Understanding EPHA5 signaling in the effects of paclitaxel-induced peripheral neuropathy on human-induced pluripotent stem cell derived sensory neurons

• Grant number: 18/00070-2
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: June 25, 2018
• End date: June 24, 2019
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Priscila Gava Mazzola
• Grantee: Amanda Canato Ferracini
• Supervisor: Deanna L. Kroetz
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of California, San Francisco (UCSF), United States
• Associated to the scholarship: 16/22335-2 - Evaluation of genetic markers and quality of life in women with ovarian carcinoma, BP.DR

Abstract

Paclitaxel is an antineoplastic drug frequently effective in first line treatment for ovarian, breast, lung and prostate cancer. However, cumulative dose of this agent is a significant predictor of sensory peripheral neuropathy. The first genome wide association studies on paclitaxel induced peripheral neuropathy (PIPN) identified a genetic variant in the ephrin receptor gene EPHA5 associated with increased risk of developing this toxicity. Furthermore, the application of human-induced pluripotent stem cell (iPSC) technology holds the potential for rapid advances in understanding PIPN on molecular level. The propose of this study is to assess the relevance of EPHA5 in the molecular mechanisms underlying PIPN, using a novel human-induced pluripotent stem cell derived sensory neuron model. Human isogenic induced pluripotent stem cell lines will be differentiated into nociceptor sensory neurons (iPSC-SNs) to study paclitaxel effects in the cellular target of toxicity. CRISPRi technology and pharmacological agents will be used to inhibit EPHA5 and the Rho GTPases and measure effects on neurite morphology. All experiments will be repeated a minimum of three times with at least three technical replicates per experiment. Dose-dependent effects of paclitaxel on quantitative measures of neurite morphology will be tested for significance (P < 0.05) using ANOVA followed by a Dunnett's post hoc multiple comparison test; the dependence of these measures on EPHA5 and Ephexin-1 will be similarly tested.

Scientific publications

(6)

(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)

FERRACINI, AMANDA CANATO; PEREIRA, GABRIELA; DE SOUZA, CINTHIA MADEIRA; DOS SANTOS, THIAGO FORTES CABELLO; SARIAN, LUIS OTAVIO; DERCHAIN, SOPHIE; MAZZOLA, PRISCILA GAVA. Physical and functional well-being and symptoms of ovarian cancer in women undergoing first-line of chemotherapy: a one-year follow-up. SUPPORTIVE CARE IN CANCER, JUN 2021. (19/24093-4, 16/22335-2, 18/00070-2)

XIONG, CHENLING; CHUA, KATHERINA C.; STAGE, TORE B.; PRIOTTI, JOSEFINA; KIM, JEFFREY; ALTMAN-MERINO, ANNE; CHAN, DANIEL; SARAF, KRISHNA; CANATO FERRACINI, AMANDA; FATTAHI, FARANAK; et al. Human Induced Pluripotent Stem Cell Derived Sensory Neurons are Sensitive to the Neurotoxic Effects of Paclitaxel. CTS-CLINICAL AND TRANSLATIONAL SCIENCE, v. 14, n. 2, DEC 2020. (18/00070-2)

FERRACINI, AMANDA CANATO; LOPES-AGUIAR, LEISA; LOURENCO, GUSTAVO JACOB; YOSHIDA, ADRIANA; LIMA, CARMEN SILVA PASSOS; SARIAN, LUIS OTAVIO; DERCHAIN, SOPHIE; KROETZ, DEANNA L.; MAZZOLA, PRISCILA GAVA. GSTP1 and ABCB1 Polymorphisms Predicting Toxicities and Clinical Management on Carboplatin and Paclitaxel-Based Chemotherapy in Ovarian Cancer. CTS-CLINICAL AND TRANSLATIONAL SCIENCE, v. 14, n. 2, DEC 2020. (16/22335-2, 18/00070-2)

PEREIRA, GABRIELA; SURITA, FERNANDA GARANHANI; FERRACINI, AMANDA CANATO; MADEIRA, CINTHIA DE SOUZA; OLIVEIRA, LETICIA SILVA; MAZZOLA, PRISCILA GAVA. Self-Medication Among Pregnant Women: Prevalence and Associated Factors. FRONTIERS IN PHARMACOLOGY, v. 12, SEP 6 2021. (18/00070-2, 16/22335-2)

FERRACINI, AMANDA CANATO; PEREIRA, GABRIELA; DE SOUZA, CINTHIA MADEIRA; DOS SANTOS, THIAGO FORTES CABELLO; SARIAN, LUIS OTAVIO; DERCHAIN, SOPHIE; MAZZOLA, PRISCILA GAVA. Physical and functional well-being and symptoms of ovarian cancer in women undergoing first-line of chemotherapy: a one-year follow-up. SUPPORTIVE CARE IN CANCER, v. 29, n. 12, p. 7421-7430, DEC 2021. (16/22335-2, 19/24093-4, 18/00070-2)

FERRACINI, AMANDA CANATO; LOPES-AGUIAR, LEISA; LOURENCO, GUSTAVO JACOB; YOSHIDA, ADRIANA; LIMA, CARMEN SILVA PASSOS; SARIAN, LUIS OTAVIO; DERCHAIN, SOPHIE; KROETZ, DEANNA L.; MAZZOLA, PRISCILA GAVA. GSTP1 and ABCB1 Polymorphisms Predicting Toxicities and Clinical Management on Carboplatin and Paclitaxel-Based Chemotherapy in Ovarian Cancer. CTS-CLINICAL AND TRANSLATIONAL SCIENCE, v. 14, n. 2, p. 9-pg., 2020-12-16. (18/00070-2, 16/22335-2)