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  • School of Breast Oncology 8 November 2007 Carol J. Fabian, M.D.
  • The pilot findings and the avialability of a pre-clinical model for breast and ovarian pre-cancer from the precancerous biology group led to a successful competiton for a multi-PI multi-institutional Komen Promise Grant. This translational effort includes a placebo controlled trial in premenopausal women asessing not only tissue risk biomarkers but also explores the mechanism of action and effect if any of SDG on follicular reserve. ER+ and ER- animal models use doses producing similar lignan levels as the human trial and assess modulation of both biomarkers and cancer incidence. . Marker and cancer correlation in the animal trials helps validate risk biomarkers as primary endpoints in the human trial. This work includes not only a large number of investigators from the CP program but interprogram investigators from CB and CCPH

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  • 1. Obesity, Metabolism and Cancer:Mechanistic Insights fromPreclinical StudiesStephen D. Hursting, PhD, MPHProfessor and ChairDepartment of Nutritional SciencesUniversity of Texas at AustinandProfessor, Department of Molecular CarcinogenesisUniversity of Texas MD Anderson Cancer Center
  • 2. Today’s Presentation• Lessons from mice (and humans): moleculartargets and strategies for breaking obesity-cancer links- Growth factors and their signals- Adipokines and their signals- Inflammatory signals• Translation of mechanistic insights throughtransdisciplinary, multilevel research
  • 3. Will Warfarin Still be in Ua Year from Now?LOOMING QUESTION:How to Decrease Cancer Risk in the~600 Million Adults Worldwide Currently Obese?Need a mechanistic approach to identify targets andstrategies to break obesity-cancer links
  • 4. Cancer: A Complex FoeObesity impacts the essential aberrations of cancer∞InflammationGenomicinstabilityTissueinvasionandmetastasisLimitless replicativepotentialSustainedangiogenesisEvadinggrowthsuppression,apoptosisand immunesurveillanceDysregulatedgrowth signals andcellular energeticsAdapted from: Hanahan & Weinberg,Cell (2000) and Cell (2011)?
  • 5. Modeling Energy Balance and Human Cancer inMice by Altering Key Genes and PathwaysInsert fig. 19.4Hursting, et al., Mutation Res, 2005
  • 6. CR (30%)OverweightDIOGrowth Factor Levels and MMTV-Wnt-1 MammaryTumor Growth in Lean, Overweight and Obese MiceIGF-1 Insulin Leptin/ Tumor Vol(ng/ml) (pg/ml) Adiponectin (mm3)390 380 0.2 120526 398 0.6 510718 596 1.8 1485(29% body fat)(35% body fat)(47% body fat)n=12 mice/groupNunez, et al., Nutrition and Cancer, 2007Dr. Nomeli Nunez
  • 7. Transplanted Wnt-1 Tumor Growth in AZIP/F-1Transplanted Wnt-1 Tumor Growth in AZIP/F-1(Fatless) Mice Versus Wild-Type Mice(Fatless) Mice Versus Wild-Type MiceAZIP/F1Wild-typeHursting et al., Cancer Res, 2007
  • 8. Genetic Reduction of Systemic IGF-1Genetic Reduction of Systemic IGF-1~75% of IGF-1 in serum is produced by liverEcuadorians with LaronSyndrome have very lowIGF-1 and inflammatorycytokines, increasedlongevity, and virtually nocancer or diabetes.NY Times 2/16/11.Serum IGF-1WT LID2001000IGF-1,ng/ml
  • 9. Transplanted Mammary Tumor GrowthTransplanted Mammary Tumor Growthin Wild-Type and Liver IGF-1 Deficient (LID) Micein Wild-Type and Liver IGF-1 Deficient (LID) MiceWild-TypeDr. Nikki Ford Ford, et al. Endocrine-Related Cancer, in*Serum IGF-1 Levels
  • 10. Energy Balance Effects on Transplanted Mammary TumorEnergy Balance Effects on Transplanted Mammary TumorGrowth Liver IGF-1 Deficient (LID) MiceGrowth Liver IGF-1 Deficient (LID) MiceWild-TypeDr. Nikki FordDiet Effects in LID MiceObese Control CRDays after tumor cell injection
  • 11. Insert fig. 19.4Grossman and Cleary, Biochimie, 2012The Balance Between Leptin and Adiponectinin the Control of Carcinogenesis
  • 12. IGF-1 Infusion or mTOR Activation Impacts Transplanted MMTV-IGF-1 Infusion or mTOR Activation Impacts Transplanted MMTV-Wnt-1 Mammary Tumor Growth in Calorie Restricted MiceWnt-1 Mammary Tumor Growth in Calorie Restricted MiceNogueira et al. Endocrine-Related Cancer, 2012Leticia Nogueira!
