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Veristat to Assist on Adaptive Enrichment Trial for Verastem’s Defactinib in Mesothelioma

Veristat, LLC., a leading, Boston-based clinical research organization, recently announced its advisory role on the implementation of an adaptive enrichment trial design for Verastem, Inc. (NASDAQ: VSTM). The enhanced design aims to optimize the current trial of defactinib, a novel, small molecule inhibitor of focal adhesion kinase (FAK) in patients with malignant pleural mesothelioma.

“We have identified a biomarker in mesothelioma that may predict increased sensitivity to defactinib,” said Dr. Joanna Horobin, Chief Medical Officer at Verastem. “We felt strongly that the application of an enrichment design would help us to accelerate the program to a potential regulatory decision. We are excited to have Veristat’s experience in enrichment trial design and execution supporting this trial.”

Veristat’s input on the overall trial design, as well as the adaptive enrichment design architecture and planned analyses will help facilitate decisions required at key development intersections of the program.

“The Verastem clinical development team has taken a dynamic approach to the design of this study,” commented Dr. John Balser, president and chief science officer at Veristat. “Our team at Veristat will be assisting them with the statistical and operational challenges inherent in the adaptive enrichment design architecture. Our goal is to produce a trial that will quickly and cost effectively yield the highest likelihood of success for their target patient population.”

Source: Veristat

Biomarker May Predict Prostate Cancers Requiring Treatment

Not all early-stage prostate cancer diagnoses are alike. While some patients have aggressive tumors, others have slow-growing, low Gleason score tumors that may not require treatment, but instead can be monitored with regular clinical evaluations. But distinguishing between prostate cancers that require treatment and those that do not is still a major challenge.

Researchers at Columbia University in New York City have now identified a 3-gene signature that could indicate whether a particular early-stage prostate cancer is indolent. The test relies on a tissue sample, and along with a prostate-specific antigen (PSA) test and a histology assessment, could help clinicians make an accurate diagnosis. The early results, including a blinded retrospective analysis of 43 patients, show that the signature can accurately predict which patients with low-risk disease would develop metastatic prostate cancer and which patients would not progress. The study is published in Science Translational Medicine.

“These types of markers will, for the first time, give us the opportunity to measure biological features of cancer in the same patient, with multiple biopsies spread out over many years,” said Eric Klein, MD, chairman, Glickman Urological and Kidney Institute at the Cleveland Clinic in Ohio.
Cory Abate-Shen, PhD, professor of urological oncology at Columbia University; Andrea Califano, PhD, professor of systems biology at Columbia University; and colleagues used a computational approach that identified three genes—FGFR1, PMP22, and CDKN1A—all associated with aging, that could accurately predict outcomes of low-risk, low Gleason score prostate tumors. Protein and mRNA levels of all three genes were high in those patients who had non-aggressive, indolent disease and low in those who had aggressive tumors.

Clinicians still rely on the Gleason score, a histology and pathology evaluation that does not incorporate any molecular assessment. Those patients with a Gleason score of 8 or higher are candidates for immediate treatment, but whether men with a score of 6 or 7 require treatment is difficult to assess—no test exists to identify the small percentage of patients who have early-stage prostate cancer that is more likely to metastasize.

The 3-gene signature was validated using an independent prostate cancer cohort. According to the study authors, the signature was prognostic and improved prognosis compared with the use of PSA and clinical assessment.

“We would predict that the test would be beneficial for patients with low Gleason score prostate tumors,” said Abate-Shen. “These patients are now typically monitored on active surveillance protocols, and the patients get a biopsy periodically. The test would be conducted on the biopsy.”

Rather than focusing on the entire genome, the researchers focused on 377 genes involved in aging, predicting that genes involved in aging and senescence are critical for tumor suppression. Cellular senescence is known to play a role in tumor suppression and is associated with benign prostate tumors both in the clinic and in mouse models, according to the researchers. Using a computational analysis called gene set enrichment analysis (GSEA), they narrowed the long gene list to 19 genes, and then to a set of 3 genes that could identify indolent tumors.

“To focus on senescence genes is intellectually interesting,” said Klein. “There is already a body of work supporting the role of these genes in prostate cancer, but to my knowledge no one has looked at them in early-stage disease before.”

Forty-three patients, who had been under active surveillance for 10 years at Columbia University Medical School, were used for the blinded retrospective analysis to assess the predictive value of the gene signature. Each patient had been diagnosed with low-risk prostate cancer, with a Gleason score of 6 or less. The test was correctly able to identify all 14 patients who eventually developed advanced prostate cancer.

