Studies on AKT pathway and mitochondrial oxidative phosphorylation implication in rectal cancer resistance to neoadjuvant chemoradiotherapy

• Grant number: 14/22813-6
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2015
• End date: June 30, 2017
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Fernanda Christtanini Koyama
• Grantee: Fernanda Christtanini Koyama
• Host Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil
• Associated researchers: Anamaria Aranha Camargo ; Fabiana Bettoni ; Paula Fontes Asprino ; Rodrigo Oliva Perez

Abstract

Resistance to chemoradiotherapy is a major obstacle to a favorable outcome in cancer treatment. Neoadjuvant chemoradiotherapy treatment (nCRT) however, can lead to complete tumor regression in a significant proportion of patients with rectal cancer (up to 40%). Conversely, approximately 60% of patients have only partial or no tumor remission after nCRT. In attempt to identify biological mechanisms that may be related to tumor resistance to RQTn, we conducted differential gene expression analysis between rectal tumors that showed complete or partial regression to nQRT e. g. no response to neoadjuvant treatment, followed by analysis of biological pathways enriched among genes differentially expressed. According to our preliminary data we identified mitochondrial oxidative phosphorylation and phosphatidylinositol signaling as the main pathways involved in resistance to nCRT in patients with rectal cancer. While mitochondrial oxidative phosphorylation genes were found down-regulated in tumors from patients that do not respond to neoadjuvant treatment, some genes form phosphatidylinositol signaling pathway such as phosphatidylinositol synthase and phospholipase C were up-regulated while genes phosphatidylinositol 4- phosphate 5-kinase beta 1, inositol 1,3,4 triphosphate 5/6 kinase and the inositol 1,4,5 triphosphate receptor type 3 (important in calcium signaling) were down-regulated. Both pathways have been reported independently as involved in resistance to radiotherapy and chemotherapy in solid tumors, so in the present work we propose to i) evaluate the role of mitochondrial dysfunction and activation of Akt through analysis of differential gene expression from RNA-Seq data before and after to the neoadjuvant treatment ii) evaluate the activation of Akt by immunohistochemistry using antibodies to phosphorylated Akt in samples of rectal tumors from biopsies as well as in colorectal cancer cell lines sensitive or resistant to neoadjuvant treatment by immunoblot and last iii) perform in vitro tests of protocols for new therapies considering Akt inhibitors as radio sensitizer in attempt to improve the effectiveness of neoadjuvant treatment. The characterization of the mechanisms that lead to regulation of these pathways would be of great importance for understanding the mechanisms of resistance to RQTn in rectal cancer as propose new therapeutic strategies. (AU)

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)

KOYAMA, F. C.; LOPES RAMOS, C. M.; LEDESMA, F.; ALVES, V. A. F.; FERNANDES, J. M.; VAILATI, B. B.; SAO JULIAO, G. P.; HABR-GAMA, A.; GAMA-RODRIGUES, J.; PEREZ, R. O.; et al. Effect of Akt activation and experimental pharmacological inhibition on responses to neoadjuvant chemoradiotherapy in rectal cancer. BRITISH JOURNAL OF SURGERY, v. 105, n. 2, SI, p. E192-E203, JAN 2018. (14/22813-6)

KOYAMA, F. C.; LOPES RAMOS, C. M.; LEDESMA, F.; ALVES, V. A. F.; FERNANDES, J. M.; VAILATI, B. B.; SAO JULIAO, G. P.; HABR-GAMA, A.; GAMA-RODRIGUES, J.; PEREZ, R. O.; et al. Effect of Akt activation and experimental pharmacological inhibition on responses to neoadjuvant chemoradiotherapy in rectal cancer. BRITISH JOURNAL OF SURGERY, v. 105, n. 2, p. 12-pg., 2018-01-01. (14/22813-6)