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Experimental Therapeutics Centre and Debiopharm Group to Collaborate for the Development of an Epigenetic Innovative Oncology Target

The Agency for Science, Technology and Research (A*STAR)’s Experimental Therapeutics Centre (ETC), a center of excellence to advance and accelerate drug discovery in Singapore, and Debiopharm Group™ (Debiopharm), the Swiss-based global biopharmaceutical company that focuses on the development of prescription drugs that target unmet medical needs including oncology as well as companion diagnostics, recently announced the signature of an exclusive research collaboration to develop oral small molecules targeting new class of epigenetic modulators.

Under the terms of the agreement, Debiopharm and ETC will co-finance the discovery phase of the project, whilst Debiopharm will be in charge of development.

FDA Grants Genentech’s Perjeta Accelerated Approval for Use Before Surgery in People With HER2-Positive Early Stage Breast Cancer

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), recently announced that the U.S. Food and Drug Administration (FDA) granted accelerated approval of a Perjeta® (pertuzumab) regimen for neoadjuvant treatment (use before surgery) in people with high-risk, HER2-positive early stage breast cancer. This approval is based primarily on data from a Phase II study showing that nearly 40 percent of people receiving the combination of Perjeta, Herceptin® (trastuzumab) and docetaxel chemotherapy had no evidence of tumor tissue detectable at the time of surgery (known as a pathological complete response, or pCR). The Perjeta regimen is the first neoadjuvant breast cancer treatment approved by the FDA and also the first to be approved based on pCR data.

Independent Study: Health Diagnostic Laboratory, Inc. Services Lead to Cost Savings of 23% and Significantly Improved Health Outcomes After Two Years

Advanced cardiometabolic testing paired with follow-up health management from Health Diagnostic Laboratory, Inc. has resulted in a 23 percent decrease in a patient’s overall healthcare costs and an improved lipid profile in just two years, according to a new independent study published recently in Population Health Management.

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

HSS Uses Grant to Test New MRI Techniques & Biomarkers for Arthritis Prevention Treatments

In recent years, researchers have been frustrated because there are no tools to identify early stages of osteoarthritis and thus no good way to test therapies for preventing or slowing the disease. Now, three institutions have been awarded $1 million from the Arthritis Foundation to validate the use of new MRI (magnetic resonance imaging) techniques and newly identified biomarkers to solve this vexing problem. Hospital for Special Surgery in New York City, University of California-San Francisco (UCSF), and Mayo Clinic in Rochester, Minnesota will share the $1 million.

“There is no magic bullet for treatment of osteoarthritis yet, but once we have a potential oral drug, therapeutic injection, or surgery for treating the disease, we will need a way to identify patients who might need it and follow their response to the treatment,” said Scott Rodeo, M.D., orthopedic surgeon and co-chief of the sports medicine and shoulder service at Hospital for Special Surgery (HSS) and co-principal investigator of the tripartite grant. “Using X-rays to measure joint space narrowing is the gold standard for assessing the presence and progression of osteoarthritis, but X-rays are next to worthless for detecting the early changes of arthritis. This study will help us understand the early factors that lead to the degenerative changes in ACL (anterior cruciate ligament) injured knees.”

Acute ACL injury is a major risk factor for developing osteoarthritis. In the past several years, researchers have discovered that long before osteoarthritic changes in joint space can be detected on X-ray, biochemical changes can be detected in cartilage using newer quantitative MRI techniques. Many studies have also shown that ACL injury is associated with quantifiable changes in biochemical biomarkers that can be detected in synovial fluid (joint fluid), blood, and urine.

The Arthritis Foundation grant will be distributed over one year and then the three grant recipients have made an institutional commitment to provide annual patient follow up after that. Each institution will recruit 25 patients who are at a maximum of 14 days out from tearing their ACL. Patients will be evaluated at baseline, six weeks, six months, 12 months and yearly thereafter with traditional MRI and newer MRI techniques.

Specifically, the new quantitative MRI techniques, developed by researchers at HSS and UCSF, measure T1ρ and T2 values of articular cartilage and the meniscus. Articular cartilage is the smooth cushion that lines the end of the bones where they meet at the joints. The meniscus is a knee structure that spans and cushions the space between the joint surfaces of the thighbone and shinbone. In scientific speak, T1ρ measures proteoglycan depletion, and T2 evaluates abnormal collagen orientation. Proteoglycans are conjugates of proteins and long carbohydrate molecules joined together with sugars.

“Imagine you are playing basketball and you jump up to make a basket, your ability to withstand the load when you come down is a function of proteoglycan,” said Hollis Potter, M.D., chief of the division of magnetic resonance imaging, director of research in the Department of Radiology and Imaging at HSS. “If you pivot and throw the ball to someone else, your ability for your cartilage to withstand that load is a function of the collagen. You need both to be healthy.” Dr. Potter is the HSS site leader of the grant.

At each time point that researchers collect MRI data, they will also collect samples of synovial fluid, blood, and urine from patients and evaluate knee function using surveys such as the Knee Outcome Survey, international knee documentation committee (IKDC) evaluation forms, and Marx Activity Level. These surveys gauge whether a patient has knee impairment; the degree of symptoms such as knee swelling and pain; and how much knee impairment impacts overall well-being, daily living, work, and athletic and social activities. The majority of participants in the study will undergo ACL reconstruction, and surgeons will evaluate these patients arthroscopically at the time of the operation. Clinicians will correlate fluid biomarkers and quantitative MRI results with traditional imaging, clinical, and functional outcomes.

Osteoarthritis is an extremely heterogeneous disorder in terms of the factors that contribute to the loss of joint function. Researchers need to be able to identify where a patient is in the progression of the disease to be able to target specific processes that are responsible for the symptoms and loss of joint function.

“Not everyone who has an ACL tear will develop osteoarthritis, but some do,” said Dr. Rodeo. “The goal is to identify biomarkers that reflect alterations in the joint environment that may be predictive of developing arthritis.” Once these are identified, researchers can test therapies to slow or prevent the disease, which can be crippling and lead to disability.

“There remain many unanswered questions regarding the optimal care of patients with ACL injuries,” said Steven Goldring, M.D., Chief Scientific Officer, St. Giles Chair, Hospital for Special Surgery. “This study is a paradigm of interdisciplinary research that brings together experts in orthopedics, radiology and basic science from multiple leading medical centers with the single goal of developing the most effective therapies to improve outcomes in patients with ACL injuries. The Arthritis Foundation should be congratulated in initiating this groundbreaking program.”

ACL ruptures affect roughly 1 in 3,000 people per year in the United States alone. The cumulative population risk of an ACL injury in people between the ages of 10 and 64 years has been estimated to be 5%, but could be considerably higher. More than 175,000 ACL reconstructions are performed each year in the United States at a cost of $2 billion. Participation in sports that involve pivoting including soccer, basketball, football, and skiing put individuals at higher risk for tearing their ACL.

Source: EurekAlert!