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2009 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report Research Interests Molecular biomarkers are widely expected to revolutionize the current trial-and-error practice of medicine by enabling a more predictive discipline in which therapies are targeted toward the molecular constitution of individual patients and their disease. This concept is often termed “personalized medicine”. Biomarkers are being widely evaluated for their ability to assess disease risk, detect and monitor disease over time, accurately identify disease stage, approximate prognosis, and predict optimal targeted treatments. The Program for Translational Medicine was launched in 2006 to extend the Institute’s translational research capabilities, with a focus on the development of molecular biomarker strategies with clinical implications. The program’s activities have focused on building the critical translational infrastructure and technologies, fostering clinical and industrial partnerships, and coordinating the multidisciplinary project teams required to implement molecular-based approaches in medicine. The Program of Translational Medicine, with its multidisciplinary partners, strives to create an efficient pipeline between the clinic and the research laboratory for efficient discovery and clinical application of novel biomarker strategies. We also work to increase the readiness of the community to implement advances in molecular medicine, benefiting human health and promoting West Michigan as a leader in biomarker research. Translational informatics To accelerate the implementation of personalized medicine, the consolidation and real-time analysis of standardized molecular and clinical/preclinical data is critical. Thus, much of our effort over the past several years has focused on the development of an integrated informatics solution known as the XenoBase BioIntegration Suite (XB-BIS; see http://xbtransmed.com). XB-BIS supports essential features of data management, data analysis, knowledge management, and reporting within an integrated framework, enabling the efficient exchange of information between the basic research laboratory and the clinic. XB-BIS has recently been licensed to industrial and academic partners with an interest in biomarker research and the development of molecular-based diagnostics; these include Children’s Memorial Medical Center, Qiagen, and Sequenom. Community partnerships and economic development Productive partnerships are pivotal to our efforts in biomarker research and personalized medicine. In the Center for Molecular Medicine, the Van Andel Institute and Spectrum Health Hospitals created a CLIA-certified/CAP-accredited clinical diagnostics laboratory for biomarker qualification and the development of associated diagnostic assays. This entity was recently acquired by Sequenom, but it continues to offer cutting-edge molecular diagnostic tests and remains central to our personalized medicine initiatives. For example, ongoing research activities with Sequenom are geared toward implementation of novel, molecular-based technologies into our personalized medicine initiative. ClinXus (http://www.clinxus.org) was developed to coordinate the emerging West Michigan translational research enterprise. In September 2006, ClinXus was awarded a Michigan 21st Century Jobs Fund grant to support early-stage development and operations, and it has membership in the Predictive Safety and Testing Consortium (PSTC) of the Critical Path Institute. The PSTC brings pharmaceutical companies together to share and validate each other’s safety testing methods under advisement of the FDA and the European Medicines Agency. Membership in this consortium will help ensure that West Michigan remains at the forefront of biomarker research and development and will further the community’s rapidly emerging life sciences and health care industry. 60

VARI | 2009 Predictive therapeutics protocol Translational research represents the interface where hypotheses advance to studies that ultimately provide definitive information for a clinical decision. A fundamental challenge in clinical cancer research remains how to make best use of current biomarker technologies, advances in computational biology, the expanding pharmacopeia, and a rapidly expanding knowledge of disease networks to deliver targeted treatments to cancer patients with optimal therapeutic index. Our research is focused on developing, testing, and refining biomarker-driven analytical methods to systematically predict combinations of drugs that target the tumor. We are also considering the means by which such information should be conveyed to the treating physician in support of medical decision-making. In 2008, we completed a feasibility study of 50 late-stage pediatric and adult cancer patients in which tumor-derived gene expression profiles were analyzed to identify potential drugs to target perturbed molecular components of each patient’s specific tumor. With patient consent, tumor biopsies were collected, qualified by pathology, and processed within the CMM to generate a standardized gene expression profile for the tumor. These molecular data were uploaded into XB-BIS along with pertinent clinical data and compared with other patient samples within the database. Within XB-BIS, deregulated patterns of gene expression were identified and analyzed to identify drugs that have predicted efficacy based upon their molecular mechanism of action and the tumor’s genomic data. A report scoring a series of drugs for predicted efficacy was generated within XB-BIS and conveyed to the treating physician in an actionable, electronic format for consideration in treatment planning. To be compatible with real-time prospective decision making, the process from patient consent to molecular report had to be completed in 5-10 days. In parallel, a series of tumor grafts was established in immune-compromised mice, which closely resembles the human disease at the phenotypic and molecular level. This resource is currently being used to test biomarkerdriven predictive models (and the identified drugs) in a more systematic fashion and to evaluate novel targeted agents. Over the long term, the treatments are captured within XB-BIS together with critical outcome variables, allowing the predictive analytical methods to be refined and optimized. Anecdotal signs of success in a handful of patients have provided the impetus to launch a series of follow-up studies with an expanded patient population using a more rigorous statistical design. Collaborative studies on glioblastoma through The Ben and Catherine Ivy Foundation and on neuroblastoma through the Vermont Cancer Center and University of Vermont are planned for 2009. In conjunction with our laboratory efforts to isolate, characterize, and target the putative cancer stem-cell subpopulation of metastatic tumors, biomarker-driven approaches that identify a rational treatment regimen targeting the molecular composition of the patient’s tumor hold promise for the future treatment of metastatic and refractory malignancies. From left: Jahn, Srikanth, Richardson, Koehler, Monsma, Dylewski, Eugster, Scott, Miller, Wood, Dumas, Cherba, Webb 61

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