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2016 Scientific Report

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JEFFREY P. MACKEIGAN,

JEFFREY P. MACKEIGAN, PH.D. Dr. MacKeigan received his Ph.D. in microbiology and immunology at the University of North Carolina Lineberger Comprehensive Cancer Center in 2002. Dr. MacKeigan joined VARI in 2006 as an Assistant Professor and was promoted to Associate Professor in 2010. STAFF STEPHANIE CELANO, M.S. LUCUS CHAN, PH.D. KRISTIN DITTENHAFER-REED, PH.D. NICOLE DOPPEL, B.S. MATT KORTUS, M.S. KATIE MARTIN, PH.D. JOSH SCHIPPER, PH.D. KELLIE SISSON, B.S. STUDENTS ADITI BAGCHI, M.D. ANNALISE BOWEN DANIELLE BURGENSKE, PH.D. LELAND DUNWOODIE NATE MERRILL, B.S. NANDA KUMAR SASI, B.S. ABIGAIL SOLITRO, B.S. MEGAN VANBAREN RESEARCH INTERESTS The MacKeigan lab focuses on two hallmarks of cancer: the deregulation of cellular energetics and resistance to cell death. These hallmarks are regulated by mTOR signaling and contribute significantly to drug resistance in cancer. We seek a systems-level understanding of the network that encompasses the cell metabolism and autophagy signaling pathways. While our research focuses on human cancers, we also apply our tumor biology expertise and pathway knowledge to study tuberous sclerosis complex. Our laboratory uses cutting-edge tools and collaborates with multidisciplinary experts for robust experimental design and comprehensive data analysis. All of our research projects have one common goal: to identify novel therapeutic targets. Autophagy and resistance to cell death The process of autophagy functions to generate energy, clear damaged organelles, and delay or prevent cell death during times of cellular stress. Chemotherapeutic agents trigger autophagy, which allows cancer cells to adapt and withstand treatment. Therefore, a better understanding of autophagy is crucial for developing new and improved treatment strategies against cancer. ADJUNCT FACULTY BRIAN LANE, M.D., PH.D. In partnership with Los Alamos National Laboratory, our lab has used predictive computational modeling and cell-based measurements to accurately model the autophagic process. We are pleased to report that we have received a collaborative National Cancer Institute R01 award to validate and extend this model. The current efforts to enhance our model will help us predict the therapeutic benefit of inhibiting autophagy in cancer. We are also working with industry partners to determine the effects of candidate drugs on autophagic flux, and we have identified novel genes that are required for drug-induced autophagy. Lastly, our group conducts optimized kinase and phosphatase assays for in vitro evaluation of compounds identified in silico. Our research suggests that kinase inhibitors modulate autophagy and may be more selective and effective than current lysosomotropic agents. 14 Van Andel Research Institute | Scientific Report

Cancer metabolism and dysregulated cellular energetics Aggressive cancers are well known for their altered metabolic profiles and ability to withstand cytotoxic therapies. Thus, defining the relationship between dysregulated metabolism and evasion of apoptosis represents a critical need in the cancer field. Our research has shown that increased glycolysis in cancer cells leads to significant enrichment of the mitochondrial lipid cardiolipin, which serves many important functions in maintaining mitochondrial health. Most intriguing is its role in preventing the release of cytochrome c, a key event in the initiation of apoptosis. Our results suggest that the altered metabolic program of cancer cells may inherently support the evasion of apoptosis through cardiolipin production. We are investigating whether increased cardiolipin allows cancer cells to avoid death and resist chemotherapy. We have partnered with experts in glioblastoma multiforme and lipid mass spectrometry to uncover the mechanisms that may underlie cardiolipin’s ability to promote cell survival. A more complete understanding of the synthesis of cardiolipin and how changes in its concentration regulate cytochrome c release will contribute toward new mitochondria-targeted therapeutics for chemoresistant cancers. Pathway of Hope Tuberous sclerosis complex (TSC) is a genetic disease resulting from mutations in the TSC1 and TSC2 genes. These mutations inactivate the genes’ tumor-suppressive function, driving tumor cell growth and causing noncancerous tumors in vital organs such as the brain, skin, eyes, lung, and heart. These tumors can cause a host of health issues, including epilepsy and autism. Using chemical screening techniques, we are identifying approved, targeted compounds as possible therapies for TSC. Our lab is also characterizing the genomic landscape of TSC tumors using next-generation sequencing. We have gained a comprehensive understanding of TSC tumor biology, and we are seeking other cellular changes that can be targeted by therapies. TSC tumors are not always associated with second-hit somatic mutations to TSC1 or TSC2, suggesting that their pathogenesis may involve other genetic events, which we are working to uncover. We are also developing preclinical models of TSC for future validation studies of our drug candidates and genomic findings. Lastly, we have partnered with physician-scientists expert in TSC to determine whether precision medicine approaches can inform treatment strategies for TSC and predict patient outcomes. RECENT PUBLICATIONS Solitro, Abigail R., and Jeffrey P. MacKeigan. 2016. Leaving the lysosome behind: novel developments in autophagy inhibition. Future Medicinal Chemistry 8(1): 73–86. MacKeigan, Jeffrey P., and Darcy A. Krueger. 2015. Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex. Neuro-Oncology 17(12): 1550–1559. Szymańska, Paulina, Katie R. Martin, Jeffrey P. MacKeigan, William S. Hlavacek, and Tomasz Lipniacki. 2015. Computational analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1. PLoS One 10(3): e0116550. Wang, Tong, Megan L. Goodall, Paul Gonzales, Mario Sepulveda, Katie R. Martin, Stephen Gately, and Jeffrey P. MacKeigan. 2015. Synthesis of improved lysomotropic autophagy inhibitors. Journal of Medicinal Chemistry 58(7): 3025–3035. CENTER FOR CANCER AND CELL BIOLOGY 15

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