David C Whitcomb MD PhD

Transcription

1 9 th International Symposium on Inherited Diseases of the Pancreas PancreasFest 2016 Pittsburgh, PA David C Whitcomb MD PhD Director, UPMC Precision Medicine Service Giant Eagle Foundation Professor of Cancer Genetics. Professor of Medicine, Cell Biology & Physiology, and Human Genetics Division of Gastroenterology, Hepatology and Nutrition. University of Pittsburgh

2 Outline 20 years ago Limits of Mendilian Syndromes NAPS2 The SAPE Mechanistic Hypothesis TIGAR-O Etiology List Complexity Precision Medicine

3 Part 1 20 YEARS AGO

4 Chronic Pancreatitis Syndrome: Pancreatic inflammation Scarring (80%) Maldigestion (50%) Diabetes mellitus (40%) Pain (variable: 0 to 10) Pancreatic cancer (5-40%) Diagnosis and Treatment Diagnosis: requires demonstration of irreversible damage Methods: repeated morphologic tests (CT, MRI, ERCP and/or EUS) Treatment = symptomatic: PERT, insulin, pain control, duct decompression, TPIAT Summary: a hopeless, irreversible condition that is expensive to diagnose and treat. 4 Whitcomb DC, Nature Reviews: G&H, 2012

5 Howes et al. Clin Gastroenterol Hepatol. 2004;2(3):252-61

6 Larry Gates MD Chuck Ulrich II, Steve Martin MD, Dave Whitcomb MD PhD Midwest Multicenter Pancreatic Study Group (MMPSG) Hereditary pancreatitis = Cationic Trypsinogen (PRSS1)

7 Innovation: The MMPSG was based on dedicated friendships and audacious plans. Hard work: Started a new multicenter research program Recruited a large family from Kentucky and West Virginia Started the Center for Genomic Sciences at the University of Pittsburgh to obtain DNA sequencers Plowed through the genome synthesizing and testing primer by primer More friends joined to obtained confirmatory families Result 1: The discovery that PRSS1 mutations caused HP revolutionized our understanding of mechanisms of acute pancreatitis and chronic pancreatitis Result 2: Many outstanding groups began searching for other genetic factors linked to acute and chronic pancreatitis

8 GATA2 PAX3 TGFB1 mir-296 signaling network PRSS1 Expression Trypsinogen Zymogen Granule Degradation Cathepsin B SPINK1 Activation Chymotrysin C Enteropetidase (duodenum) Trypsin Ca 2+ Trypsinogen is synthesized in the pancreatic acinar cells With stimulation trypsinogen is transported to the intestine by fluid from the duct cells. Premature activation to trypsin inside the pancreas may lead to acute pancreatitis.

9 1989 CFTR (Cystic Fibrosis) 1996 PRSS1 (+) (Hereditary Pancreatitis: RAP-CP) 1998 CFTR Atypical CF CFTR/SPINK SPINK1 Familial and disease modifier 2003 CASR complex (with SPINK1, CFTR.) 2003 SBDS Shwachman Diamond Syndrome 2006 CEL pancreatitis and diabetes (MODY8) 2008 CTRC complex (with SPINK1, CFTR ) 2011 CFTR bicarbonate defective variants 2012 CLDN2 / PRSS1 (protective) alcohol 2013 CPA1 UPR GGT1, MMP1, MTHFR, IL23R, etc.

10 Part 2 LIMITS OF MENDELIAN SYNDROMES

11 Cystic fibrosis Hereditary Pancreatitis Shwachman-Diamond Syndrome Johanson-Blizzard syndrome Occasional Familial Pancreatitis Less than 5% of most CP populations Where is the missing heritability?

12 Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461(7265): Whitcomb, Shelton, Brand. Gastroenterology 2015 PMID:

13 Part 5 NAPS2 NORTH AMERICAN PANCREATITIS STUDY II

14 NAPS2 Sites (Site-PI) Bold=NAPS2-CV Brigham & Women s MC, Boston (Banks) Cedars-Sinai MC, Los Angeles (Simon Lo) Dartmouth-Hitchcock MC, NH (Gardner) Evanston NWU. Chicago (Brand) Indiana Univ., Indianapolis, IN (Sherman) Mayo Clinic Jacksonville, FL (Lewis) MUSC, Charlestown, SC (Hawes) No. Mississippi MC, Tupelo, MS (Amann) Ochsner MC, New Orleans (Etemad) St Louis Univ. (Burton) Rush UMC, Chicago (DeMeo) Univ. Alabama Birmingham (Wilcox) Univ. Cincinnati (Gelrud) Univ. Florida (Forsmark) Univ. Michigan (Anderson) University of Pennsylvania (Kochman) Univ. Pittsburgh, UPMC (Slivka) Univ. Utah (DiSario) Virginia Comm. U (Sandhu) Washington Co, Hagerstown, MD (Money) Washington Hospital, DC (Steinberg) Funding: NIDDK, NPF, UPMC NAPS2-AS (PI-Site) + Aurora-St. Luke s MC, Milwaukee (Guda) + UABMD, Birmingham (Wilcox) + Griffin Hospital, Derby, CT (Muniraj) o Brigham & Woman s MC (New PI: Conwell) o Indiana Univ. (New PI: Cote) o MUSC (New PI: Romagnuolo) o Pittsburgh Shadyside (Brand, Gelrude) o St Louis Univ. (PI: Alkaade ) NAPS2 DNA & Biomarker Core DNA - David Whitcomb MD PhD (DNA) Biomarkers Brand, Papachristou Database manager O Connell Stello, Elinoff, Boggano, Hendricks, Solomon NAPS2- Analysis Cores Clinical Epidemiology Yadav Epidemiology Data Center Wisniewski Genetic modeling Barmada, Langmead Computational Genetics Devlin Collaborating Programs (Site PI) Liverpool, England (Neoptolemos) Greifswald, Germany (Lerch) Penn Statue Univ, Hershey (Smith) Alzheimer s Disease Genetics Consortium NeuroGenetics Research Consortium

