P roliferating tumor cells have different metabolic

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1 Keystone Symposia is a nonprofit organization headquartered in Colorado, directed and supported by the scientific community. Keystone Symposia is pleased to present Tumor Metabolism joint with the meeting on PI 3-Kinase and Interplay with Other Signaling Pathways February 24 March 1, 2013 Keystone Resort Keystone, Colorado P roliferating tumor cells have different metabolic requirements than most normal differentiated cells. All cells consume nutrients to generate ATP and maintain homeostasis; however, cell proliferation requires additional nutrient uptake to support macromolecular synthesis needed for cell growth. How metabolic pathways are regulated to balance these needs is not well understood, but mounting evidence suggests that metabolism is actively regulated to support cell growth, and that this regulation is intimately linked with the signal transduction pathways that control cell growth and proliferation. Metabolic changes represent some of the first differences ever noted between tumors and normal tissues. Yet, only recently has it been appreciated that many genetic events associated with cancer result in signal transduction changes to promote metabolism that is conducive to growth. This has accelerated research to understand metabolism in tumors with an eye toward targeting these pathways for improved cancer therapy. Bringing together scientists with expertise in signal transduction, nutrient and oxygen sensing, genetic events affecting metabolism, metabolic flux measurements and network modeling will provide an opportunity to discuss the latest data informing metabolic regulation in tumors. These discussions will impact studies of metabolism in other contexts. Similarly, emerging data related to metabolic regulation in the immune systems can inform studies of tumor metabolism. PI-3 kinase is a critical regulator of metabolism and there have been numerous advances in understanding this signaling pathway; a joint meeting addressing PI-3 Kinase will enrich the dialogue across disciplines to explore how metabolism influences multiple aspects of biology. Session Topics: > Metabolic Regulation > Nutrient Sensing > Metabolic Adaptation > Understanding the Metabolic Network > Influence of the Microenvironment on Metabolism > Insights from in vivo Experiments > Targeting Metabolism > Influence of Metabolism on Epigenetic Regulation Abstract & Scholarship Deadline: October 25, 2012 Late-Breaking Abstract Deadline: November 28, 2012 Early Registration Deadline: December 19, (US & Canada) Keystone Symposia is a nonprofit organization headquartered in Colorado, directed and supported by the scientific community. Note: Scholarships are available to students and postdoctoral fellows and require a brief application and submission of an abstract. Short talk speakers will also be selected from abstracts. Early registration saves US$150 on later fee. Information shown is subject to possible change. Please visit meeting website for the most up-to-date program information.

2 Sponsored by AVEO Oncology and Bayer Foundation February 24-March 1, 2013 Keystone Resort Keystone, Colorado, Sponsored by Bayer Foundation, Gilead Sciences, Inc., Infinity Pharmaceuticals and Pfizer Inc. SUNDAY, FEBRUARY 24 Arrival and Registration Welcome and Keynote Session (X3) *Kevan M. Shokat, University of California, San Francisco, *José Baselga, Memorial Sloan-Kettering Cancer Center, Roger L. Williams, Medical Research Council, UK Tuning Locomotions in the PI3K Pathway MONDAY, FEBRUARY 25 Welcome and Keynote Address (X4) Craig B. Thompson, Memorial Sloan Kettering Cancer Center, Metabolic Control of Tumor Cell Growth and Survival Metabolic Regulation (X4) *Karen H. Vousden, Crick Institute, UK Almut Schulze, University of Würzburg/Theodor-Boveri Institute, Germany The Role of Glucose and Lipid Metabolism in Growth and Survival of Cancer Cells Linda Z. Penn, Princess