Aging, Energy Balance, Cancer and HCT

Transcription

1 The Geoffrey P. Herzig Memorial Symposium April 8 9, 2016 University of Louisville Louisville, Kentucky Aging, Energy Balance, Cancer and HCT Nathan A. Berger, M.D. Distinguished University Professor Hanna-Payne Professor of Experimental Medicine Professor of Medicine, Biochemistry, Oncology & Genetics Director, Center for Science, Health & Society Case Western Reserve University Cleveland, Ohio

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5 IMPACT PHYSICAL ACTIVITY ON CANCER BENEFITS EXERCISE Reduces Cancer Risk - Convincing Evidence Colon Cancer (WCRF/AICR) - Probable Evidence Breast (Post Menopausal) and Endometrial Cancers -Suggested Evidence Lung, Pancreas, Premenopausal Breast, Prostate No Increased Risk Helps to Control Weight Reduces Risk Death from Cardiovascular Death Promotes Psychological Well Being

6 IMPACT PHYSICAL ACTIVITY ON CANCER BENEFITS EXERCISE IN CANCER SURVIVORS Improved Physical Well Being Improved Regulation Tumor Promoters and Cytokines - Insulin, IGF-1, Leptin, Adiponectin, IL-6 May Prevent and/or Extend Time to Recurrence May Improve Survival May Improve Ethnic Disparities in Survival

7 IMPACT PHYSICAL ACTIVITY ON CANCER RECOMMENDATIONS Moderate Intensity PA, 30 Minutes, 5 Days/Week OR Vigorous PA, 20 Minutes, 3 Days/Week

8 PHYSICAL ACTIVITY RECOMMENDATIONS FOR CACER SURVIVORS Moderate Intensity PA, 30 Minutes, 5 Days/Week OR Vigorous PA, 20 Minutes, 3 Days/Week There are No Specific Recommendations for PA in Patients Undergoing HCT

9 Enzymatic Function PEPCK

10 Metabolic Role of Phospho Enol Pyruvate Carboxy Kinase Cytoplasmic PEPCK Glucose Insulin Leptin Gluconeogenesis OAA + GTP PEPCK-C PEP + CO2 + GDP Glyceroneogenesis camp Glucagon Fasting Glucocorticoids Thyroid Hormone Triglycerides

11 Transgene Used for the Expression of PEPCK-C in the Muscle of Mice (PEPCK-C mus mice) Human -skeletal actin gene promoter Mouse PEPCK-C cdna 3 end of the bgh gene

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13 Activity of PEPCK-C mus and Control Mice Activity of PEPCK-C mus and Control Mice Distance (meters) Distance (meters) Velocity (cm/s) Velocity (cm/s) Rearing Rearing Frequency Frequency (per 12h cycle) (per 12h cycle) 0 Mobility Mobility (% of (% timeof time strongly mobile) strongly mobile) Control PEPCK-C mus Control PEPCK-C mus 0 0

14 PEPCK-C mus Mice Sustain Long Distance of Running 6 Distance run (km) No training Running to exhaustion 1 0 WT 1 WT 2 WT 3 WT 4 A11 A12 A13 A18 A4 PEPCK-C mus mice

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16 PEPCK-C mus Mice Are Still Active at Old Age old age Maximum speed (m / min) WT 60 (6) PEPCK-C mus mice (6) (6) (6) 40 (2) (3) (4) (7) 20 (4) (3) 0 Age (month) 1~2 2~6 6~12 12~18 18~24 >24

17 Magnetic Resonance Imaging PEPCK-C mus mouse WT mouse WT mouse (18 months old) (18 months old) (6 months old) Visceral fat (ml) Subcutaneous fat (ml) 0.4 ± ± ± ± ± ± 0.4

18 Phenotypic Characteristics PEPCK-C mus TG Mice - Greatly Increased Exercise Capacity, Mobility, Rearing, Running - Greatly Increased Endurance - Greater Food Intake, with reduced body weight - Extended Fertility - Increased Bone Density and Strength - Look Better, Live Longer (3-4 years) - Reduced Spontaneous Malignancies

19 Skeletal Muscles of PEPCK-C mus Mice and Controls Succinate NADH H & E staining Dehydrogenase Dehydrogenase WT PEPCK-C mus mice

20 Soleus Muscle From PEPCK-C mus Mouse and Control Littermate Mt. Mt. S. M. S. M.

21 Insulin Levels In Aging PEPCKC mus Vs. Control Female Pg/mL PEPCK Control months Insulin Levels In Aging PEPCK C mus Vs. Control Male Pg/mL PEPCK Control months

22 Hormone and Cytokine Characteristics PEPCK-C mus TG Mice - Decreased Insulin - Decreased IGF-1 - Increased Glucagon - Decreased Leptin - Decreased TNFα - Decreased IL-6 in males

23 Question Does the enhanced exercise phenotype of the PEPCK-C mus mice alter the development or progression of cancer? Approach Evaluate adenomatous polyp development in PEPCK-C mus TG.Apc min/+ mice compared to non TG mice

24 % of Mice Effect of PEPCK-C mus on the Survival of Female APC min Mice Age at Death (Days) B6.APC min/+ B6.SJL.APC min/+ PEPCK.APC min/+

25 No. of Polyps No. of Polyps No. of Polyps Polyp Development in APC min/+ B Months Polyp Development in APC min/+ SJLB Months Polyp Development in APC min/+ PEPCK Months

26 Feng, Hanson Berger Trubitsyn, Oncotarge t2016 IMPACT ENERGY METABOLISM ON AGING

27 Physical Inactivity and Low Fitness Deserve More Attention to Alter Cancer Risk Prognosis Sanchis-Gomar, Lucia, Yvert, Ruiz-Casado, Pareja-Galeano, Santos-Lozano, Fiuza-Luces, Garatachea, Lippi, Bouchard, Berger. Cancer Prev Res 2015;8: by American Association for Cancer Research

28 Fiuza-Luces, Garatachea, Berger, LuciaREVIEWS PHYSIOLOGY Volume 28 September

29 Fiuza-Luces et al. Med Sci Sports Exercise, 2013,

30 Exercise Benefits in cgvhd Model: CD4 T cell Dependent Sclerodermatous cgvhd Recipient: BALB/C Females, Age 8 Weeks Donor: BIO.D2 Male Fiuza-Luces et al. Med Sci Sports Exercise, 2013,

31 FIGURE 3. Daily clinical disease progression (total and individual cgvhd severity scores) by group. The P value for each score corresponds to the interaction (group-time) effect. Effect size ([eta]2) and the statistical power of significant interaction (group-time) effects were as follows: and (total clinical score), and (weight), and (posture), and and (activity), respectively. FIUZA-LUCES et al, Medicine & 4 Science in Sports & Exercise. 2013, 45(9):

32 Fiuza-Luces et al. Med Sci Sports Exercise, 2013,

33 Wood et al, Cancer 2016, 91-98

34 Patient- Reported Physical Functioning Predicts the Success of Hematopoietic Cell Transplantation (BMT CTN 0902) Effect of HR QoL on Survival Following HCT SF-36 Administered Pre and 100 Days Post HCT SF-36 Analyzed for PCS Physical Component Scale MCS Mental Component Scale Wood et al, Cancer 2016, 91-98

35 Patient- Reported Physical Functioning Predicts the Success of Hematopoietic Cell Transplantation (BMT CTN 0902) Participation 336 Autologous, 23 Centers 310 Allogeneic, 19 Centers Diseases AML, ALL, CML, MDS, MM, Lymphomas, CLL Baseline SF-36 Scores PCS MCS Autologous 43 (13-64) 52 (12-74 Allogeneic 44 (13-65) 52 (7-68) Wood et al, Cancer 2016, 91-98

36 Wood et al, Cancer 2016, 91-98

37 Wood et al, Cancer 2016, 91-98

38 Wood et al, Cancer 2016, 91-98

39 Authors Conclusion Patient-reported data (SF-36) may play a critical role in improving HCT treatment risk stratification Berger Suggestion Biobehavioral modification, especially prehabilitation and rehabilitation focused on improving physical fitness, could improve HCT outcomes

40 Jacobsen et al 2014,

41 RCT Exercise and Stress Management Training Prior to HCT: (BMT CTN) 0901 Randomized: Usual Care/Exercise/Stress Management/Exercise and Stress Management Exercise Goal: Walking 3-5 Times/Wk, Minutes at 50-75% Estimated Heart Rate Reserve Training: for Self Directed Program Pamphlet Review Provide 3 DVDs (HCT, Exercise, Stress Reduction) Provide Diary Calculate Target Heart Rate Provide Pedometer Reinforcement Contact 30 and 60 Days Post HCT Jacobsen et al, ASBMT (2014) 20,

42 RCT Exercise and Stress Management Training Prior to HCT: (BMT CTN) 0901 Outcomes No Differences SF36 and Multidimensional QoL, Physical Component Summary or Mental Component Summary at Day 100 No Difference Overall Survival at 1 Year Increased Physical Activity at Day 180 in Exercise Training Group Conclusion BMT CTN 0902 RCT did not demonstrate any measurable benefit from a brief training session to encourage patients to use self-directed exercise and/or stress management during HCT. CRITIQUE BMT CTN 0902 RCT did not adequately test impact exercise on HCT outcomes Jacobsen et al 2014,

43 PHYSICAL ACTIVITY IN HCT, RESEARCH NEEDS RCT to Evaluate Exercise Training Before, During and After HCT Intensive Training and Monitoring of Endurance and Resistance Exercise Outcomes to Evaluate - Adherence and Barriers - Treatment Related Side Effects - Hematopoietic Reconstitution - Immune Reconstitution - Circulating Promoters and Cytokines - Physical Performance - Quality of Life - Fatigue - GVHD - Length of Hospital Stay - Recurrence Rate - Survival