  • 13. Dietary EnergyBalance Modulation ofAkt/mTOR Signaling(normal and tumor tissue)AktmTORp70S6K4E-BP1S6 ribosomalGSK-3Cyclin DTranslationProliferationPI3KRTKCRDIOSkinLiverProstateColonPancreasMammaryHursting, et al., Cancer Res, 2007Moore, et al., Cancer Prev Res, 2008;Olivo-Marston, et al., Mol Carcinogenesis 2009Lashinger, et al, Cancer Prev Res, 2011Blando, et al., Cancer Prev Res, 2011Nogueira, et al, Endocr Rel Cancer, 2012deAngel, et al., Mol Carcinogenesis, 2013LIDA-Zip
  • 14. RAD001 (Afinitor®) Inhibits mTOR and Wnt-1 Mammary TumorGrowth in Lean, Control and Obese MiceDeAngel, et al. Mol Carcinogenesis, 2013Rebecca DeAngel
  • 15. Cancer: A Complex FoeObesity, CR impact the essential aberrations of cancer∞InflammationGenomicinstabilityTissueinvasionandmetastasisLimitless replicativepotentialSustainedangiogenesisEvadinggrowthsuppression,apoptosisand immunesurveillanceDysregulatedgrowth signals andcellular energetics✔??
  • 16. Control Obese02000400060008000 VehicleGemHCLGemC18 NPabcaabTumorsize(mm3)Before tumor cell injection0 5 10 150204060ControlObeseWeeks on studyBodyweight(g)PurchaseorSubscribePurchase article for $29Subscribe to Cancer Biology &TherapyRecommend this PublicationSubscriber LoginResearchPaperStearoyl gemcitabinenanoparticlesovercomeobesity-inducedcancercellresistancetogemcitabineinamousepostmenopausal breastcancermodelVolume 14, Issue 4 April 2013Keywords: chemoresistance, nanoparticles, obesity, tumorAuthors: Rebecca E. De Angel, Jorge M. Blando, Matthew G. Hogan, Michael A. Sandoval, Dharmika S.P.Lansakara-P., Sarah M. Dunlap, Stephen D. Hursting and Zhengrong CuiView affiliationsAbstract:Obesity is associated with increased breast tumor aggressiveness and decreased responseto multiple modalities of therapy in postmenopausal women. Delivering cancerchemotherapeutic drugs using nanoparticles has evolved as a promising approach toimprove the efficacy of anticancer agents. However, the application of nanoparticles incancer chemotherapy in the context of obesity has not been studied before. The nucleosideanalog gemcitabine is widely used in solid tumor therapy. Previously, we developed a novelstearoyl gemcitabine solid-lipid nanoparticle formulation (GemC18-NPs) and showed thatthe GemC18-NPs are significantly more effective than gemcitabine in controlling tumorgrowth in mouse models. In the present study, using ovariectomized diet-induced obese female C57BL/6 mice with orthotopicallytransplanted MMTV-Wnt-1 mammary tumors as a model of postmenopausal obesity and breast cancer, we discovered that obesityinduces tumor cell resistance to gemcitabine. Furthermore, our GemC18-NPs can overcome the obesity-related resistance togemcitabine chemotherapy. These findings have important clinical implications for cancer chemotherapies involving gemcitabine orother nucleoside analogs in the context of obesity.Preview:Cancer Biology and TherapySimilar findings with pancreatic cancerequilibrative nucleotide transporter 1,ribonucleotide reductase M1
  • 17. Mechanisms and Mediators of Adipose Tissue-Stimulated AngiogenesisY. Cao. Nature Reviews Drug Discovery, 2010PAI-1 PAI-1
  • 18. Cancer: A Complex FoeObesity, CR impact the essential aberrations of cancer∞InflammationGenomicinstabilityTissueinvasionandmetastasisLimitless replicativepotentialSustainedangiogenesisEvadinggrowthsuppression,apoptosisand immunesurveillanceDysregulatedgrowth signals andcellular energetics✔??✔✔?Does Obesity Promote Invasion, Metastases, EMT? Enrich Breast Cancer Stem Cells?Dunlap, et al. Cancer Prevention Research 2012; 5:932-42
  • 19. (75% CD44+/24-/Aldefluor+) (2% CD44+/24-/Aldefluor+)2012SpesignCellsdisaCe(andceEMT migration, invasion!