15 Part 3 THE SAPE MECHANISTIC HYPOTHESIS BASIS OF NAPS2

16 Random Injury Alcohol withdrawal Gallstones Modifying factors ETOH, smoking, genes Stressors Normal Biomarkers (High Risk) No Mφ Acute Pancreatitis Sentinel AP (RAP) active Mφ CP Fibrosis PEI DM Pain PDAC Patients have high-risk genes for years without evidence of disease Modifying factors appear to have minimal effect in asymptomatic people An random episode of acute pancreatitis clearly activates the immune system An active immune system can be influenced by modifying factors to drive all of the features of chronic pancreatitis. Whitcomb DC.. Gut. 1999;45: PMID: Whitcomb Gastroenterology 2013;144: Deng X, et al. Am J Pathol. 2005;166(1): PMID: (first animal model)

17 Effects of a modifying factor on AP CP Progression is influenced by continued alcohol consumption Follow up information on alcohol consumption (n=450): Complete cessation (39.3%); Decreased but occasional (23%) Decreased but daily (6.7%); Continued drinking as before (30.4%) Takeyama Y.et al Clin Gastroenterol Hepatol. 2009;7 Yadav D. Curr Gastroenterol Rep. 2011;13(2):157-65

18 Etiology affects the risk of RAP RAP is a primary driver of CP Yadav D, O'Connell M, Papachristou GI. Natural history following the first attack of acute pancreatitis. The American Journal of Gastroenterology Jul;107(7): [PMID: ]

19 Part 4 TIGAR-O INVENTED FOR NAPS2

20 Rationale for the TIGAR-O system Chronic pancreatitis (CP) is a complex syndrome without a single etiology. Subjects have multiple risks The overall risk is a product of all risk factors. Multiple risk factors may be required for CP to develop. Some risk factors can be reduced or eliminated to help prevent CP from developing. TIGAR-O provided an organized list for each individual person. TIGAR-O (Version 1) Toxic-Metabolic Alcoholic Tobacco smoking Hypercalcemia Chronic Renal Failure Idiopathic Tropical Genetic Autosomal Dominant Autosomal Recessive Complex Autoimmune Recurrent and Severe Acute Obstructive Etemad & Whitcomb, Gastroenterology 2002

21 Part 6 COMPLEXITY

22 Fraction of Population Mechanism 1 Mechanism 2 Mechanism 3 Mechanism 4 Best evidence with NNT>>1 NO evidence! Less severe Inclusion/Exclusion criteria Disease Severity More severe

23 Fraction of Population Mechanism 1 Mechanism 2 Mechanism 3 Mechanism 4 Non-responders Highest cost Less severe Inclusion/Exclusion criteria Disease Severity More severe

24 Millions USD ($) Click BH, et al. Gastroenterology 2015; 148:S-40 S-41. Median $14,191 High $683, Patient # (N=2203) Slide courtesy of David Binion MD, University of Pittsburgh and UPMC

25 Part 7 PRECISION MEDICINE

26 Chronic Pancreatitis Syndrome: Pancreatic inflammation Scarring (80%) Maldigestion (50%) Diabetes mellitus (40%) Pain (variable: 0 to 10) Pancreatic cancer (5-40%) Diagnosis and Treatment Diagnosis: requires demonstration of irreversible damage Methods: repeated CT, MRI, ERCP and/or EUS Treatment: symptomatic, pain treatments, PERT, insulin Summary: a HOPELESS, irreversible condition that is expensive to diagnose and treat. CONCLUSION: We must prevent the development of syndromes that are irreversible 26 Whitcomb DC, Nature Reviews: G&H, 2012

27 Current Approach Precision Approach First Symptoms Time in years Symptoms Testing for Organ damage Clinical Diagnosis Testing for Genetic Factors Mechanistic Diagnosis Preventative Treatment Symptoms Symptomatic Treatment Patient is Disabled Patient is much better

28 1. Must re-define chronic pancreatitis Define the LATE characteristics (done) Define the essence of CP (missing) 2. Must develop a progressive model 1. Must include all STAGES 2. Must include all SYSTEMS 3. Must include all ETIOLOGIES 4. Must be PREDICTIVE 5. Must gain international CONSENSUS

