Looking backwards & forwards in GI: Difference of a decade

Transcription

1 Looking backwards & forwards in GI: Difference of a decade Prof. Daniel K. Podolsky Harvard Medical School/Mass. General Hospital Falk Symposium #164 Budapest, Hungary May 3, 2008

2 GI The past decade: Top ten advances 1. Identification of IBD susceptibility genes 2. Models of IBD pathophysiology 3. Biologic therapy of IBD Anti-TNF 4. CT colonography for CRC screening 5. Chemoprevention of GI cancer 6. Targeted Rx based on molecular pathogenesis of GI cancer 7. Clarification of the prevalence and pathogenesis of GSE 8. Demonstration of key GI involvement in energy balance 9. Visualization of small bowel processes by VCE 10. Expanded endoscopic imaging technology

3 Advances of the Decade - IBD Identification of genes conferring risk Refined pathophysiologic models Biologic therapy anti-tnf

4 Confirmed genetic contributors to Crohn s disease

5 IBD-1: Nucleotide binding oligomerization Domain (NOD)2 or CARD15: Intracellular Bacterial Sensor Muramyl Dipeptide CARD CARD NOD RICK IKKγ PO 4 Oligermization with NOD2 LRR R702W G908R Δ33 Mutations in CD (loss of function) IKKα IKKβ NF-κB Activation LRR = leucine rich repeats

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7 Meta-analysis implicates more than 20 genes in IBD susceptibility 46 p < 1e-5 p < 1e Belg./Fr. NIDDK WTCCC Combination Numbers represent independent regions of the genome associated

8 p = p < p = NS (n = 110) (n = 113) (n = 112) 40% 35% 30% 25% 20% 15% 10% 5% 0% ACCENT I: Clinical remission with infliximab at week 54* 38% 28% 14% Single Dose 5 mg/kg q 8 wk 10 mg/kg q 8 wk *Week 2 responders (58%) Hanauer S, et al. Lancet. 2002;359:1541. Proportion of Patients (%)

9 GI Malignancy A Decade of Advances 1. New chemotherapeutics oxiplatinum improves colon cancer survival 2. Molecularly targeted therapy- bevacizimab for colon cancer, imatinib for GIST 3. Identification of chemopreventative target (COX2) in colon cancer and demonstration of adenoma prevention 4. Identification of cancer stem cell in cancer progression 5. Delineation of the genetic events and histologic precursors (PanINs) in pancreatic cancer pathogenesis 6. Widespread acceptance of CRC screening 7. Development of CT colonography as potential alternative for CRC screening 8. Genetic tests for risk assessment

10 CT Colonography

11 Virtual colonoscopy: performance characteristi Sensitivity Fenlon Pickhardt Cotton Rockey Polyp size > 10 mm 91% 94% 55% 59% > 6 mm 82% 89-94% 39% 51% (No. subjects) (100) (1233) (600) (614)

12 Finding the Critical Kinase Mutation in the Gastrointestinal Sarcoma: GIST Science 279: , 1998

13 In Vitro: GIST Cells Arrest GIST882 and undergo Apoptosis with Imatinib 100 Cell Number x 10,000 #cells x 10, Continued growth with no drug Imatinib STOPS GROWTH um Days DAYS Tuveson D, et al. Oncogene

14 < 2 year survival from time of metastasis The Only Therapy For Metastatic GIST Before Imatinib Chemotherapy never worked A definitive unmet medical need

15 Metastatic GIST before and after Imatinib Baseline Pre-Imatinib 1 month on Imatinib Avid PET Uptake No PET Uptake

16 Anatomy 16 th Century Advance Molecular Anatomy 21 st Century Advance

17 Regulators of tumor angiogenesis Hypoxia from Ferrara & Kerbel, Nature, 2005

18 Anti-angiogenic therapies are effective in CRC Anti-VEGF antibody (Bevacizumab) Small molecule VEGFR antagonists Hurwitz, NEJM 2004

19 Chemoprevention comes of age: ASA and recurrent adenoma % of randomized patients placebo bid celecoxib 200 mg bid * * * * * * celecoxib 400 mg bid 33% 45% All patients Aspirin users Aspirin non-users *p< compared to placebo All patients Risk Ratio (95% CI) Bertagnolli, Hawk, Eagle AACR 2006