CDKN1A has been shown to be linked to senescence and to regulate the cell cycle. Previous studies have shown that downregulation of the gene is linked to cancer progression. The correlation of FGFR1 (fibroblast growth factor receptor 1) with indolent tumors was surprising, as fibroblast growth factors have been shown to play a role in prostate cancer development. But, as the authors highlight in their discussion, FGFR1 signaling in prostate cancer is likely complex. The third gene in the signature, PMP22, encodes a glycoprotein expressed in neurons and has not been previously associated with prostate cancer.

This 3-gene signature is different from previously identified biomarkers, which have largely focused on advanced tumors. The potential biomarker test could complement other approaches in development, such as urine or blood tests, according to the authors.

A trial to validate the genetic signature is underway at Columbia University, and a national trial is being planned.

“It is really important to find novel ways to help to define early-stage tumors that may or may not progress to aggressive disease,” said Abate-Shen. “This will ultimately really help to minimize overtreatment, while capitalizing on the benefits of cancer screening.”

Other genomic approaches to distinguish indolent and aggressive disease are also underway. The first-generation expression-based tests, including Oncotype DX prostate and Prolaris, can facilitate clinical decisions based on the molecular characteristics of a prostate tumor. Both the available tests and the new ones “promise to reduce overtreatment and help men make the right decisions based on biology rather than uncertainty,” said Klein. 

Study: A Molecular Signature Predictive of Indolent Prostate Cancer [Science Translational Medicine]

Source: CancerNetwork

Mayo Clinic Study: Blood Biomarker Could Mark Severe Cognitive Decline, Quicker Progression Among Parkinson’s Patients

A genetic mutation, known as GBA, that leads to early onset of Parkinson’s disease and severe cognitive impairment (in about 4 to 7 percent of all patients with the disease) also alters how specific lipids, ceramides and glucosylceramides are metabolized. Mayo Clinic researchers have found that Parkinson’s patients who do not carry the genetic mutation also have higher levels of these lipids in the blood. Further, those who had Parkinson’s and high blood levels were also more likely to have cognitive impairment and dementia. The research was recently published online in the journal PLOS ONE.

The discovery could be an important warning for those with Parkinson’s disease. Parkinson’s is the second most common neurodegenerative disease after Alzheimer’s disease. There is no biomarker to tell who is going to develop the disease — and who is going to develop cognitive impairment after developing Parkinson’s, says Michelle Mielke, Ph.D., a Mayo Clinic researcher and first author of the study.

Cognitive impairment is a frequent symptom in Parkinson’s disease and can be even more debilitating for patients and their caregivers than the characteristic motor symptoms. The early identification of Parkinson’s patients at greatest risk of developing dementia is important for preventing or delaying the onset and progression of cognitive symptoms. Changing these blood lipids could be a way to stop the progression of the disease, says Dr. Mielke.

There is a suggestion this blood lipid marker also could help to predict who will develop Parkinson’s disease and this research is ongoing.

“There is currently no cure for Parkinson’s, but the earlier we catch it — the better chance we have to fight it,” says Dr. Mielke. “It’s particularly important we find a biomarker and identify it in the preclinical phase of the disease, before the onset even begins.”

Dr. Mielke’s lab is researching blood-based biomarkers for Parkinson’s disease because blood tests are less invasive and cheaper than a brain scan or spinal tap — other tools used to research the disease.

This work was supported by grants from the National Institute on Aging (U01 AG37526) and from George P. Mitchell and the late Cynthia W. Mitchell. The DEMPARK study was being funded by an unrestricted grant from Novartis and a grant from the International Parkinson Fonds (Deutschland) gGmbH (IPD). The continuation of the study (LANDSCAPE) is part of the Competence Network Degenerative Dementias (KNDD), which is funded by the German Federal Ministry of Education and Research (project number 01GI1008C)).

Study: Plasma Ceramide and Glucosylceramide Metabolism Is Altered in Sporadic Parkinson’s Disease and Associated with Cognitive Impairment: A Pilot Study [PLOS ONE]

Source: Mayo Clinic

Study Expands Use of Biomarker for Early Diagnosis of Acute Kidney Injury

A biomarker test developed initially to identify early acute kidney injury (AKI) after surgery has been shown to successfully detect AKI in emergency room patients with a variety of urgent health issues.

In a study published online Sept. 5 in the Clinical Journal of the American Society of Nephrology, the findings expand the overall utility and potential medical settings for using the test, according to researchers.

The test measures the protein neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker of early AKI. It was invented by researchers at Cincinnati Children’s Hospital Medical Center to detect AKI earlier than existing methods, and to more promptly begin treatment.

