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Researchers Find That Tumor DNA and Cells in the Blood Can Be Used to Diagnose Prostate Cancer and Drug Resistance in Breast Cancer

Last month, the “Molecular Diagnostics” issue of Clinical Chemistry, the journal of AACC, featured new research on a genetic test for prostate cancer that could replace the unreliable prostate specific antigen (PSA) test, as well as a more accurate test for breast cancer drug resistance. Both tests could help patients receive more targeted treatment for prostate and breast cancer, which in the U.S. are the second leading causes of cancer death in men and women, respectively.

Utility Of Rubicon Genomics’ ThruPLEX-FD Kit Validated In Study Showing “Liquid Biopsy” Can Track Genomic Evolution Of Cancer In Response To Therapy

Rubicon Genomics, Inc., a leader in the development and commercialization of innovative sample-specific nucleic acid library preparation products used in research and clinical testing, recently reported that its ThruPLEXTM-FD Prep Kits contributed to the success of a breakthrough study recently published in Nature1 that showed that genomic data extracted from the plasma of cancer patients can be used to track drug resistance and potentially guide treatment.

Nodality, Inc. Reports Promising Rheumatoid Arthritis Study Results to Predict Patient Treatment Response to TNF Inhibitors

Nodality, Inc., an innovative biotechnology company advancing discovery, development and use of transformative therapies by revealing functional systems biology, recently announced results of the Company’s comprehensive research study to identify cell markers (biomarkers) of disease activity and treatment success in rheumatoid arthritis (RA) patients. The study findings demonstrated that Nodality’s SCNP technology, which measures functional pathways at the single cell level, can be used to identify biomarkers of responsiveness to treatment with tumor necrosis factor inhibitors (TNFIs). RA affects an estimated two million Americans, and TNFIs constitute the most commonly prescribed therapy. Approximately half of patients respond to treatments such as TNFIs, leaving a substantial unmet need to identify which patients are more likely to respond to current therapies. Optimizing use of currently available therapies could potentially delay tissue damage and progression of disease.

SCNP provides the core technology foundation for Nodality’s programs dedicated to improving clinical medicine by increasing the efficiency of therapeutic R&D programs, enhancing life cycle management for commercialized drugs, and introducing new predictive diagnostics. The study results were featured in an oral presentation titled, Comparison of functional immune signaling profiles in peripheral blood mononuclear cells (PBMC) from rheumatoid arthritis (RA) patients versus healthy donors (HD) using Single Cell Network Profiling (SCNP) (Abstract W7.02.04), at the 15th International Congress of Immunology (ICI) in Milan, Italy, taking place August 22 to 27, 2013. The findings were presented by S. Louis Bridges, Jr., M.D., Ph.D., Marguerite Jones Harbert-Gene V. Ball, MD Professor of Medicine, Director, Division of Clinical Immunology and Rheumatology, University of Alabama School of Medicine.

“Nodality’s research program demonstrates the great promise and potential in gaining a better understanding of disease biology and applying this to the development of prognostic and predictive biomarkers for autoimmune diseases such as RA,” commented Alessandra Cesano, M.D., Ph.D., Chief Medical Officer of Nodality. “I look forward to the final results of this program, one of the most comprehensive of its kind. Our technology, based on immune-biology, can predict which RA patients will respond to specific therapies and reveal the mechanisms of drug resistance, thus informing alternative therapeutic strategies.”

The Nodality research program compares healthy and diseased peripheral blood cells at the single cell level, studying samples obtained through the national Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository (TETRAD). Nodality anticipates completing its research program and announcing the key findings later this year.

Laura Brege, Nodality’s President and Chief Executive Officer, stated, “ICI has provided an important opportunity to showcase one of our key programs in immunology, further validating our broadly enabling SCNP platform. This platform has led to major collaborations in immunology addressing significant unmet needs among patients, as well as new predictive diagnostic modalities in blood cancers. Ultimately, Nodality’s goal is to accelerate and make more efficient the development of new therapeutic agents for serious diseases affecting large patient populations within immunology and oncology, two areas of continuing significant unmet clinical need.”

Additional program results were featured in a second oral presentation at the ICI Congress in a presentation titled, Functional proteomic interrogation of immune cell crosstalk and the effects of cytokine-targeted inhibitors using Single Cell Network Profiling (SCNP) (Abstract W7.02.03).

Source: Nodality, Inc

University Hospitals Case Medical Center and Case Western Reserve University Announce Licensing Agreement for the Development of Diagnostic Tests for HIV Drug Resistance

Case Western Reserve University has signed an exclusive worldwide licensing agreement granting University Hospitals (UH) Case Medical Center rights to a series of diagnostic tests to determine drug resistance and co-receptor tropism in human immunodeficiency virus (HIV).

