Influence of aerobic exercise on drug delivery and doxorubicin-based chemotherapy response in obesity-associated breast cancer

• Grant number: 16/21320-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: March 06, 2017
• End date: March 05, 2018
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Carlos Eduardo Negrão
• Grantee: Igor Lucas Gomes dos Santos
• Supervisor: Dai Fukumura
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Institution abroad: Massachusetts General Hospital, United States
• Associated to the scholarship: 14/13690-8 - Role of exercise training on prevention of cardiotoxicity provoked by doxorubicin, BP.PD

Abstract

More than two-thirds of women in US are classified as overweight or obese. This scenario represents a growing public health problem even in Brazil. Obesity increases the risk of developing invasive breast cancer (BC). Increased adiposity nourishes an environment propitious for tumor establishment and progression associated with increased hypoxia, desmoplasia and reduced perfusion, contributes to tumor aggressiveness and impairment in drug delivery. Doxorubicin (Dox) is a potent antibiotic, used in several cancer treatments, including BC. However, this medication is associated with a dose-dependent increase in risk of cardiac dysfunction. Considering that Dox dosage is based on body surface area, it tends to be increased in women with obesity. However, even receiving more amounts of Dox and be at greater risk for cardiotoxicity, it seems that obesity associated BC hosts experience reduced drug delivery and treatment response. Exercise training is a non-pharmacological approach to defeat overweight and obesity. In addition, it appears to improve BC survivorship. Several studies have demonstrated the effect of exercise training on attenuating Dox-induced cardiotoxicity. However, it is unknown whether exercise training can surpass the highly desmoplastic obesity-associated with BC tumor microenvironment, outdoing solid stress to increase tumor perfusion, oxygenation and drug delivery. We raise the hypothesis that acute exercise will increase tumor perfusion and oxygenation in a mice model of obesity-associated BC. Moreover, we propose that this response depends upon exercise intensity. The second goal of the present proposal is to test the hypothesis that chronic exercise will enhance Dox-based chemotherapy responses associated with increase in drug delivery and tumor growth.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GOMES-SANTOS, IGOR L.; AMOOZGAR, ZOHREH; KUMAR, ASHWIN S.; HO, WILLIAM W.; ROH, KANGSAN; TALELE, NILESH P.; CURTIS, HANNAH; KAWAGUCHI, KOSUKE; JAIN, RAKESH K.; FUKUMURA, DAI. Exercise Training Improves Tumor Control by Increasing CD8(+) T-cell Infiltration via CXCR3 Signaling and Sensitizes Breast Cancer to Immune Checkpoint Blockade. CANCER IMMUNOLOGY RESEARCH, v. 9, n. 7, p. 765-778, JUL 2021. (14/13690-8, 16/21320-1)

INCIO, JOAO; LIGIBEL, JENNIFER A.; MCMANUS, DANIEL T.; SUBOJ, PRIYA; JUNG, KEEHOON; KAWAGUCHI, KOSUKE; PINTER, MATTHIAS; BABYKUTTY, SUBOJ; CHIN, SHAN M.; VARDAM, TRUPTI D.; et al. Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2. Science Translational Medicine, v. 10, n. 432, MAR 14 2018. (16/21320-1)

GOMES-SANTOS, IGOR L.; JORDAO, CAMILA P.; PASSOS, CLEVIA S.; BRUM, PATRICIA C.; OLIVEIRA, EDILAMAR M.; CHAMMAS, ROGER; CAMARGO, ANAMARIA A.; NEGRAO, CARLOS E.. Exercise Training Preserves Myocardial Strain and Improves Exercise Tolerance in Doxorubicin-Induced Cardiotoxicity. FRONTIERS IN CARDIOVASCULAR MEDICINE, v. 8, APR 1 2021. (16/21320-1, 15/19076-2, 15/22814-5, 14/13690-8)