29 July 9, 2016 ESSENCE: Chronic pancreatitis is a pathologic fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathologic responses to parenchymal injury or stress. CHARACTERISTICS: Common features of established and advanced CP include pancreatic atrophy, fibrosis, pain syndromes, duct distortion and strictures, calcifications, pancreatic exocrine dysfunction, pancreatic endocrine dysfunction, and dysplasia. Focused on the normal and abnormal response to the injury inflammation resolution regeneration sequence Whitcomb DC, Frulloni L, Garg P, Greer JB, Schneider A, Yadav D, et al. Chronic pancreatitis: An international draft consensus proposal for a new mechanistic definition. Pancreatology. 2016, 16: PMID:

30 Five progressive Stages Linked to biological systems (Acinar cell, ducts, islets, nervous system, immune system [stellate cells], DNA repair) A dysfunctional response to inflammation in one system is not a surrogate for dysfunction responses in others (e.g. fibrosis does not = pain severity) Does not include etiology or modifiers of trajectory.

31 PF16 Stage A Stage B Stage C Stage D Stage E Risk AP/RAP Early CP Established CP End-Stage CP (other designations) (controls: Healthy) SAPE (Indeterminate) (Definite) (Definite) Essence Characteristics (controls: with symptoms) Risk factors without disease activity no current or past signs or symptoms of pancreatic inflammation RAP Innate Inflammatory response to acute pancreatic injury Characteristic acute abdominal pain; Elevated serum digestive enzymes (>3X nl); Imaging evidence Sendai Japan August 2016 Persistent inflammation with biomarkers of CP that do not meet diagnostic criteria for Established CP or End-Stage CP Persistence of post-ap: pain, serum digestive enzymes, inflammatory markers, imaging features Inflammation-associated pathology and/or dysfunction of two or more biologic systems Imaging evidence of pathologic fibrosis; calcifications, glandular atrophy, glucose intolerance, pancreatic pain Inflammation-associated pathology and failure of two or more systems TBD Criteria Biomarkers of Disease State Biomarkers of Disease Activity Evaluation of histories, exposures and genetics (if indicated) Two or more characteristic features of AP Imaging (TBA) TBD PEI >10% <30% Post AP glucose intolerance Post AP pathologic pain TBD TBD TBD CRP TBD TBD TBD

32 Variable Progression Classic CP Minimal Change Chronic Diarrhea Diabetes Fibrosis Fibrosis Fibrosis Fibrosis PEI PEI PEI PEI T3cDM T3cDM T3cDM T3cDM Pancreatic Pain Pancreatic Pain Pancreatic Pain Pancreatic Pain PDAC PDAC PDAC PDAC 32

33 Genetic testing is not needed to aid in the diagnosis classic, end-stage CP. Genetic testing will be useful in managing: RAP Patients (based on high risk of progression) Defining management plans Mendelian disorders System dysfunction Diagnosing Atypical CP (minimal fibrosis) presenting with: Pain ( minimal change CP) Diarrhea (CP dominated by PEI with maldigestion) Glucose intolerance (CP-associates islet dysfunction) Identifying patients for targeted treatments 33

34 RAP Episodes Inflammatory Markers Fibrosis / obstruction Enzyme secretion / Nutrition Glucose tolerance Pain Cancer Markers Genetics = linked to systems and pathways Biomarkers = linked to specific systems (normal and dysfunctional). Measured repeatedly to determine trajectory and response to treatment Clinical studies aimed at subpopulations with similar etiology and stage of disease

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36 Thousands of patients RAP CRP Severity Fibrosis Enzymes Blood Glucose Pain Cancer Bioarkers Time

37 Symptoms of Pancreatitis Standard Rx Yes W/U No Genetic Testing Yes Improved? No Mendelian Complex Observe Special Multidisciplinary Group (e.g. CF Center) (referral +/-) (referral +/-) Yes Etiology based Rx Improved? No System based Rx Observe Manage

38 Precision Medicine Integration Team David Whitcomb MD PhD (Director) Pancreatitis Jaideep Behari MD PhD Fatty Liver Disease David Binion MD - IBD Philip Empey PharmD PhD Pharmacogentics Erin Kershaw MD Diabetes, Obesty, HTG Larry Morland MD Rheumatoid Arthritis Ajay Wasan MD MSc Pain Zongqi Xia MD PhD Multiple Sclerosis

39 John C Whitcomb Father 92yo / Biography Chris Whitcomb wife of 34 years 4 Children: Jessica, David, Laura, John 5 grandchildren: Weston, Logan, Holden, Roman, Adler Special Thanks: NAPS2 team Clinical and laboratory teams many trainees Mike Barmada PhD (Human Genetics) collaborator Jessica LaRusch PhD Kimberly Stello lab manager Joy Merusi GI Programs / PancreasFest Pancreas Center of Excellence - UPMC

40 Part 8 QUESTIONS AFTER THE SESSION / PANCREASFEST 2016

41 END

42 Background RAP Episodes Inflammatory Markers Fibrosis / obstruction Enzymes / Nutrition Glucose tolerance Pain / Affect Cancer Markers