PROTEIN ANABOLIC RESISTANCE IN CANCER

PROTEIN ANABOLIC RESISTANCE IN CANCER Dr. Barbara van der Meij CRICOS CODE 00017B

CONTENTS Obesity and body composition Metabolic alterations in cancer Protein anabolic resistance Implications for clinical practice

% O b e s i t y The obesity epidemic in cancer O b e s i t y t r e n d s i n t h e U S, 1 9 9 0-2 0 1 2 4 0 3 5 3 0 2 5 2 0 2 0 1 0 G e n e r a l P o p u l a t i o n C a n c e r S u r v i v o r s N S C L C 0 1 9 9 0 1 9 9 2 1 9 9 4 1 9 9 6 1 9 9 8 2 0 0 0 2 0 0 2 2 0 0 4 2 0 0 6 2 0 0 8 2 0 1 0 2 0 1 2 Y e a r Engelen et al. Curr Opin Clin Nutr Metab Care. 2015

Correlation BMI and FFMi Correlation between BMI and FFMI in 186,975 healthy white individuals R = 0.62, P <0.001. Franssen et al. J Am Med Dir Assoc. 2014;15(6):448 e1-6

Metabolic alterations in cancer

Argiles, Nat Rev Cancer 2014

Muscle and fat loss in cancer n=368 lung, colorectal, pancreatic and cholangiocarcinoma Prado, AJCN 2013

Protein metabolism in cancer Studies in different types of cancer: Changes in plasma amino acids (e.g. decreased arginine, glutamine, citrulline) Increased protein turnover Increased muscle protein breakdown Lai Sem Cancer Biol 2005, Miyagi et al. PLoS One. 2011, Fukutake et al. PLoS ONE. 2015, van Dijk, J Cach Muscle Wasting 2015, van der Meij, unpublished data

Weight loss / muscle wasting in cancer: Associated with Fatigue and apathy Hospital length of stay Increased susceptibility to infection Postoperative complications and mortality Delay in return to work Poor quality of life Response to chemo/radiotherapy Treatment toxicity Komurcu, SO, 2000, Rosenbaum, JPEN, 2000, Curt, Oncol, 2000; Grossmann, Surg, 2002; Spelten, EJC, 2003, Argiles, Eur J Oncol Nurs, 2005, Gordon, QJM, 2005, Prado, Appl Physiol Nutr Metab, 2014, Barret, Nutr Cancer, 2014

Sarcopenia and toxicity Breast cancer, n=55 Sarcopenia: n=14 (25.5%) Sarcopenic patients: more dose limiting toxicity Prado, Clin Cancer Res 2009

Can cancer patients have an anabolic response to food?

n=16 cancer patients and n=16 healthy subjects T=-1h T=0h T=1h T=2h T=3h T=4h T=5h T=6h T=7h T=7.5h Primed and constant continuous stable isotope infusion: 2 H 5 -Phe, 13 C 9 15 N-Tyr, D5-Trp Stable isotope pulse: 2 H 3 -Leu, [ 2 H 3 ]-3-MetHis, 2 H 2 -Gly, 2-D-OHPro, 1-13 C-KIC, 15 N 2 -ARG, 2 H 2 -CIT, 13 C-Urea, 1,2-13 C 2 Taurine X X Intake of complete high protein meal and 13 C-Phe, 13 C 3 -Tripalmitin, 2 H 2 -Palmitic acid, 15 N-Spirulina X DXA (wb, hip and spine) & BIA Respiratory and handgrip muscle function X X Kin Com one leg exercise X Questionnaires (wellbeing, diet, and cognition) Blood sampling

Maximum Inspiratory Pressure (MIP) Maximum Expiratory Pressure (MEP) Leg extension (KinCom) Hand grip strength

Body composition Cancer (n=16) Healthy (n=16) P-value Gender n (%) M / F 9 / 7 9 / 7 1.00 Age y 60.1 (16.6) 59.8 (15.9) 0.97 Weight kg 72.7 (16.1) 77.3 (12.9) 0.38 BMI Overweight n (%) Obesity n (%) kg/m² 26.8 (5.4) 4 (25) 4 (25) 26.7 (3.2) 7 (43.8) 4 (25) 0.95 0.47 FFM-i kg/m² 17.7 (2.2) 18.1 (2.4) 0.56 Arms FFM kg 5.2 (1.8) 5.8 (1.7) 0.30 Legs FFM kg 15.0 (3.2) 16.7 (3.5) 0.14

Myofibrillar protein breakdown - fasted van der Meij, unpublished data

MEAL: BOOST High Protein drink (237 ml) 15g protein, 6g fat, 33 g carbohydrates van der Meij, unpublished data

Muscle function Mean (SD) Unit Healthy controls (n=16) Muscle function Cancer patients (n=16) P-value Maximal inspiratory pressure cmh2o 102.8 (40.2) 72.2 (30.6) 0.17 Maximal expiratory pressure cmh2o 112.8 (41.7) 96.2 (33.9) 0.45 Handgrip strength N 292 (66) 236 (96) 0.06 /FFM 5.5 (1.0) 4.8 (1.3) 0.08 Handgrip endurance % lost 25.4 (6.8) 23.5 (13) 0.61 Leg extension strength N 374 (140) 253 (118) 0.01 N/FFM 42.6 (10.2) 32.6 (10.8) 0.01 Leg extension endurance % lost 25.4 (13.3) 29.3 (11.4) 0.42

High-protein supplement anabolism n=8 pancreatic cancer and n=7 healthy controls FORTISIP High Protein drink (200 ml) 12g protein, 6g fat, 37 g carbohydrates van Dijk, J Cach Muscle Wasting 2015

Net protein anabolism Essential Amino Acids (EAA) anabolism 14 g EAA/leucine mixture Engelen, Ann Oncol 2015 EAA intake (umol/kg FFM)

Conclusion: Not enough solid evidence for protein supplements in cancer HMB, arginine and glutamine: Increase in lean body mass after 4 weeks in advanced solid tumour patients No benefits in lung cancer after 8 weeks L-carnitine in pancreatic caner: increase of BMI and survival Mochamat, J Cachexia Sarcopenia Muscle 2016

Summary Body composition in cancer is relevant: Obesity and aging epidemic High body fat and low muscle mass: associated with toxicity, muscle weakness, impaired quality of life and mortality Cancer patients have a higher protein turnover than healthy subjects Higher muscle protein breakdown Similar anabolic potential Protein supplementation works (short-term) Limitation: small sample sizes Where to go from here?

Recommendations ESPEN guidelines on Nutrition in Cancer Patients: Aim: 1.2 1.5 g protein/kg body weight Higher quality protein is recommended Promote physical exercise throughout cancer treatment Future research: Effects of long-term protein supplementation (>1.2 g/kg) Effects on muscle mass, muscle function, quality of life Additional effect of physical exercise and pharmaceutics (multimodal interventions) Arends, Clin Nutr 2017

ACKNOWLEDGEMENT Dr. Mick Deutz Dr. Marielle Engelen Department of Health and Kinesiology Center for Translation Research on Aging and Longevity Texas A&M College Station, TX, USA

THANK YOU VERY MUCH bvanderm@bond.edu.au CRICOS CODE 00017B