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Activity of WNT signaling pathway inhibitors in in vitro models

Grant number: 21/05230-0
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): August 01, 2021
Effective date (End): March 31, 2025
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Sara Teresinha Olalla Saad
Grantee:Maura Lima Pereira Bueno
Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:17/21801-2 - Predictors of severity and new treatments for bone marrow neoplasias, AP.TEM
Associated scholarship(s):22/14101-2 - Novel strategies for AML treatment: developing new technologies targeting the bone marrow niche, BE.EP.DD

Abstract

Hematological neoplasms correspond to diseases that imply abnormal and disordered proliferation of immature blood and bone marrow cells, including Myelodysplastic Syndromes (SMD), Acute Myeloid Leukemia (AML), Acute Lymphoid Leukemia (ALL), Lymphoma and Multiple Myeloma (MM), prevalent in people over the age of 65 years. Bone marrow transplantation is considered the only curative treatment. However, most patients are not applicable due to age and the presence of comorbidities. In addition, the chemotherapy drugs currently administered in the medical clinic result in high morbidity and limited efficiency due to the little capacity to differentiate between healthy and neoplastic cells, causing adverse effects and high toxicity. Thus, there is a need to develop new more efficient therapeutic strategies with less side effects. In this perspective, compounds whose actions are based on the modulation of deregulated pathways in hematological neoplasms, such as PI3K, MAPK and BCL-2, or on the interaction between hematopoietic cells and niche, WNT and SPINT/HGF, are equivalent to possible candidates for the development of new ones. treatments. In view of the above, we propose the development of new strategies for antitumor therapy based on newly synthesized and not yet commercialized compounds. For this, we will analyze the in vitro, ex vivo and in vivo effects of new compounds that can modulate interconnected signaling pathways. In addition, we propose the development and/or improvement of methods for the analysis of the tumor microenvironment, such as 3D culture using scaffold, and identification of co-localization of antigens of interest and cell types, indirect immunofluorescence with confocal analysis. (AU)

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