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Provided by MediCom Worldwide, Inc.

Provided by MediCom Worldwide, Inc. Supported by an educational grant from Celgene Corporation. Not an official event of the 2016 Gastrointestinal Cancers Symposium. Not sponsored or endorsed by any of the cosponsoring organizations of the 2016 Gastrointestinal Cancers Symposium.

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  1. Provided by MediCom Worldwide, Inc. Supported by an educational grant from Celgene Corporation Not an official event of the 2016 Gastrointestinal Cancers Symposium. Not sponsored or endorsed by any of the cosponsoring organizations of the 2016 Gastrointestinal Cancers Symposium.

  2. Emerging Biology in Pancreatic Cancer James L. Abbruzzese, MD, FACP, FASCO Professor of Medicine Chief, Division of Medical Oncology, Department of Medicine Associate Director for Clinical Research and Training Duke Cancer Institute Durham, North Carolina

  3. Pancreatic Adenocarcinoma • Highly lethal tumor • 3% of all cancer cases in the US • 7% of all cancer deaths • 4th leading cause of cancer death • Lung • Colorectal • Breast • Pancreas http://www.cancer.org/cancer/pancreaticcancer/detailedguide/pancreatic-cancer-key-statistics http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-041783.pdf

  4. Recent Translational Progress • Initial histologic and molecular characterization of precursor lesions • Initial descriptions of mutational profile of pancreatic cancer • Development of GEMMs and patient-derived xenografts (PDX) • Importance of tumor-related stroma, stellate cells, and immunocytes • Recognition of the role of diabetes and obesity in pancreatic cancer risk and survival

  5. Recent Clinical Progress • Initial screening efforts for patients with FPC or known germ-line mutations conferring risk • Understanding the natural history of mucinous cystic neoplasms and development of initial criteria for surgical resection • Recognition that development of targeted agents will require understanding pancreatic cancer cellular heterogeneity • Development and FDA approval of nab-paclitaxel + gemcitabine • Integration of currently available modalities (surgery, radiation, chemotherapy)

  6. Critical Questions - Areas of Greatest Need • Can we identify cohorts of individuals at high risk? • Can we screen patients deemed to be at high risk and identify pre-invasive pathologic precursors or very early cancer? • Can we develop effective systemic therapies?

  7. Pancreatic Cancer: Scanning the Horizon for Focused Interventions A Report to the Director of the National Cancer Institute The Pancreatic Cancer Working Group Clinical Trials and Translational Research Advisory Committee March 13, 2013 National Cancer Institute (NCI). Division of Extramural Activities. CTAC Working Group Reports and Supplements. http://deainfo.nci.nih.gov/advisory/ctac/archive/0313/PCwgReport.pdf

  8. Four Initiatives • Understand the biological relationship between PDAC and nutrient excess • Develop and evaluate longitudinal screening protocols for biomarkers for early detection of PDAC and its precursors • Develop new treatment approaches that interfere with KRAS oncogene-dependent signaling pathways • Study new therapeutic approaches: Immunotherapy and stromal disruption National Cancer Institute (NCI). Division of Extramural Activities. CTAC Working Group Reports and Supplements. http://deainfo.nci.nih.gov/advisory/ctac/archive/0313/PCwgReport.pdf

  9. Four Initiatives • Understand the biological relationship between PDAC and nutrient excess • Develop and evaluate longitudinal screening protocols for biomarkers for early detection of PDAC and its precursors • Develop new treatment approaches that interfere with KRAS oncogene-dependent signaling pathways • Study new therapeutic approaches: Immunotherapy and stromal disruption National Cancer Institute (NCI). Division of Extramural Activities. CTAC Working Group Reports and Supplements. http://deainfo.nci.nih.gov/advisory/ctac/archive/0313/PCwgReport.pdf

  10. Pancreatic Cancer Risk Factors • Environmental • Cigarette smoking (~25%) • Chronic pancreatitis • Metabolic (>25%) • Obesity • Diabetes • Genetic • Pancreatic cancer families • Hereditary syndromes • Mucinous pancreatic cysts • Mucinous cystic neoplasm • Intrapancreatic mucinous neoplasm (IPMN) MORE CONTROL LESS CONTROL Decker GA, et al. Gastroenterol Hepatol (N Y). 2010;6(4):246-254.; Andersen DK, et al. Pancreas. 2013;42(8):1227-1237.; NCCN Guidelines Pancreatic Adenocarcinoma. Version 2.2015.; McWilliams RR, et al. Pancreas. 2015 Dec 5. [Epub ahead of print].