The phenotypic and genotypic HIV tests (or assays) were invented by Eric Arts, PhD, Professor of Medicine in the Division of Infectious Diseases, Department of Medicine at Case Western Reserve School of Medicine, and Miguel Quiñones-Mateu, PhD, Assistant Professor, Department of Pathology at the School of Medicine and Scientific Director at the University Hospitals Translational Laboratory (UHTL, www.uhtl.org).

The HIV assays provide a platform of diagnostic tests used by physicians and researchers to monitor the success of anti-HIV treatment by determining drug resistance and the ability of the virus to infect different cells within the patient. The HIV assays also can be used by academic and corporate researchers to develop novel strategies to block HIV replication.

In July 2011, UH Case Medical Center created the UHTL with the goal of advancing and further developing new molecular diagnostic methodologies originally conceived in the academic and clinical laboratories at UH Case Medical Center and Case Western Reserve. UHTL’s main objective is to facilitate the development of translational research into commercial assays or products, including characterization, verification, and validation in a College of American Pathologists and Clinical Laboratory Improvement Act (CAP/CLIA) certified environment under a Good Laboratory Practice (GLP) framework.

The UHTL occupies 4,200 sq.ft. of office and laboratory space, including BSL-2+, in the Baker Electric Building (MidTown, Cleveland, OH) and was recently CAP accredited. The first series of cell-based and molecular HIV diagnostic tests will be offered by the UHTL during the second quarter of this year.

“The UHTL has provided us with an exciting opportunity to develop new molecular diagnostic tests, and the collaboration of Drs. Quiñones-Mateu and Arts has been particularly fruitful for developing these new tests that will benefit patients by allowing individually targeted selection of therapies for HIV infection,” said Clifford V. Harding, MD, PhD, the Joseph R. Kahn, MD Professor of Pathology and Chair of Department of Pathology, Case Western Reserve and UH Case Medical Center.

“A personalized, four-in-one integrated assay has been launched to provide a highly advanced way to ensure optimal care for HIV infected patients. New collaborations between Case Western Reserve and UH are in process to provide enhanced care for patients with hepatitis and cancer,” said Dr. Arts.

“The UHTL allows UH Case Medical Center to remain on the leading-edge of molecular diagnostic testing. It clearly demonstrates our commitment to our mission: ‘To heal, To teach and To discover,” said Ronald E. Dziedzicki, Chief Operating Officer at UH Case Medical Center. “This new capability will clearly benefit patients with HIV infection in a more targeted manner, thereby impacting the quality of their life. UHTL also provides a platform to assist with the movement of other new and novel testing modalities from a concept to reality. The establishment of this lab and new testing modalities also demonstrates the value of the relationship between UH Case Medical Center and Case Western Reserve University and our quest to improve patient care with new leading edge technologies.”

Dr. Quiñones-Mateu joined UH Case Medical Center as Scientific Director of the UHTL after leading the technical and commercial development of novel molecular and cell-based HIV diagnostic tests at Diagnostic Hybrids, Inc., A Quidel Company. “Our HIV phenotypic (VIRALARTS™HIV and VERITROP™) assays and the novel all-inclusive HIV genotyping and coreceptor tropism test (DEEPGEN™HIV) based on next-generation sequencing will allow us to enhance the care and treatment of HIV-infected individuals not only in Northeast Ohio but nationally as well as worldwide.

DEEPGEN™HIV is a first-in-class assay based on the latest technology developed to rapidly detect variants and mutations in any given genome with high sensitivity. Current tests are able to detect drug resistant viruses with a sensitivity of 20 percent, while DEEPGEN™HIV is able to detect these mutant viruses at frequencies as low as 1 percent. This will give the opportunity to the physicians to “see” the mutant viruses many months in advance and decide whether or not change the treatment before the patient begins to fail HIV therapy.

According to Quiñones-Mateu, “With the collaboration of Dr. Christine Schmotzer, UHTL Medical Director and Assistant Professor of Pathology at the School of Medicine, we are ready to introduce our unique products and services to HIV physicians, pharmaceutical drug companies developing the next generation of effective drugs, and national laboratory service organizations that interact with both groups.”

Source: University Hospitals

Details of Gene Pathways Suggest Fine-Tuning Drugs for Child Brain Tumors

Pediatric researchers, investigating the biology of brain tumors in children, are finding that crucial differences in how the same gene is mutated may call for different treatments. A new study offers glimpses into how scientists will be using the ongoing flood of gene-sequencing data to customize treatments based on very specific mutations in a child’s tumor.

