Panobinostat (LBH589) increase survival in adult xenografic model of acute lymphoblastic leukemia with t(4;11) but promotes antagonistic effects in combination with MTX and 6MP

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Moreno, Daniel Antunes ; Ribeiro Junior, Howard Lopes ; Albertoni Laranjeira, Angelo Brunelli ; Veiga Cruzeiro, Gustavo Alencastro ; Borges, Kleiton Silva ; Salomao, Karina Bezerra ; Ramalho, Fernando Silva ; Yunes, Jose Andres ; Araujo Silva, Cleide Lucia ; Rego, Eduardo Magalhaes ; Scrideli, Carlos Alberto ; Tone, Luiz Gonzaga

• Tipo de documento: Artigo Científico
• Fonte: MEDICAL ONCOLOGY; v. 39, n. 12, p. 10-pg., 2022-09-29.

Resumo

Patients diagnosed with acute lymphoblastic leukemia (ALL) bearing t(4;11)/MLL-AF4 have aggressive clinical features, poor prognosis and there is an urgent need for new therapies to improve outcomes. Panobinostat (LBH589) has been identified as a potential therapeutic agent for ALL with t(4;11) and studies suggest that the antineoplastic effects are associated with reduced MLL-AF4 fusion protein and reduced expression of HOX genes. Here, we evaluated the in vitro effects of the combination of LBH589 with methotrexate (MTX) or 6-mercaptopurine (6MP) by cell proliferation assays and Calcusyn software in ALL cell line (RS4;11); the in vivo effects of LBH589 in xenotransplanted NOD-scid IL2Rgamma(null) mice measuring human lymphoblasts by flow cytometry; and the expression of HOX genes by qPCR after treatment in an adult model of ALL with t(4;11). LBH589 combination with MTX or 6MP did not promote synergistic effects in RS4;11 cell line. LBH589 treatment leads to increased overall survival and reduction of blasts in xenotransplanted mice but caused no significant changes in HOXA7, HOXA9, HOXA10, and MEIS1 expression. The LBH589, alone, showed promising antineoplastic effects in vivo and may represent a potential agent for chemotherapy in ALL patients with t(4;11). (AU)

• Processo FAPESP: 12/18383-0 - Estudo dos efeitos da inibição do gene HDAC9 em leucemia linfoide aguda
• Beneficiário: Daniel Antunes Moreno
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado