Investigation of the antineoplastic potential of new drugs that modulate microtubule dynamics in acute leukemias.

Author(s)

Hugo Passos Vicari

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2024-08-05

Examining board members

João Agostinho Machado Neto; Patricia Maria Bergamo Favaro; Mariana Lazarini; Elvira Deolinda Rodrigues Pereira Velloso

• Advisor: João Agostinho Machado Neto

Abstract

Acute leukemias represent a continuous challenge in clinical practice due to high rates of relapse and resistance to chemotherapy treatments. Microtubules emerge as important pharmacological targets in cancer treatment, including leukemias, due to their essential role in cell division. In this context, the discovery and repositioning of antimicrotubule drugs arise as promising strategies to expand the anti-neoplastic arsenal and overcome therapeutic resistance. Stathmin 1 (STMN1), a microtubule dynamics regulator protein, stands out as a potential therapeutic target, given its relevance in the leukemic proliferative phenotype and its integration into various signaling pathways associated with hematologic neoplasms. The objective of this study is to investigate the therapeutic potential of antimicrotubule agents in acute leukemias, focusing on the expression and activity of stathmin 1 (STMN1) and the cellular and molecular effects of compound 2 (C2E1), a novel derivative of synthetic cyclopenta[<font face = \"symbol\">b]indoles, and eribulin, a microtubule inhibitor proposed for repositioning. Divided into three parts, the study initially revealed high expression of STMN1 in patients with acute promyelocytic leukemia (APL), with bioinformatics analyses associating this high expression with proliferation and metabolism gene signatures in APL. Inhibition of STMN1 by shRNA resulted in reduced cellular clonogenicity, while microtubule stabilization with paclitaxel induced cell death, including in cells resistant to standard treatment with all-transretinoic acid (ATRA). In the second part, three novel synthetic compounds of the cyclopenta[<font face = \"symbol\">b]indole class were tested in cellular models of APL, and C2E1 showed selective cytotoxicity through microtubule dynamics interruption. Expanded investigation of the cellular and molecular effects of cyclopenta[<font face = \"symbol\">b]indole C2E1 on the leukemic phenotype in a broad, molecularly heterogeneous panel of acute leukemia cell lines demonstrated its high cytotoxicity, reduced clonogenicity, induction of apoptosis, and cell cycle arrest. Finally, the third part investigated the effect of eribulin in experimental models of hematologic neoplasms, demonstrating high cytotoxicity and effectiveness in reducing cell viability by disrupting microtubule dynamics, leading to mitotic catastrophe and cell death. The expression and activation of MDR1 (ABCB1 and ABCC1), PI3K/AKT, and NFB were identified as potential biomarkers of response to eribulin, and combined treatment of eribulin with elacridar potentiated eribulin effects and overcame resistance in hematologic neoplasms. Overall, the study provides insights into the role of STMN1 and microtubule inhibitor agents in the treatment of acute leukemias, offering preclinical evidence in the identification of potential new therapeutic agents and strategies to overcome resistance to conventional treatments. (AU)

• FAPESP's process: 21/01460-1 - Investigation of the antineoplastic potential of new drugs that modulate microtubule dynamics in Acute Myeloid Leukemia
• Grantee: Hugo Passos Vicari
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)