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Evidence-Guided Molecular Profiling Offers New Hope for Oncologists Managing Difficult-to-Treat Cancers

Caris Life Sciences recently announced data from two studies presented at the 2013 European Cancer Congress (ECC 2013), which demonstrate the potential of evidence-guided molecular profiling to improve the treatment of patients with hard-to-treat cancers, including cancers of unknown primary (CUP) origins as well as rare tumors and cancers that have been refractory to treatment.

Test Could Identify Which Prostate Cancers Require Treatment

The level of expression of three genes associated with aging can be used to predict whether seemingly low-risk prostate cancer will remain slow-growing, according to researchers at the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center. Use of this three-gene biomarker, in conjunction with existing cancer-staging tests, could help physicians better determine which men with early prostate cancer can be safely followed with “active surveillance” and spared the risks of prostate removal or other invasive treatment. The findings were published recently in the online edition of Science Translational Medicine.

Gentris Corporation Launches Next Generation Human Transcriptome Array

Gentris Corporation (www.gentris.com), a global leader in pharmacogenomics and biorepository solutions, recently announced that it is expanding its genomic biomarker offering with the launch of Affymetrix GeneChip(R) Human Transcriptome Array (HTA) services. The GeneChip(R) HTA is a high resolution microarray for gene expression that is designed to empower next-generation expression profiling studies. The new array goes beyond gene-level expression profiling by providing the coverage and accuracy required to detect all known transcript isoforms produced by a gene.

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

Mount Sinai and Exosome Diagnostics Partner to Accelerate Translation of Body Fluid Molecular Diagnostics to Overcome Limitations of Tissue Biopsy in Areas of Critical Unmet Medical Needs

The Icahn School of Medicine at Mount Sinai and Exosome Diagnostics today announced a collaboration on the research and development of real-time nucleic acid-based body-fluid diagnostics to advance personalized medicine. Exosome will provide technical and development support to Mount Sinai researchers along with early access to proprietary technology products upgrades. The agreement will allow Exosome and Mount Sinai to establish targeted research and biomarker discovery programs in oncology, inflammation and other disease areas. Exosome anticipates pursuing commercial development and FDA review of successful validations for in vitro diagnostics.

“This collaboration represents the model that research centers and private companies need to adopt in the post-recession, sequestered economy to develop diagnostic products that can improve clinical outcomes, help advance drug development programs and help lower healthcare costs,” said James McCullough, Chief Executive Officer of Exosome Diagnostics. “New York State has taken an aggressive and appropriate approach to promoting cooperation of its leading research centers, such as Mount Sinai, with private industry resources and commercial capability to drive translational medicine. Mount Sinai and Exosome together can accelerate cutting-edge diagnostic products to serve the clinical market.”

Carlos Cordon-Cardo, MD, PhD, Chair, Department of Pathology, Icahn School of Medicine at Mount Sinai, added, “As we advance our precise medicine program in the Departments of Pathology and Genomics at Mount Sinai, biofluid-based, point-in-time analyses, made possible by the Exosome Diagnostics-Mount Sinai relationship, will undoubtedly lead to an improved, patient-centric understanding of disease, thereby guiding more informed treatment decisions and response to therapy.”

The agreement was negotiated by Mount Sinai Innovation Partners (Mount Sinai IP), which encourages the commercialization of novel research conducted at the Icahn School of Medicine at Mount Sinai. Mount Sinai plans to leverage the considerable expertise of its clinical investigators in areas of key unmet medical needs to develop clinical study programs taking advantage of Exosome’s unique technology that has the ability to extract high-quality RNA from blood, urine and cerebrospinal fluid.

Under the agreement, Mount Sinai will retain rights to molecular biomarkers associated with disease progression and drug response, and Exosome will retain commercial development rights for molecular in vitro diagnostic products. The collaboration will extend for five years. Dr. Cordon-Cardo receives financial compensation from Exosome Diagnostics as a member of its scientific advisory board.

Source: PR Newswire