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2013 Scientific Report

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VARI | 2013 Research Interests The Laboratory of Translational Medicine (LTM) is a multidisciplinary group with both basic and applied research components. Our basic research is focused on deciphering the molecular basis of solid tumor metastasis, with particular emphasis on the role of the putative cancer stem cell and tumor-host interactions during the early establishment and subsequent progression of metastases in critical organs such as the liver and lung. We focus on pancreatic cancer, triple-negative breast cancer, melanoma, adult and pediatric brain tumors, and pediatric osteosarcoma. Our applied research efforts have resulted from our development of the translational research infrastructure needed to permit real-time, precision medicine (PMed) clinical trials for patients with metastatic and/or refractory disease. Through our expertise and resources in bioinformatics, genomics, preclinical models, clinical trial design, and regulatory affairs, the lab is currently supporting prospective PMed trials in pediatric and adult human patients, as well as in canines with advanced-stage tumors. Given these collective capabilities, the laboratory is initiating collaborative efforts to repurpose existing drugs for specific patient populations. Pancreatic cancer Pancreatic cancer (PCa) is the fourth leading cause of cancer-related mortality in the United States, with an estimated 37,000 deaths per year and a dismal 5-year survival of less than 6% that has not improved greatly over the past 30 years. As in other cancers, the development of secondary metastases within critical organs, notably the liver, accounts for the majority of PCa-related morbidity and mortality. Identifying the key determinants that drive the early establishment and progression of liver metastases is paramount to improving long-term outcomes for patients. Current efforts within the LTM include investigating the interaction between PCa cells and the host macrophages (Kupffer cells) and stellate cells within the micro-metastatic niche of the liver. Metastatic melanoma Patients who develop metastatic melanoma (MM) have a poor prognosis, with a median survival of 6–9 months and a 3-year survival rate of 10–15%. The tumors of approximately 40% of MM patients harbor an activating mutation in the BRAF gene which confers sensitivity to B-Raf inhibitors such as the recently approved agent vemurafenib. Through the award of a Stand- Up-2-Cancer grant, we are enhancing the lab’s PMed bioinformatics framework to incorporate next-generation sequencing and phosphoproteomic technologies. The goal of this project is to identify, in real time, the key molecular drivers of B-Raf wild-type MM and align these findings to a series of experimental agents from biopharmaceutical companies; patients will be treated on the basis of these real-time findings. In patients whose MM harbors an oncogenic BRAF mutation, the tumors initially show an impressive response to B-Raf inhibitors such as vemurafenib. However, the synchronous regrowth of tumors after a period of treatment is a common occurrence. To investigate the molecular mechanism of drug resistance, the lab has developed a large number of primary patient tumorgrafts for many solid tumors (including MM) that closely resemble the patient’s tumor at the molecular, histopathological, and treatment-response levels. These models preserve a number of key aspects of the tumor-host microenvironment. We are using these tumorgraft models to investigate the role that the innate immune systems play in the onset of drug resistance in MM and developing combination treatment strategies to treat vemurafenib-resistant MM. 61

Van Andel Research Institute | Scientific Report Triple-negative breast cancer The breast cancers referred to as triple negative (ER – , PR – , HER2 – ) represent a highly aggressive subtype for which no effective therapies exist. Thus, patients with triple-negative breast cancer (TNBrCa) have a poor prognosis. Within a heterogeneous tumor there resides a subpopulation of cells with stem cell–like properties known as cancer stem cells (CSCs). According to the CSC hypothesis, a hierarchical tumor organization exists in which deregulated, self-renewing CSCs drive tumorigenesis. CSCs are believed to be the key malignant cell contributing to metastasis and drug resistance, and targeting these cells therefore represents an excellent therapeutic opportunity against multiple tumor types including TNBrCa. Through a Komen Promise grant, the lab is working to characterize the CSCs from TNBrCa patients of different ethnic backgrounds at the genetic, epigenetic, and genomic levels to identify candidate targets for therapy. Adult and pediatric glioblastoma Glioblastoma (GBM) represents a group of highly aggressive and often recurrent brain tumors that affect both adults and children. Adult and pediatric GBM are largely indistinguishable by morphology or pathology, and their treatment regimens have been similar, with overall poor success. Some recent molecular characterization of GBMs from the two patient populations suggests that the molecular drivers of disease may be quite distinct, warranting different treatment considerations. Efforts in the lab include the identification of key signaling pathways in both adult and pediatric GBM and the evaluation of combinational treatment strategies for each. Osteosarcoma Osteosarcoma (OSA) is the most common primary bone malignancy in children, with a high rate of local recurrence and metastasis to the lungs. We have recently initiated efforts to characterize the CSCs within pediatric OSA with the goal of identifying CSC-directed therapies. These efforts will soon be expanded to implement a prospective PMed clinical trial in pediatric patients with OSA. As the most common primary bone tumor in dogs, canine OSA is comparable to the human disease at many levels, including its high propensity to metastasize to the lungs. We are also assessing our PMed approach for canine OSA patients to determine the feasibility of genomically profiling the disease in real time to support therapy selection by veterinarians. Recent Publications Sholler, Giselle L. Saulnier, William Ferguson, Genevieve Bergendahl, Erika Currier, Shannon R. Lenox, Jeffrey Bond, Marni Slavik, William Roberts, Deanna Mitchell, Don Eslin, et al. In press. A pilot trial testing the feasibility of using molecularguided therapy in patients with recurrent neuroblastoma. Journal of Cancer Therapy. Mazzarella, Richard, and Craig P. Webb. 2012. Computational and bioinformatic strategies for drug repositioning. In Drug Repositioning: Bringing New Life to Shelved Assets and Existing Drugs, Michael J. Barratt and Donald E. Frail, eds. New York: Wiley and Sons, pp. 91–128. Monsma, David J., Noel R. Monks, David M. Cherba, Dawna Dylewski, Emily Eugster, Hailey Jahn, Sujata Srikanth, Stephanie B. Scott, Patrick J. Richardson, Robin E. Everts, et al. 2012. Genomic characterization of explant tumorgraft models derived from fresh patient tumor tissue. Journal of Translational Medicine 10: 125. Lee, Chih-Shia, Karl J. Dykema, Danielle M. Hawkins, David M. Cherba, Craig P. Webb, Kyle A. Furge, and Nicholas S. Duesbery. 2011. MEK2 is sufficient but not necessary for proliferation and anchorage-independent growth of SK-MEL-28 melanoma cells. PLoS One 6(2): e17165. 62

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