Margaret Cancer Centre, Canada The Mevalonate Pathway, Signaling and Tumor Vulnerability Daniel S. Peeper, Netherlands Cancer Institute, Netherlands Short Talk: A Critical Role for the Mitochondrial Gatekeeper Pyruvate Dehydrogenase in Oncogene-Induced Senescence Jing Chen, Winship Cancer Institute, Emory University, Short Talk: Phosphoglycerate Mutase 1 Coordinates Glycolysis and Biosynthesis to Promote Tumor Growth PI3K/Akt/mTOR Pathway in Cancer (Clinical - Part 1) (X3) *José Baselga, Memorial Sloan-Kettering Cancer Center, Breast Cancer Brett S. Carver,, Targeting the PI3K and AR Pathways in Prostate Cancer: Defining Mechanisms of Response and Resistance Vito J. Palombella, Surface Oncology, Development of the Potent PI3K-delta,gamma Inhibitor IPI-145 Khaled Ali, Barts Cancer Institute, UK Short Talk: Inactivation of p110delta PI 3-Kinase Releases Anti-Tumor Immune Responses Kyle A. Edgar, Genentech, Inc., Short Talk: Mechanisms of Acquired Resistance to the PI3K Inhibitor, GDC-0941 in Colorectal Cancer Cell Lines Workshop 1: Metabolic Regulation and Adaptation (X4) Ji Zhang, Indiana University, Why Cancer Cells Die without Glutamine? Brandon N. Nicolay, Agios Pharmaceuticals, Loss of RBF1 Changes Glutamine Catabolism Ming Yang, Beatson Institute for Cancer Research, UK Candidate Roles for Protein Succination in Altered Metabolism and Oncogenesis Talya L. Dayton, Massachusetts Institute of Technology, Elucidating a Role for Pkm Isoform Expression Specificity in vivo Darin Salloum, Memorial Sloan Kettering Cancer Center, Human Cancer Cells Harboring Ras Mutations Display Elevated Requirement for Serum Lipids Wei Liu, Frederick National Laboratory for Cancer Research, National Institutes of Health, Proline Biosynthesis Augments MYC-Induced Aerobic Glycolysis and Cell Growth Nutrient Sensing (X4) *Joan S. Brugge, Harvard Medical School, Eileen P. White, Rutgers University, Autophagy Maintains Mitochondrial Function and Tumorigenesis Matthew G. Vander Heiden, Massachusetts Institute of Technology, Metabolic Pathways Important for Cell Growth David M. Sabatini, Whitehead Institute for Biomedical Research Large-Scale Approaches to Study Cancer Metabolism Issam Ben-Sahra, Northwestern University, Short Talk: Growth Signaling Stimulates Nucleotide Synthesis through mtor PI3K/Akt/mTOR Pathway (Clinical - Part 2) (X3) Neal Rosen, Memorial Sloan-Kettering Cancer Center, Interplay Signaling Kui Lin, Genentech, Inc., Akt Mark G. Manfredi, Raze Therapeutics, The Development of MLN0128, an Investigational mtor Active Site Inhibitor Kathryn Balmanno, Babraham Institute, UK Short Talk: Modelling Acquired Resistance to mtor Kinase Inhibitors

3 Sponsored by AVEO Oncology and Bayer Foundation February 24-March 1, 2013 Keystone Resort Keystone, Colorado, Sponsored by Bayer Foundation, Gilead Sciences, Inc., Infinity Pharmaceuticals and Pfizer Inc. Poster Session 1 TUESDAY, FEBRUARY 26 Metabolic Adaptation (X4) *David M. Sabatini, Whitehead Institute for Biomedical Research Brian J. Altman, Wistar Institute, Regulation of Cell Growth and Metabolism by Myc Karen H. Vousden, Crick Institute, UK The Role of p53 in Metabolic Adaptation and Survival Zachary Schug, Wistar Institute, Targeting Lipid Metabolism in Breast Cancer Reuben J. Shaw, The Salk Institute for Biological Studies, The LKB1 Tumor Suppressor Pathway: Decoding Metabolic Links and Therapeutic Targeting Costas A. Lyssiotis, University of Michigan, Short Talk: Glutamine Metabolism Supports Pancreatic Tumor Growth and Redox Homeostasis Zhimin Lu, University of Texas MD Anderson Cancer Center, Short Talk: The Warburg Effect and Beyond PI3K/Akt/mTOR Pathway in Cancer (Clinical Translational) (X3) *Jeffrey A. Engelman, Novartis Institutes of BioMedical Research, Resistance Mechanisms Sebastian M. B. Nijman, CeMM, Austrian Academy of Sciences, Austria Gene-Drug Interaction Screens in Cancer *Lori Friedman, Genentech, Inc., PI3K Inhibitor Combination Therapies Jonathan M. Backer, Albert Einstein