  11. Aberrant Metabolism is Both a Cause and a Result of Pancreatic Carcinogenesis Germ line genetic modifiers Nutrient Signaling Pathway Activation Physiologic Metabolic Alterations Obesity Diabetes Effects on Pancreas Cells Hyperglycemia Metabolic Syndrome Genotoxic Stress KRAS mutation Genomic Instability Altered Cellular Metabolism Cohen R, et al. Oncotarget. 2015;6(19):16832-16847.; Blum R, et al. Cell Death Dis. 2014;5:e1065.

  12. Nutrient Excess is a Risk Factor for Pancreatic Cancer Germ line genetic modifiers Nutrient Signaling Pathway Activation Physiologic Metabolic Alterations Obesity Diabetes Effects on Pancreas Cells Hyperglycemia Metabolic Syndrome Genotoxic Stress KRAS mutation Genomic Instability Altered Cellular Metabolism Cohen R, et al. Oncotarget. 2015;6(19):16832-16847.; Blum R, et al. Cell Death Dis. 2014;5:e1065.

  13. What are the observations linking alterations in whole-body energy metabolism to pancreatic carcinogenesis?

  14. Pancreatic Cancer Risk and DiabetesGeneral Observations • Pancreatic cancer induces the diabetic state • Patients with new-onset diabetes • 1/125 new onset diabetics develop pancreatic cancer in 2-3 years • Diabetics with recent initiation of insulin • Longstanding (type II) diabetes and insulin resistance influences pancreatic carcinogenesis • Individuals with a history of diabetes >5 years have SRR of 2.0 (95% CI 1.2-3.2) Chari ST, et al. Gastroenterology. 2005;129:504–511.; Everhart J, Wright D. JAMA. 1995;273:1605-1609.; Hart PA, Chari ST. Pancreas. 2013;42(8):1207-1209.; Li D. Am J Cancer Res. 2015;5(10):3260-3269.

  15. Diabetes and Risk of Pancreatic Cancer Li D, et al. Gastroenterology. 2009;137(2):482-488.

  16. Pancreatitis, Diabetes, and Pancreatic Cancer Pancreatogenic (T3cDM) DM Islet cell loss Type II Diabetes Chronic Pancreatitis “Diabetogenic” Pancreatic cancer Pancreatic Cancer Pancreatogenic (T3cDM) DM (PC-DM) ? paraneoplastic Andersen DK, et al. Pancreas. 2013;42(8):1227-1237.

  17. SummaryWhole-body energy metabolism: Diabetes • New onset (or worsening) diabetes is a risk factor for pancreatic cancer • Patients with long-standing diabetes are also at slightly increased risk • Diabetic patients treated with insulin or insulin secretagogues were at higher risk; metformin-treated patients had a significantly lower risk of pancreatic cancer compared with those who had not taken metformin

  18. Obesity • Overweight and obesity are associated with 14% of all cancer deaths in men and 20% of cancer deaths in women1 • Obesity increases the risk of insulin resistance and overt diabetes2 1Calle EE, et al. N Engl J Med. 2003;348(17):1625-1638. 2Kahn SE, et al. Nature. 2006;444(7121):840-846.

  19. Obesity and Pancreatic Cancer Hospital-Based Case Control Study • Goals: • Examine the impact of excess body weight across life span and risk of pancreatic cancer • Examine the influence of BMI on age of onset of pancreatic cancer • Examine the influence of BMI on patient survival • Design • Case-control study (841 patients and 754 matched controls) • Height and body weight collected by personal interview Li D, et al. JAMA. 2009;301(24):2553-2562.

  20. All Study Participants Association of BMI and risk of pancreatic cancer Li D, et al. JAMA. 2009;301(24):2553-2562.

  21. Obesity and Pancreatic Cancer Age of Onset Overall Survival Normal weight Overweight Obese Normal weight Overweight Obese Li D, et al. JAMA. 2009;301(24):2553-2562.

  22. Pancreatic Inflammation, Obesity, and Pancreatic Cancer Pancreatogenic (T3cDM) DM Islet cell loss Obesity Chronic Pancreatitis Pancreatic Cancer “Nutrient Excess -Related” Pancreatic cancer Andersen DK, et al. Pancreas. 2013;42(8):1227-1237.

