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May 1, 2014 (Vol. 34, No. 9)

Discovering More Telling Biomarkers

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    At the Novartis Institutes for BioMedical Research, proposals for new drug targets include the identification of biomarkers. For example, developing drugs for complex respiratory diseases requires identifying subpopulations of patients that share the same molecular pathology. Well-annotated clinical samples are central to the process of identifying biomarkers (proteins or genes) in blood that track disease changes in the lung.

    “Biomarker discovery and validation requires a robust and highly reproducible metabolite profiling platform,” notes Dr. Bölke. “Aside from an untargeted (unbiased) metabolite profiling platform, access to targeted methods (such as lipidomics, energy metabolites, stress hormones, and eicosanoids) is also important.”

    Dr. Bölke describes the company’s systematic approach to biomarker identification and validation: “First, we seek about 30 patients and matched controls and perform a fairly general analysis to see if the technology is a good fit. Then, in an identification phase, we take a couple hundred patients and matched controls to identify the ~5–20 crucial metabolites providing a unique signature for the target. Of these, we nominate ~5–10 biomarkers, and we perform clinical follow-up studies to validate the data. Finally, we translate our findings into standard diagnostic technologies for everyday clinical use.”

    Obtaining signatures is arduous, but they may, suggests Dr. Bölke, provide better patient stratification and differential diagnostics: “Because of its broad coverage, metabolic profiling enables a deeper understanding of pathological mechanisms, more in-depth toxicity testing, and, of course, the identification of potential drug candidates.”

  • Pulmonary Disease Biomarkers

    Diseases of the airways such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) result from a complex, subtle interplay of environmental and genetic susceptibility factors. To better understand the pathophysiological nuances of these diseases (and to improve the evaluation of new drugs), companies are focusing on biomarkers. One such company is Novartis, which is evaluating biomarkers through its research organization, Novartis Institutes for Biomedical Research.

    “The complexity of respiratory diseases makes it difficult to develop new therapies targeting their underlying molecular pathology,” remarks Paul Whittaker, Ph.D., director, biomarkers, respiratory disease area. “Biomarkers help us identify groups of patients with the same dysregulated molecular pathway, or the same active disease process that our novel drugs are targeting. This increases the signal-to-noise ratio in our clinical trials by ensuring that the right drug is tested in the right patients and that the right outcome is measured.”

    The identification of appropriate biomarkers for respiratory diseases presents several challenges. In Dr. Whittaker’s view, these challenges include 1) poor understanding of respiratory disease heterogeneity, 2) inadequate access to well-annotated clinical samples, particularly matched blood and lung tissue, and 3) difficulties in building and proving the link between the biomarker(s) and the disease process that is being targeted.

    According to Dr. Whittaker, access to clinical samples is crucial for solving these problems. “The good news is that the proliferation of publicly funded biobanks (such as the Lung Tissue Research Consortium of the NIH’s Heart, Lung, and Blood Institute) as well as commercial suppliers (such as ProteoGenex and Tissue Solutions) has facilitated access to hard-to-get clinical tissue samples.”

    Identifying biomarkers utilizing such available resources involves a number of approaches, observes Dr. Whittaker. “An area we’ve made good progress in is the identification of candidate biomarkers for remodeling of lung tissue, a process that is common to a number of respiratory diseases, including pulmonary arterial hypertension and IPF. The experimental approaches involve a combination of omics technologies, bioinformatics, literature mining, and pathway analysis. Use of human tissue is an integral part of this whole process. As we move steadily into the era of personalized medicine, these biomarkers will be the basis for companion diagnostics for our novel therapies.”

  • Oncology Biomarkers

    On average, only about 5 out of 10 patients receiving a given therapy benefit from it, while some may experience troubling side-effects. Identifying clinically meaningful patient subgroups to remedy this is a key element of the Roche Pharma Early Research and Development (pRED) oncology programs. Miro Venturi, Ph.D., site head for biomarkers and experimental medicine, oncology, says, “We are pursuing tailored biomarker strategies to identify mechanistic and pharmacodynamic as well as selection or stratification markers to improve patient benefit.”

    To characterize tumors, Roche employs a broad range of platforms such as genetics, genomics, and protein and cellular phenotyping tools. “Our biomarker discovery efforts start very early in the research process,” explains Dr. Venturi. “First, we formulate predictive biomarker hypotheses by understanding the mechanism of action of our candidate drug and looking broadly at many targets. This requires the adoption of multiplexing technologies. Next, we look for confirmation of the key biomarkers as the most accurate descriptors of appropriate pharmacodynamics and clinical response. Finally, we identify biomarkers of resistance to the drug.”

    Finding the appropriate biomarker is difficult. “Some of the challenges are deeply connected to the biology of cancer, especially for new compounds in onco-immunology that stimulate a patient’s immune system,” comments Dr. Venturi. “Because patient responses can vary, it is important to correctly identify both tumor- and patient-specific biomarkers. It is also critical to understand tumor heterogeneity.

    “Often a small amount of tumor material—a patient biopsy—is removed and made available for further analysis. Since tumors can be heterogeneous, one needs to consider the limitations of such investigations and have a strategy at hand that allows conducting the analysis in more accessible patient samples or via imaging modalities.”

    Biomarker identification also presents the opportunity for development of a companion diagnostic to predict or monitor patients’ response to treatment. As Dr. Venturi notes, “It’s important to start developing biomarkers for use as companion diagnostics as early as possible. Usually, this is done in Phase I trials or earlier. The more specific the biomarker, the more likely it will evolve into a diagnostic.”

    Dr. Venturi sees some exciting new developments on the horizon. “In the future, there will be less invasive techniques. For example, it will be possible to characterize cell-free DNA in blood; that is, liquid biopsies will allow surveillance of DNA from tumors. We will still face challenges in identifying and validating companion diagnostics; however, we will have many more tools to do so and a progressively deeper understanding of the biology to build biomarker hypotheses upon.”

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