2008 Scientific Report

VARI | 2008
Community partnerships
Productive partnerships are pivotal to our efforts in biomarker research and personalized medicine. In the Center for
Molecular Medicine (CMM, http://www.commex.org), the Van Andel Institute and Spectrum Health Hospitals have created a
CLIA-certified/CAP-accredited clinical diagnostics laboratory for biomarker qualification and the development of associated
diagnostic assays. CMM offers cutting-edge molecular diagnostic tests, and also performs fee-for-service genomics and
proteomics work for commercial firms. Under Dr. Daniel Farkas, a national leader in molecular diagnostics, CMM provides
access to molecular technologies of today that will become central to our personalized medicine initiatives in the future.
ClinXus (http://www.clinxus.org) was developed to coordinate the West Michigan translational research enterprise. ClinXus
was awarded a Michigan 21st Century Jobs Fund grant to support early-stage development and operations, and it was recently
recognized for its efforts to develop biomarker strategies in translational studies by 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 prestigious 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 healthcare industry.
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 perturbed molecular systems within a tumor. We have also begun to consider means by which such information
should be conveyed to the treating physician in support of medical decision-making.
We recently completed a feasibility study of 50 late-stage pediatric and adult cancer patients: 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 are collected, qualified by pathology, and processed within the CMM to generate a
standardized gene expression profile for the tumor. These molecular data are uploaded into XB-BIS along with pertinent clinical
data, and these are compared with other patient samples. Deregulated patterns of gene expression are identified and analyzed
within XB-BIS to identify drugs that have predicted efficacy based upon the genomic data. A report scoring a series of drugs
for predicted efficacy is generated within XB-BIS, and this is conveyed to the treating physician in an actionable and electronic
format for consideration in treatment planning. The process from patient consent to molecular report must be completed in 10
days, which provides significant workflow challenges. In parallel, a series of tumor grafts is established in immune-compromised
mice, and these appear to closely resemble the human disease at the phenotypic and genotypic level. This resource is being
used to test biomarker-driven predictive models (and the identified drugs) in a more systematic fashion and to evaluate novel
targeted agents in partnership with industrial sponsors. 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 follow-up study with an expanded
population of 220 patients and a more rigorous statistical design. 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.
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