College of Medicine, GPCR Mediated Activation of p110beta by Gbetagamma Is Required for Cellular Transformation and Invasiveness Wayne A. Phillips, Peter MacCallum Cancer Centre, Australia Short Talk: Ubiquitous Expression of a Heterozygous Pik3ca Mutation Results in Increased Body Size, Hypoglycemia and Sudden Death Mamatha Bhat, University Health Network, Canada Short Talk: Metformin Induces Apoptosis of Hepatocellular Carcinoma Downstream of mtorc1 through eif4e Understanding the Metabolic Network (X4) *Ralph J. DeBerardinis, University of Texas Southwestern Medical Center, Tomer Shlomi, Technion, Israel An Integrated Computational-Experimental Approach for Finding Metabolic Synthetic Lethality in Cancer Joshua D. Rabinowitz, Princeton University, Revealing Cancer Metabolism with Isotope Tracers Linda C. Hsieh-Wilson, California Institute of Technology, Linking O-GlcNAc Signaling to Cancer Metabolism and Tumor Growth Stefan Kempa, Max Delbrück Center for Molecular Medicine, Germany Short Talk: Quantifying Metabolic Routes in Cancer Cells Using Pulsed Stable Isotope Resolved Metabolomics (psirm) PI3K/mTOR Pathway - Signaling Networks (Preclinical) (X3) *Kevan M. Shokat, University of California, San Francisco, Chemical Genetic Investigations of Protein and Lipid Kinase Signaling John Blenis, Weill Cornell Medical College, Convergence and Integration of mtor and Ras-ERK Signaling in Cancer David M. Sabatini, Whitehead Institute for Biomedical Research, Regulation of Growth by the mtor Pathway Tamara Chessa, Babraham Institute, UK Short Talk: Dissecting the ClassIA PI3K Signalosome Poster Session 2 WEDNESDAY, FEBRUARY 27 Influence of the Microenvironment on Metabolism (X4) *Sally A. Kornbluth, Duke University Medical Center, Jacques Pouysségur, University of Nice, France Hypoxia Signaling, phi Regulation and Tumor Metabolism: Novel Therapeutic Approaches M. Celeste Simon, University of Pennsylvania, Tumor Cell Adaptation to the Microenvironment Amato J. Giaccia, Stanford University, Oxygen Sensing and Metabolic Control Brendan D. Manning, Harvard School of Public Health, Tumor Cell Intrinsic Biosynthesis Driven by mtor Signaling Russell G. Jones, McGill University, Canada Short Talk: AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth in vivo *Lewis C. Cantley, Weill Cornell Medicine, PI 3-Kinase, AMPK and Disease Judith A. Varner, University of California, San Diego, PI3K gamma Control of Innate Immunity in Cancer Karen M. Cichowski, Brigham and Women's Hospital, Harvard Medical School, Developing Combination Therapies with PI3K/mTOR Pathway Inhibitors

4 Sponsored by AVEO Oncology and Bayer Foundation February 24-March 1, 2013 Keystone Resort Keystone, Colorado, Sponsored by Bayer Foundation, Gilead Sciences, Inc., Infinity Pharmaceuticals and Pfizer Inc. Hong Wu, UCLA/IMED c/o Cyndi Haddad, Cross-Talk between the PI3K and MAPK Pathways Determines Prostate Cancer Metastasis Kira Gritsman, Albert Einstein College of Medicine, Short Talk: RAS-Mutated Myeloid Leukemias Are Dependent on the PI3 Kinase Isoform p110alpha Maurizio Scaltriti, Memorial Sloan-Kettering Cancer Center, Short Talk: p90rsk Mediates Resistance to PI3K-Pathway Inhibitors in Breast Cancer Insights from in vivo Experiments (X4) *M. Celeste Simon, University of Pennsylvania, Tak W. Mak, Campbell Family Institute for Breast Cancer, Canada Tumor Metabolism: Insight from Mouse Models Yanping Zhang, University of North Carolina at Chapel Hill, The RP-Mdm2-p53 Pathway Links Nutrient Restriction to Lipid Homeostasis Ralph J. DeBerardinis, University of Texas Southwestern Medical Center, Measuring Metabolism and Metabolites in vivo Norman Koglin, Piramal Imaging GmbH, Germany PET Imaging of Glutamate/Cystine Transporter Activity in Cancer Patients PI3K Pathway: Cross-Talk, Feedback, Scaffold (Preclinical) (X3) Julian H. Downward, Cancer Research UK, UK Links between RAS Family GTPases and PI3K Signaling Peter K. Vogt, The Scripps Research Institute, The PI3K Pathway in Cancer