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Novel strategies and therapeutic targets in medulloblastoma exploring tumor microenviroment trough in vivo models of subgroup SHH and Group 3

Grant number: 18/20635-4
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): February 01, 2019
Effective date (End): January 31, 2020
Field of knowledge:Health Sciences - Medicine - Maternal and Child Health
Principal researcher:Luiz Gonzaga Tone
Grantee:Gustavo Alencastro Veiga Cruzeiro
Supervisor abroad: Rakesh K Jain
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: Massachusetts General Hospital, United States  
Associated to the scholarship:17/06511-8 - Investigation of Smad2/3-YAP complex as a chemoresistant factor in TP53, BP.PD

Abstract

Besides surgery, the standard treatment options for newly diagnosed medulloblastoma (MB) include radiotherapy and chemotherapy, which induce severe adverse effects and compromise the quality of life in pediatric patients. Group 2 (Sonic Hedgehog [SHH]) and Group 3 (MYC) MB tumors are highly aggressive with moderate and worst prognoses, respectively. These two subgroups also have an intactblood-brain barrier (BBB) that limits drug penetration; furthermore, druggable targets aimed at the inherently immunosuppressive MB tumor microenvironment have not yet been identified. Therefore, my proposal to develop an efficacious treatment for MB that promotes durable response without therapy-associated morbidity will address an unmet need. Targeting MB tumor-stroma interactions may prove advantageous over solely targeting the tumor cell compartment given the critical role of the tumor microenvironment in MB progression, immunosuppression, and resistance to treatment. Low-dose, non-toxic radiation has been shown to disrupt the BBB and increase permeability in cerebral vessels (1). The proposed therapeutic strategy - combining anon-toxic upstream inhibitor of YAP or STAT3 (frequently overexpressed in MB SHH and MB respectively, and as known drivers of tumorigenesis and immunosuppression with low-dose radiotherapy (which allows enhanced drug permeability via partial disintegration of BBB and primes the immune system) - is not only innovative but has the potential to dramatically improve MB treatment (2,3,4). The proposal will also clarify whether minimal radiation can sensitize medulloblastomas SHH and Group 3 MYC driven tumors to anti-Sphingosine Kinase 2 (SK2)/STAT3 therapy in vivo, or thereby reducing detrimental side effects of standard radiation dosages. This attractive strategy of lowering radiation dose, counter-balanced by potent but non-toxic therapy of SK2/STAT3 inhibition is 1) highly novel and relevant to MB treatment and 2) is informative regarding the design of a multi-institutional phase I/II clinical trial. The team at Massachussetts General Hospital (MGH)/Harvard Medical School has the appropriate expertise and collaborators in place to rapidly translate these findings in an efficient manner to improve treatment outcome in this devastating pediatric brain cancer (5,6).

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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)
ALENCASTRO VEIGA CRUZEIRO, GUSTAVO; DE ALMEIDA MAGALHAES, TACIANI; RIBEIRO DE SOUSA, GRAZIELLA; BONFIM SILVA, RICARDO; ALBERTO OLIVEIRA DE BIAGI JUNIOR, CARLOS; FERREIRA DAS CHAGAS, PABLO; GOMES DE PAULA QUEIROZ, ROSANE; ALBERTO SCRIDELI, CARLOS; GONZAGA TONE, LUIZ; TERCI VALERA, ELVIS. YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells. CANCERS, v. 13, n. 24, . (14/20341-0, 17/06511-8, 18/20635-4)

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