginald H et al.: Foxl1 is a marker of bipotential hepatic progenitor cells in mice. Hepatology DOI: 10.1002/hep.22705 (2008) (Epub ahead of print).