20 EGFR EP2 β-catenin PGE 2 β-catenin+tcf4 Cox-2 15-PGDH TGF-β c-myc cyclin D1 MMP7 PPARδ

21 Cox2 Inhibition: anti-tumor efficacy Celecoxib reduces 3-year adenoma detection rates by: 33-45% for all adenomas 57-66% for high risk adenomas 53-74% for high risk adenomas in patients with baseline risk factors for recurrent disease For patients who do develop recurrent adenomas while taking celecoxib, these adenomas are fewer and smaller in number

22 Prevalence & Variability of GSE The Iceberg Metaphor

23 GI Key Component of Interacting Pathways of Energy Regulation CNS Gut hormones Afferent neurons Glucose homeostasis Lipid metabolism Energy regulation Gastrointestinal tract Liver Pancreas Adipose tissue

24 Advances in Obesity Science & GI: A Convergence Identification of CNS nutrient sensing mechanisms that regulate peripheral metabolic function Identification of several genes that contribute to common obesity FTO, INSIG-2, MCR4 Demonstration of the impact of hepatic steatosis on metabolic function and the outcome of unrelated liver disease Demonstration that alterations in luminal flora can regulate energy balance and body weight Recognition of the role of the GI tract and GI hormones in regulation of body weight and metabolic function GLP1, PYY, ghrelin Demonstration that bariatric surgery esp. Gastric bypass, work s through physiologic mechanisms to improve obesity and resolve TypII DM

25 Appetite is diminished after gastric bypass Hindgut signals Exposure of distal small bowel to undigested food PYY GLP-1 Foregut signals Proximal gastric distension Ghrelin Distal gastric exclusion Duodenal exclusion

26 Decade of technological development integral to progress of GI Videocapsule endoscopy Refined endoscopic imaging

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29 Endoscopic Confocal Microscopy Ralf Kiesslich, M.D.

30 In vivo Histology: Optical Coherence Tomography The Gastroenterologist as his/her own Pathologist

31 GI in the Future Prediction is difficult: Especially when it concerns the future* * Niels Bohr

32 GI in the new millennium -- Change a constant Demographics and Secular Disease Trends Knowledge Generation Technology Development Information Technology Quality Imperative Economics of Research & Clinical Care

33 GI The next decade: 1. Definitive delineation of IBD pathogenesis clarification of the host-environment interaction 2. Development of clinically useful surrogate biomarkers 3. The $500 genome and real-time incorporation into practice 4. Endoscopic management of obesity 5. Medical diagnosis & management of neoplastic precursors 6. Convergence of GI & Surgery - NOTES 7. Effective anti-fibrotic therapy

34 GI in the new millennium: Impact of the genomic revolution PRE-SYMPTOMATIC DIAGNOSIS IBD CELIAC DISEASE MALIGNANCY DISEASE SUSCEPTIBILITY HCV - CIRRHOSIS ETOH - CIRRHOSIS DRUG TOXICITY/RESPONSE

35 AmpliChip CYP450 Test Gene expression analysis Stratify disease Identify poor, extensive, or ultra-rapid metabolizer Make better therapeutic choices Individualize treatment doses Predict clinical outcomes Consumer choice or insurance coverage?

36 GI in the new millennium -- implications of the genomic revolution Pre-symptomatic diagnosis Genetic counseling as component of GI clinical practice Expanded responsibility from individual patient to entire family

37 Disease Biological systems Disease Environmental factors

38 GI in the new millennium -- Change a constant Demographics and Secular Disease Trends Knowledge Generation Technology Development Information Technology Quality Imperative Economics of Research & Clinical Care Unknowns

39 Natural Orifice Transluminal Endoscopic Surgery (NOTES) Gastric bypass/reduction Cholecystectomy Closure of perforation Entero-enteric/colonic bypass Gastrojejunostomy Fallopian tubal ligation Splenectomy Omental fat removal

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41 GI in the new millennium: A future without endoscopy? Improved scanning In vivo intelligent probes Metabolic scanning Target/homing specific therapeutics

42 GI in the new millennium: Innovative approaches to organ replacement Organ fabrication Cell engineering Bone marrow/allo-transplantation Xenotransplantation Cloned organs ELAD

43 GI & the Future: Opportunities New needs, e.g. obesity New scope of practice e.g. GI oncology New technologies, e.g. Organ fabrication, Tissue engineering, Real time metabolic/functional scanning Endoluminal therapeutics and surgery New therapeutics, e.g. Biologics, Gene Therapy, Small molecules

44 GI in the new millennium -- Change a constant Demographics and Secular Disease Trends Knowledge Generation Technology Development Information Technology Quality Imperative Economics of Research & Clinical Care Unknowns

45 The future is not what it once was