  23. SummaryWhole-body Energy Metabolism: Obesity • Obesity is closely associated with increased risk and earlier age of onset of pancreatic cancer • Obesity has a negative prognostic impact on survival for all stages of patients with pancreatic cancer

  24. These observations serve to emphasize the important relationship between pancreatic carcinogenesis, and whole-body energy metabolism

  25. What are the cellular genomic and metabolic consequences of hyperglycemia and obesity for pancreatic carcinogenesis?

  26. Cellular Impacts of Nutrient Excess • Insulin resistance and hyperinsulinemia • Increased signaling through nutrient sensing signaling pathways • Hexosamine signaling pathway • mTOR signaling pathway • Increased ROS leading to genotoxicity Wellen KE, Thompson CB. Mol Cell.2010;40(2):323-332.

  27. Nutrient Deficiency and Nutrient Excess Cause Cellular Stress Wellen KE, Thompson CB. Mol Cell.2010;40(2):323-332.

  28. Aberrant Metabolism Is Also a Result of Pancreatic Carcinogens Germ line genetic modifiers Nutrient Signaling Pathway Activation Physiologic Metabolic Alterations Obesity Diabetes Effects on the Pancreas Hyperglycemia Metabolic Syndrome Genotoxic Stress KRAS mutation Genomic Instability Altered Cellular Metabolism Cohen R, et al. Oncotarget. 2015;6(19):16832-16847.; Blum R, et al. Cell Death Dis. 2014;5:e1065.

  29. Mutated KRAS Initiates Pancreatic Carcinogenesis Morris JP 4th, et al. Nat Rev Cancer. 2010;10(10):683-695.

  30. Pancreatic InflammationCritical Mechanistic Link Between KRAS Mutation and Pancreatic Cancer • Activation of KRAS in adult mice does not induce mPanINs and mPDAC • Adult acinar cells are resistant to oncogenic insults • Pancreatitis induces mPanINs and mPDAC in mutant KRAS expressing adult acinar cells • Pancreatic inflammation contributes to mPanIN development by inhibiting oncogene induced senescence • Pancreatic inflammation blocks senescence in human PanINs Guerra C, et al. Cancer Cell. 2007;11(3):291-302.; Guerra C, et al. Cancer Cell. 2011;19(6):728-739.

  31. What are the cellular metabolic consequences of activating KRAS mutations?

  32. KRAS Mutation Metabolic Reprograming • Increased glucose uptake and metabolism (Warburg effect) • Increased GLUT1, HK1, HK2 expression • Differential channeling of glucose intermediates • Hexosamine biosynthetic pathway • Non-oxidative pentose phosphate pathway • Reprograming glutamine metabolism • Increased autophagy • Mitophagy • Increased macropinocytosis Locasale JW, et al. Cell. 2012;149(3):656-670.

  33. KRAS Mutation Metabolic Reprograming • Increased glucose uptake and metabolism (Warburg effect) • Increased GLUT1, HK1, HK2 expression • Differential channeling of glucose intermediates • Hexosamine biosynthetic pathway • Non-oxidative pentose phosphate pathway • Reprograming glutamine metabolism • Increased autophagy • Mitophagy • Increased macropinocytosis Locasale JW, et al. Cell. 2012;149(3):656-670.

  34. Increased Rates of Macropinocytosis in Ras-transformed Cells Commisso C, et al. Nature. 2013;497(7451):633-637.

  35. Summary • Metabolic alterations leading to hyperglycemia and hyperinsulinemia activate nutrient sensing pathways and increase ROS contributing to pancreatic carcinogenesis • Obesity is an important risk factor with excess adipose tissue resulting in high levels of circulating adipokines and inflammatory mediators activating many pro-carcinogenic pathways • Epidemiology and mechanistic studies suggest that chronic pancreatic inflammation is a common driver of pancreatic carcinogenesis

  36. Summary • Mutations in KRAS activate canonical cancer-related pathways, but also contribute to extensive metabolic reprograming of pancreatic cancer cells • A greater understanding of these metabolic alterations may lead to novel therapeutic strategies

  37. The Current Treatment Landscape of Pancreatic Cancer: Optimizing Outcomes through Individualized Therapy Philip A. Philip, MD, PhD, FRCP Professor of Oncology and Internal Medicine Dr. Kathryn Cramer Endowed Chair in Cancer Research Leader, GI & Neuroendocrine Multidisciplinary Team Vice President for Medical Affairs Barbara Ann Karmanos Cancer Institute Wayne State University School of Medicine Detroit, Michigan

  38. Spectrum of Pancreatic Cancer 4 Cured Resectable R0/R1 16 Surgically explored 3 4 20 100 Pancreatic Cancer 35 Localized unresectable Metastatic 37 96 End stage 8

  39. Increasing Availability of Therapies for Pancreatic Cancer Liposomal irinotecan Erlotinib Nab-paclitaxel Gemcitabine FOLFIRINOX 1998 2002 1994 2006 2010 2014 2015 S1 U.S. Food and Drug Administration (FDA).