“By better understanding the basic biology of these tumors, such as how particular mutations in the same gene may respond differently to targeted drugs, we are moving closer to personalized medicine for children with cancer,” said the study’s first author, Angela J. Sievert, MD, MPH, an oncologist in the Cancer Center at The Children’s Hospital of Philadelphia.

Sievert, working with co-first author Shih-Shan Lang, MD, in the translational laboratory of neurosurgeon Phillip Storm, MD, and Adam Resnick, PhD, published a study ahead of print recently in the Proceedings of the National Academy of Sciences.

Studying mutation behavior in the BRAF gene in astrocytoma

The study, performed in cell cultures and animals, focused on a type of astrocytoma, the most common type of brain tumor in children. When surgeons can fully remove an astrocytoma (also called a low-grade glioma), a child can be cured. However, many astrocytomas are too widespread or in too delicate a site to be safely removed. Others may recur. So pediatric oncologists have been seeking better options—ideally, a drug that can selectively and definitively kill the tumor with low toxicity to healthy tissue.

The current study focuses on mutations in the BRAF gene, one of the most commonly mutated genes in human cancers. Because the same gene is also mutated in certain adult cancers, such as melanoma, the pediatric researchers were able to make use of recently developed drugs, BRAF inhibitors, which were already being tested with some success against melanoma in adults.
The current study provides another example of the complexity of cancer: in the same gene, different mutations behave differently. Sievert and her colleagues at Children’s Hospital were among several research groups who reported almost simultaneously in 2008 and 2009 that mutations in the BRAF gene were highly prevalent in astrocytomas in children. “These were landmark discoveries, because they suggested that if we could block the action of that mutation, we could develop a new, more effective treatment for these tumors,” said Sievert.

However, follow-up studies in animal models were initially disappointing. BRAF inhibitors that were effective in BRAF-driven adult melanomas made brain tumors worse—via an effect called paradoxical activation.

Further investigation revealed how tumor behavior depended on which type of BRAF mutation was involved. The first-generation drug that was effective in adult melanoma acted against point mutations in BRAF called V600E alterations. However, in most astrocytomas the mutation in the BRAF gene was different; it produced a fusion gene, designated KIAA1549-BRAF. When used against the fusion gene, the first-generation drug activated a cancer-driving biological pathway, the MAPK signaling cascade, and accelerated tumor growth.

Newly identified second-generation BRAF inhibitor disrupted cancer-promoting signals without adverse effects

By examining the molecular mechanisms behind drug resistance and working with the pharmaceutical industry, the current study’s investigators identified a new, experimental second-generation BRAF inhibitor that disrupted the cancer-promoting signals from the fusion gene, and did not cause the paradoxical activation in the cell cultures and animal models.

Results lay foundation for multicenter clinical trials

This preclinical work result lays a foundation for multicenter clinical trials to test the mutation-specific targeting of tumors by this class of drugs in children with astrocytomas, said Sievert. As this effort progresses, it will benefit from CHOP’s commitment to resources and collaborations that support data-intense research efforts.

The direction of brain tumor research over the past several years reflects some of those data-driven advances, says Adam C. Resnick, PhD, the senior author of the current paper and principal investigator of the astrocytoma research team in the Division of Neurosurgery at Children’s Hospital. “For years, astrocytomas have been lumped together based on similar appearance to pathologists studying their structure, cell shape and other factors,” said Resnick. “But our current discoveries show that the genetic and molecular structure of tumors provides more specific information in guiding oncologists toward customized treatments.”

Earlier this year, Children’s Hospital announced its collaboration with the gene-sequencing organization BGI-Shenzhen in performing next-generation sequencing of pediatric brain tumors at the Joint Genome Center, BGI@CHOP. The center’s sophisticated, high-throughput sequencing technology will greatly speed the discovery of specific gene alterations involved in childhood brain cancers.

This genomic discovery program dovetails with the work of the Childhood Brain Tumor Tissue Consortium, a multi-institutional collaboration recently launched by CHOP, with support from the Children’s Brain Tumor Foundation. Because even large research centers may not hold enough tumor tissue specimens to power certain research, the consortium pools samples from a group of institutions, providing an important scientific resource for cooperative studies.

“The better we understand the mutational landscape of tumors, the closer we’ll be to defining therapies tailored to a patient’s specific subtype of cancer,” added Resnick.

Study: Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas

Source: The Children’s Hospital of Philadelphia