  • 20. Cancer: A Complex FoeObesity, CR impact the essential aberrations of cancer∞InflammationGenomicinstabilityTissueinvasionandmetastasisLimitless replicativepotentialSustainedangiogenesisEvadinggrowthsuppression,apoptosisand immunesurveillanceDysregulatedgrowth signals andcellular energetics✔✔✔✔✔✔?
  • 21. Inflammation and Cancer• Malignancies often arise from areas ofchronic infection and inflammation• Chronic inflammatory conditions linked totumorigenesis include:-Gastritis (H. Pylori) – Gastric Cancer-Cystitis – Bladder Cancer-Bronchitis – Lung Cancer-Esophagitis – Esophageal Cancer-Dermatitis – Skin Cancer-Ulcerative colitis – Colon Cancer-Inflammatory bowel disease – Colon Cancer-Hepatitis (including NASH) – Liver Cancer-Pancreatitis – Pancreatic Cancer (up to 55-fold increased risk)
  • 22. Mechanisms Underlying the Obesity-Cancer Link: 2013?Microenvironment (EMT,CSCs)Obesity and Cancer: Emerging Mechanistic TargetsS. Hursting and M. Hursting.Arterioscler Thromb Vasc Biol, 2012
  • 23. The Obesity-Cancer LinkIncreasedIncreasedInsR/IGF-1RInsR/IGF-1RSignalingSignalingIncreasedIncreasedHormone/Hormone/Growth FactorGrowth FactorSignalingSignalingEnergy Balance, Metabolism and Cancer:Transdisciplinary Research Approaches
  • 24. Example 1. Diet and Exercise Pilot Trial inObese Postmenopausal WomenProliferation(Ki-67)MammographicBreast DensitySeruminsulin, cytokines,adipokines,IGF1, IGFBP-3,Response BiomarkersmRNAestrogenresponsegenes,cytokines28 High RiskWomen:BMI >30 kg/m2No HRT6-monthInterventionRPFNA Repeat RPFNA
  • 25. Diet/Exercise Intervention• NHLBI low-calorie (1250 kcal/day) Step Idiet, achieved with 2 shelf-stableprepackaged meals, 3 high proteinshakes, 5 fruits and vegetables/day• Goal of 45 minutes exercise 5 days/week(usually walking)• In-person, group behavior modificationclass weekly (including weigh-in andsubmission of exercise and food diaries)
  • 26. Proc Nutr Soc, 20122012
  • 27. Example 2. Integrated Phase II Trial andAnimal Studies of Lovaza® (omega-3-acidethyl esters)C. Fabian, MD Placebo1 yrLovaza (4g/d)High-Risk WomenSerum/Benign Breast Tissue Biomarkers1. Response: Ki-67, cytomorphology2. Mechanism: qRTPCR: ER-genes; miR’s;Proteomics: mTOR, MAPK signaling;CytokinesChange inBiomarkersLovaza (208 mg/kg diet)PlaceboCancerEndpoint3 mosER-Mouse ModelsS. Hursting, PhD, MPHKomen Promise Grant; BCRF
  • 28. AcknowledgementsUniversity of Texas at AustinJohn DiGiovanni, Michele Forman, Nomeli Nunez, Rong CuiUniversity of Texas-M.D. Anderson Cancer CenterSue Fischer, Donna Kusewitt, JJ Shen, Powel BrownMt. Sinai Medical CenterDerek LeRoith, Shoshana YakarNational Cancer InstituteCurt Harris, Chuck Vinson, Lyuba VarticovskiKansas University Medical CenterCarol Fabian, Brian Petroff, Bruce KimlerUNC-Chapel HillChuck PerouWeill-Cornell Cancer CenterAndrew DannenbergFunding: National Cancer Institute, National Institute of Environmental Health Sciences, AmericanInstitute for Cancer Research, Breast Cancer Research Foundation, Susan G. Komen Foundation