  40. Incremental Benefits With New Agents in Frontline Burris HA, et al. J Clin Oncol. 1997;15:2403-2413.; Moore MJ, et al. J Clin Oncol. 2007;25:1960-1966.; Conroy T, et al. N Engl J Med. 2011;364:1817-1825.; Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703.

  41. FOLFIRINOX versus Gemcitabine in Metastatic Pancreatic Cancer FOLFIRINOX R A N D O MI Z E Metastatic Good PS Good LFTs Gemcitabine Primary endpoint = overall survival (11.8 vs 6.1, P < .0001) Doubling of RR, PFS, survivals at 6 and 12 months Conroy T, et al. N Engl J Med. 2011;364(19):1817-1825.

  42. Time Until Definitive Deterioration >20 Points in EORTC-QLQ C30 Global Health Status Gourgou-Bourgade S, et al. J Clin Oncol. 2013;31(1):23-29.

  43. Nab-Paclitaxel + Gemcitabine: Phase 3 Study (MPACT)1,2 Nab-paclitaxel 125 mg/m2 Gem 1,000 mg/m2QW 3/4 wk (n = 431) R 1:1 Gem 1,000 mg/m2 QW for 7 wk, then QW 3/4 wk (n = 430) Primary endpoint: OS Secondary endpoints: PFS, ORR (n = 431) (n = 430) Months Nab-P=Nab-paclitaxel 1Von Hoff D, et al. N Engl J Med. 2013;369:1691-1703. 2Von Hoff D, et al. ASCO GI 2013. Abstract LBA148.

  44. Nab-P/Gem or FOLFIRINOX? Cross-trial comparisons should be interpreted with caution a 29% by investigator and 23% by independent review (IR). b 44% of patients resumed therapy when neuropathy was ≤ grade 1. RR=response rate 1Von Hoff D, et al. N Engl J Med. 2013;369:1691-1703. 2Conroy T, et al. N Engl J Med. 2011;364:1817-1825.

  45. Major Determinants of Treatment Choice in Advanced Pancreatic Cancer • Performance status • Age • Major liver dysfunction/biliary stent • Patient preference • UGT1A1 • Pre-existing neuropathy • Albumin • Platelet count • Ascites • ?? Biomarkers NCCN Guidelines Pancreatic Adenocarcinoma. Version 2.2015. Release date 3/6/2015.

  46. Deeper Responses with Combination Therapy Before After Courtesy Dr. P. Philip

  47. How to Improve on Current Gains • Increasing cytotoxic power • Rational sequencing of therapies • Using maintenance therapies of biological value • Changing cytotoxics • Targeted therapy • Immune modulation • Exploiting biology to predict patient outcome • Incorporating ablative/surgical strategies to treat residual disease Chiorean E, et al. Drug Des Devel Ther. 2015;9:3529-3545.

  48. Evolution of Frontline Regimens Over Next 5 Years erlotinib Nab-paclitaxel 5-FU Oxaliplatin FOLFIRINOX Gemcitabine/nab-paclitaxel Gemcitabine Nab-paclitaxel/5-FU MM-398/5-FU MM-398/Nab-paclitaxel/5-FU Oxaliplatin/nab-paclitaxel/5-FU Oxaliplatin/MM-398/5-FU Gemcitabine/Cisplatin MM-398 Gemcitabine Cisplatin Irinotecan Teague A, et al. Ther Adv Med Oncol. 2015;7(2):68-84.

  49. Nab-paclitaxel + mFOLFOX (FOLFOX-A) in Good PS Patients: Active and Safe • Phase I trial from Brown University • N = 15, previously untreated, PS 0-1 • FOLFOX/Nab-paclitaxel (125-175 mg/m2/2w) • Recommended phase 2 dose is 150 mg/m2 • DLTs were nausea and fatigue • Two patients with grade 3 neuropathy ≥10 cycles • Objective response rate = 53% • Phase II is underway Safran H, et al. GI Symposium, #258, 2014.

  50. Nab-P/Gem After FOLFIRINOX: Retrospective Review1 • Retrospective review from Yale; 23 patients identified who received nab-P/Gem after a median of 12 cycles FOLFIRINOX; endpoints: dose, toxicity, ORR, TTF, OS Time to Treatment Failure and Survival Response Assessment Dose Reductions and Density 1Zhang Y, et al. Exp Hematol Oncol. 2015;4:29.

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