“The majority of our studies on NGAL have been performed in well controlled settings of hospital-acquired AKI, such as cardiac surgery, contrast administration or other critically ill patients,” said Prasad Devarajan, MD, senior author and director of Nephrology and Hypertension at Cincinnati Children’s. “The purpose of this study was to determine the biomarker’s accuracy in a diverse group of patients admitted from the emergency department, where patients with early signs of AKI are often misdiagnosed.”

The study involved patients admitted through the emergency room of Fernando Fonseca Hospital in Portugal, which also closely collaborated on the study. The findings demonstrate the NGAL test, which uses a single drop of blood and provides results within 15 minutes, was able to accurately distinguish AKI from reversible transient kidney dysfunction.

Of 616 patients who participated in the study, individuals who were subsequently diagnosed with true AKI had the highest levels of NGAL detected at the time of hospital admission. The study also identified a cutoff point in NGAL levels above which the risk of acute kidney injury increases tenfold.

Results of a study previously published in 2008 by Devarajan showed that the NGAL test predicted AKI in pediatric heart surgery patients within hours instead of days, allowing treatment that prevented serious damage to kidneys. Prior to the NGAL test, serum creatinine was the only reliable method for detecting kidney damage; however, the long wait for results often resulted in permanent kidney damage.

With a growing number of patients coming to emergency rooms with community-acquired AKI, Devarajan says having a rapid, reliable method of detecting kidney injury is increasingly important.

“This latest study showed that this simple laboratory test provides an accurate prediction of acute kidney injury and its severity in a diverse clinical setting,” said Devarajan. “The identification of biomarkers that differentiate intrinsic AKI from transient reversible forms of renal dysfunction and predict outcomes is a high priority.”

Study: Plasma NGAL for the Diagnosis of AKI in Patients Admitted from the Emergency Department Setting [Clinical Journal of the American Society of Nephrology]

Source: EurekAlert!

BIDMC Cardiovascular Institute Researchers Will Lead $4 Million NIH Grant to Study MicroRNAs

A cardiovascular research team from Beth Israel Deaconess Medical Center (BIDMC) and Brigham and Women’s Hospital (BWH), led by BIDMC Principal Investigator Saumya Das, MD, PhD, has been awarded a $4 million Common Fund grant from the National Institutes of Health (NIH) as part of a newly formed program on Extracellular RNA Communication. The five-year grant will focus on identifying microRNA biomarkers in heart disease.

Each year, complications from heart attacks (myocardial infarctions) contribute to more than half a million cases of heart failure and 300,000 cases of sudden cardiac arrest, when the heart suddenly stops. Both of these conditions are closely related to a process known as remodeling, in which the structure and function of the heart changes – or remodels — following a heart attack.

“Our goal is to explore the role that microRNAs play in predicting which heart-attack patients will go on to experience complications,” explains Das, an electrophysiologist in BIDMC’s Cardiovascular Institute and co-director of the cardiovascular genetics program within the Outpatient Cardiovascular Clinic.

“Current strategies used to identify the highest risk patients have often been inaccurate,” he adds. “We think that a blood test that makes use of microRNA biomarkers could replace existing strategies and more accurately predict which patients might experience poor outcomes and thereby identify who would most benefit from frequent monitoring and medical care.” Other investigators who are part of the NIH grant, “Plasma miRNA Predictors of Adverse Mechanical and Electrical Remodeling After Myocardial Infarction,” include BIDMC Director of Cardiovascular Research Anthony Rosenzweig, MD, and BWH investigators Raymond Y. Kwong, MD, MPH, and Mark Sabatine, MD, MPH.

microRNAs are one type of extracellular RNA. Once considered nothing more than genomic “junk,” microRNAs have more recently been recognized as playing a key role in cellular functions. Several years ago, scientists began to recognize that these small, noncoding RNAs were not only found inside cells, but could also be found in blood and other tissue fluids.

Using patient plasma samples from extensively characterized patients who have suffered heart attacks, the scientific team will first identify which specific microRNAs are related to poor heart remodeling. They will then use cell culture and animal models of heart disease to further prioritize which microRNAs play a functional role in disease progression. Finally, the investigators will validate these prioritized microRNAs as prognostic markers for poor health outcomes after heart attacks in a large prospective clinical trial.

“Ultimately, we think that miRNA-based tests could replace current tests to predict which patients might be at risk of complications and, therefore, be good candidates to receive an implanted defibrillator,” says Das. “At the same time, we hope to be able to better predict which individuals are at less risk of complications – and thereby spare them unnecessary and costly procedures.”

Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School, and currently ranks third in National Institutes of Health funding among independent hospitals nationwide.

BIDMC has a network of community partners that includes Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, Signature Health Care, Commonwealth Hematology-Oncology, Beth Israel Deaconess HealthCare, Community Care Alliance, and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Senior Life and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.org.

Source: Beth Israel Deaconess Medical Center