Pier Paolo Pandolfi, Beth Israel Deaconess Medical Center, Harvard Medical School, Role of Mutant PTEN in Tumorigenesis John P. O'Bryan, Medical University of South Carolina, Short Talk: PI3KC2beta: Role in Tumorigenesis and Regulation by Nucleotide-Ras (nf-ras) Poster Session 3 THURSDAY, FEBRUARY 28 Targeting Metabolism (X4) *Jacques Pouysségur, University of Nice, France Bing Lim, Genome Institute of Singapore, Singapore Targeting Glycine Metabolism for Cancer Therapy Susan E. Critchlow, AstraZeneca, UK Targeting Lactate Metabolism in Cancer Sally A. Kornbluth, Duke University Medical Center, Metabolic Control of Caspase 2-Mediated Cell Death Joan S. Brugge, Harvard Medical School, Use of 3D Culture Models to Understand the Impact of Targeted Therapy on Metabolism Georgia Hatzivassiliou, Genentech, Inc., Short Talk: Dissecting the Role of Glutaminase in Cancer Genshi Zhao, Eli Lilly and Company, Short Talk: Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), an Enzyme Essential for NAD+ Biosynthesis, in Human Cancer Cells: Metabolic Basis and Potential Clinical Implications *Bart Vanhaesebroeck, University College London, Cancer Institute, UK PI 3-Kinase Isoforms in Cancer and Metabolism Davide Ruggero, University of California, San Francisco, Reprogramming Translational Control of mrna Networks in Cancer and its Therapeutic Implications Jonathan R. Hart, The Scripps Research Institute, Pulsed SILAC: Enabling the Direct Observation of Changes in Protein Synthesis Caused by mtor Inhibition William A. Weiss, University of California, San Francisco, Kinases in Autophagy as Therapeutic Targets in Brain Cancer Vikki Flemington, AstraZeneca, UK Short Talk: Phosphatidylinositol-4-Kinase Potent and Selective Inhibitors of Type III PI 4-Kinases Emilio Hirsch, Fondazione per la Ricerca Biomedica ONLUS, Italy Short Talk: PI3K Class II alpha Controls Primary Cilium Function and Cell Proliferation in Development and Cancer Workshop 2: Novel Therapeutic Approaches (X4) *Katharine Yen, Agios Pharmaceuticals, Steve Colebrook, Cancer Research UK, UK A First-in-Man Phase I Trial of AZD3965, a Monocarboxylate Transporter 1 Inhibitor (MCT1), in Patients with Advanced Cancer Krushna C. Patra, Massachusetts General Hospital, Harvard Medical School, Hexokinase 2 Is Required for Oncogenesis and its Systemic Deletion Is Therapeutic in Mouse Models of Cancer Alexandra R. Grassian, Novartis Institutes for BioMedical Research, Mutant Isocitrate Dehydrogenase Promotes a Reversible Epithelial-Mesenchymal Transition and Alters Metabolic Flux Kelly E. Sullivan, Cornell University, Elucidating the Regulation of Mitochondrial Glutaminase in Cancer Progression David R. Plas, University of Cincinnati, Transition to Fatty Acid Oxidation Mediates Survival of BCR-ABL-Transformed Cells after Inhibition of mtorc1-s6k1

5 Sponsored by AVEO Oncology and Bayer Foundation February 24-March 1, 2013 Keystone Resort Keystone, Colorado, Sponsored by Bayer Foundation, Gilead Sciences, Inc., Infinity Pharmaceuticals and Pfizer Inc. Influence of Metabolism on Epigenetic Regulation (X4) Lewis C. Cantley, Weill Cornell Medicine, Metabolic Control of Histone Methylation Kathryn E. Wellen, University of Pennsylvania, Use of Metabolic Pathways to Sense Cell State Katharine Yen, Agios Pharmaceuticals, Mutation Selective IDH Inhibitors Mediate Histone and DNA Methylation Changes Raul Mostoslavsky, Harvard Medical School, Short Talk: The Histone Deacetylase SIRT6 Suppresses Cancer Metabolism *David A. Fruman, University of California, Irvine, Immune Effects of Anti-Cancer Drugs Targeting PI3K/mTOR Brendan D. Manning, Harvard School of Public Health, Linking Oncogenic Signaling to Anabolic Metabolism through mtor Ramon Parsons, Icahn School of Medicine at Mount Sinai, PTEN Signaling Ralph M. Fritsch, Cancer Research UK London Research Institute, UK Short Talk: RAS and RHO Family GTPases Directly Regulate Distinct Phosphoinositide 3-Kinase Isoforms Panel Discussion (X4) FRIDAY, MARCH 1 Departure