Ms. Kathy Killeen Thank you!

1. Energy Balance and Pancreatic
Cancer: A Mechanistic
Perspective
Stephen D. Hursting, PhD, MPH
Professor and Chair
Department of Nutritional Sciences
University of Texas at Austin
and
Professor, Department of Molecular Carcinogenesis
University of Texas MD Anderson Cancer Center

2. Today’s Presentation
• Lessons from mice: molecular targets and
strategies for breaking obesity- pancreatic
cancer links
- Inflammatory signals
- Growth factors and their signals
- Adipokines and their signals
• Adipocyte-macrophage-pancreatic epithelial
interactions: triggers of inflammatory and
metabolic perturbations in pancreata

3. Inflammation and Pancreatic Cancer
!
Farrow and Evers. Surg Oncol 2002
3

4. • Differential gene expression from humans and mice in
response to acute inflammation: sepsis (endotoxemia) and burns
• No comparisons of low-level chronic inflammatory responses (as occur
with obesity)
• Recommendation: “By first requiring comprehensive genomic
descriptions in patient studies to define the human disease, the disease
altered pathways could be used as a guide to develop the animal model.
The quality of the animal model could then be determined by how well it
reproduces the human disease on a molecular basis rather than simply
phenotype”
4

5. Modeling Energy Balance and Human Cancer in
Mice by Altering Key Genes and Pathways
Insert fig. 19.4
Hursting, et al., Mutation Res, 2005

6. BK5.COX-2 Transgenic Mouse Model of
Pancreatitis-Induced Pancreatic Tumors
5’ Keratin 5 promoter Murine COX-2 cDNA SV40 poly A 3’
acinar
• 100% pancreatitis by 3-4 months
islet
cells • 20% spontaneous adenocarcinoma by
9 months in normoweight mice
• Obesity increases (CR decreases):
blood
-Pancreatic steatosis
vessel duct -Pancreatitis
-Malignant conversion (~40%)
-Serum IGF-1 levels
Pancreatic
Pancreatitis -Serum inflammatory cytokine levels
adenocarcinoma
-IGF-1R/Akt/mTOR signaling
-NF-kB signaling
Lashinger, et al., Cancer Prev Res, 2011

7. Pancreatic Cancer Progression Model
Hruban R H et al. Clin Cancer Res 2000;6:2969-
2972
©2000 by American Association for Cancer Research

8. Effect of Energy Balance on PanIN and Pancreatic
Adenocarcinoma Development in Kras/Ink4A+/- Mice
Hypothesis: CR will diminish, and DIO will enhance, PanIN/PDAC
formation in Pdx1-Cre/LSL-KrasG12D/INK4A+/- mice
Diet Groups qMR(8/20wks) Interim Timepoint (10wks) Survival
30% Calorie Restriction (CR) all 15M 25M
Control (CON) all 15M 25M
Diet-induced Obesity (DIO) all 15M 25M
45 75
Total Mice: 120
Primary Endpoints: Prevalence of PanIN/PDACs, fibrosis, inflammation, and atypia; survival

9. Pathological Assessment at
10-Week Interim Timepoint
B. Prevalence of pathological indices
A. Incidence of pancreatic lesions
No PanIN- PanIN- PanIN- PDAC
lesion 1 2 3
CR 1 5 4 5 0
Control 1 4 4 3 3
DIO 1 1 3 3 7
n=15
!
CR Control DIO
mostly normal; mix of normal, mix of PanIns,
some PanINs PanINs, PDAC PDAC
Lashinger, et al., Cancer Res (under review)

10. IGF-1 Infusion Restores Growth of Orthotopically Transplanted
Kras Ink4A+/- and K5.COX-2 Pancreatic Tumors in LID Mice
c
a
b
Dr. L. Lashinger:
mTOR pathway
a
a
K. Devlin: MicroRNAs
b
(Lashinger, et al. Cancer Res, under review) A. Harvey: NF-kB

