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2007 Scientific Report

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VARI |

VARI | 2007 Research Interests The Program for Translational Medicine was launched on June 1, 2006. While maintaining a research effort focused on enhancing our understanding of the molecular basis of tumor metastasis, the program is also developing community capabilities around translational research and the future clinical applications of molecular-based medicine. These efforts are very much focused on the practical implementation of biomarkers for improving diagnostic and therapeutic strategies against chronic human diseases, including cancer. The program has recently launched a proof-of-concept personalized medicine initiative to identify novel treatment options for patients with late-stage cancer. The research portion of this community protocol includes the enhancement of computer-based predictive models, by overlaying knowledge of molecular networks and drug-target interactions to identify potential combination targeting strategies for late-stage disease. These predictions are evaluated for efficacy in xenograft models for each patient’s tumor. Our informatics system, XB-BioIntegration Suite (XB-BIS), has also been enhanced to permit reporting of molecular drug information back to the medical oncologists, who may use the information for treatment decisions. In the coming years, we plan on expanding our molecular profiling efforts to identify drugable targets within the cancer stem cell components of several malignancies and to improve our predictive modeling and reporting capabilities, with the hope of identifying the optimal combinational strategies for treating cancers using FDA-approved agents and/or drugs in the drug discovery pipeline. Our research typically begins with the analysis of human specimens. We aim to identify molecular correlates of important clinical phenotypes, such as the propensity to metastasize and drug resistance. The standardized collection of human specimens, along with information about the patient’s medical history, diagnosis, treatment, and response to therapy, represents a crucial component of our research. Identifying the molecular correlates of a given phenotype, whether nucleic acid or protein, often represents the first step in our translational pipeline. We have developed the essential workflow and integrated informatics that are required to manage and interpret complex data sets of longitudinal clinical/preclinical and molecular data across different experimental platforms. XB-BIS is now interfaced with the electronic medical records system of Spectrum Health, through the co-development of an IRB data exchange portal maintained by the Spectrum Health Research Department. This permits the transfer of de-identified medical record information from consenting patients into XB-BIS so that it can be combined with molecular data generated from the processing of the patient’s tissue, blood, or urine. In 2006, XB-BIS was commercialized and has been licensed by XB-TransMed Solutions (http://www.xbtransmed.com), who now provide professional support services related to the sales and support of the tool, while our laboratory maintains focus on XB-BIS research and development. 71 In the research lab, and increasingly within the Center for Molecular Medicine, we use various molecular technologies to generate the molecular data pertaining to a clinical or preclinical sample. XB-BIS permits the analysis of these data in conjunction with the clinical/preclinical information, and coupled with systems biology tools such as GeneGo’s MetaCore TM product or Ingenuity’s IPA suite, we identify potential diagnostic signatures that can predict clinically meaningful phenotypes. For example, using Affymetrix gene expression analysis, we have identified tumor profiles associated with metastatic outcome in colorectal cancer and with patient survival in mesothelioma. These signatures are now being validated within the CLIA/CAP-accredited Center for Molecular Medicine, a joint venture between VAI and Spectrum Health. Potential therapeutic intervention strategies are also identified and validated in the laboratory using a variety of approaches including RNA interference and/or existing therapeutic agents in the appropriate model systems. At this time, our focal diseases are pancreatic cancer and multiple myeloma. We have begun to identify potential new targets in these tumors and are using both inducible shRNA systems for gene knock-down and targeted nanoparticles to validate possible intervention strategies in mouse xenograft models developed and characterized within our laboratory. While our research is focused on discovering new diagnostic and therapeutic strategies for metastatic and refractory disease, the translational infrastructure we have developed can be applied to a broad spectrum of other diseases. The optimal therapeutic target is no longer the disease based on organ site, but rather the molecular networks driving the clinical phenotype within the disease and the individual.

Van Andel Research Institute | Scientific Report Community initiatives As our research discoveries move closer to clinical application, we continue working to increase the readiness of the community to offer advances in molecular medicine. To translate our discoveries into human benefit, we must work in highly coordinated, multidisciplinary partnerships with community institutions. The synergistic goals are to benefit human health and promote Grand Rapids as a leader in translational medicine. The combination of powerful informatics, regulated diagnostics, and clinical trial coordination have aligned our collective community strengths with industrial demand and the FDA’s critical path intitiative. The following initiatives were successfully launched in 2006. • Innovative Clinical Research Alliance. Under the name “ClinXus”, this is a multi-institutional alliance that offers new biomarker-driven clinical trials to patients and physicians, and it will provide a single destination for pharmaceutical and biotech companies looking to carry out biomarker-drug co-development. In 2006, ClinXus obtained a .5 million state grant to accelerate the development of this community alliance. Partner institutions include VARI, Spectrum Health, Saint Mary’s Health Care, Jasper Clinic, Grand Valley Medical Specialists, and Grand Valley State University. Other members will join in 2007 as we continue to expand our collective capabilites for innovative clinical research. More information can be found at http://www.clinxus.com. 72 • The Center for Molecular Medicine. The CMM is a joint venture with Spectrum Health that is bringing cutting-edge, molecular-based diagnostic tests to physicians and their patients. It can offer a broad range of molecular services and has recently been certified by the College of American Pathology to run molecular diagnostic tests, including the Roche AmpliChip cytochrome p450 test indicating the correct dose for many prescription drugs. More information can be found at http://www.cmmdx.org. From left: Scott, Dobb, Hessler, Hillary, Koehler, Monsma, Cherba, Reinhold, Dylewski, Srikanth, Ross, Eugster, Webb

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