11. Serum Cytokine Levels Are Reduced in LID Mice
Cytokine LID Mice Wildtype Mice P value
mean +/- sd(pg/ml) Mean +/- sd(pg/ml)
GM-CSF 218.7 + 14.6 307.7 + 15.3 0.0008
IFN-γ 65.8 + 4.9 100.5 + 3.4 0.001
IL-1 18.3 + 2.6 33.4 + 7.6 0.03
IL-2 39.7 + 11.2 56.5 + 22.3 0.47
IL-4 7.6 + 0.4 11.7 + 0.5 <0.0001
IL-5 16.1 + 1.9 30.8 + 4.1 0.0007
IL-6 46.7 + 8.6 56.9 + 9.5 0.48
IL-10 199.6 + 17.0 427.4 + 52.2 <0.0001
IL-12 401.6 + 47.4 645.5 + 29.1 0.003
TNF-α 6.3 + 0.7 11.3 + 1.5 0.002
Lashinger, et al., Cancer Prev Res, 2011
P values calculated from Student’s t-test Similar Findings: Olivo-Marston, et al., Mol Carcinog 2009

12. GF-1 and Leptin Modulate NF- кB Signaling
IGF-1, Insulin
Lepti
n
Plasma m
embrane
JAK
PI3K
P Akt/mT
OR P
(raptor)
Stat3
26S Proteasome
IKKα IKKβ
IKKγ s32
s36
IкBα
RelA/
p50
p65
Nucleus
Inflammatory Gene Transcription
(COX-2, Survivin, Cyclin D1, VEGF)
12
Harvey, et al. Mol Carcinogenesis, 2012; Lashinger, et al., Cancer Res, submitted

13. Obesity, Diabetes and Pancreatic Cancer
Dr. Rudolf Kaaks,
German Cancer
Research Center
Diabetes Care 35:299-304, 2012
CJ. Currie, C.D. Poole, S. Jenkins-Jones, E.A.M. Gale, J.A. Johnson, C.L. Morgan
1) Cohort 1: Metformin
Dr. Michael Pollak
2) Cohort 2: Sulfonylurea McGill Univ.
62,809 T2D patients:
3) Cohort 3: Metformin + Sulfonylurea
4) Cohort 4: Insulin

14. Differential Effects of Glucose-Lowering
Therapies on Cancer Survival in Type 2
Diabetes
HR (met v sulf)= 1.36 (p<0.001) HR (met v sulf)= 4.95 (p<0.001)
Met + Sulf
Metformin
Metformin
Met + Sulf
Insulin
Insulin Sulfonylurea
All Cancers Sulfonylurea Pancreatic Cancer
Years to event/censor ! Years to event/censor
Currie, et al. Diabetalogia, 2009

15. Diet-induced obesity causes inflammation
in organs and visceral fat.
Andrew Dannenberg,
Weill-Cornell Cancer Center
Crown-like Structures
(Macrophage/Adipocyte/Epithelial
Tumor Cell Interactions)
Subbaramaiah K, et al. Cancer Prev Res
2011 Ouchi, et al. Nature Rev Immunol, 2011

16. Ford, DiGiovanni, Hursting. In: Adipose Tissue and Cancer. M. Kolonin, ed. 2012

17. Acknowledgements
University of Texas at Austin
John DiGiovanni, Michele Forman, Nomeli Nunez, Rong Cui
University of Texas-M.D. Anderson Cancer Center
Sue Fischer, Donna Kusewitt, JJ Shen, Powel Brown
Mt. Sinai Medical Center
Derek LeRoith, Shoshana Yakar
National Cancer Institute
Curt Harris, Chuck Vinson, Lyuba Varticovski
Kansas University Medical Center
Carol Fabian, Brian Petroff, Bruce Kimler
UNC-Chapel Hill
Chuck Perou
Weill-Cornell Cancer Center
Andrew Dannenberg
Funding: National Cancer Institute, National Institute of Environmental Health Sciences, American
Institute for Cancer Research, Breast Cancer Research Foundation, Susan G. Komen Foundation