The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia
López-Millán, Belén (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Costales, Paula (EntreChemSL)
Gutiérrez-Agüera, Francisco (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Díaz de la Guardia, Rafael (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Roca Ho, Heleia (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Vinyoles, Meritxell (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Rubio Gayarre, Alba (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Safi, Rémi (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Castaño Cardoso, Julio (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Romecín, Paola Alejandra (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ramírez Orellana, Manuel (Instituto de Investigación Hospital Universitario de la Princesa)
Anguita, Eduardo (Hospital Clínico San Carlos (Madrid))
Jeremias, Irmela (Research Unit Apoptosis in Hematopoietic Stem Cells. Helmholtz Zentrum München)
Zamora, Lurdes (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Rodríguez-Manzaneque, Juan Carlos (GENYO. Centre for Genomics and Oncological Research. Pfizer. Universidad de Granada. Junta de Andalucía)
Bueno, Clara (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Morís, Francisco (EntreChemSL)
Menéndez Bujan, Pablo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)

Data:	2022
Resum:	Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITD) in the FMS-like kinase tyrosine kinase (FLT3) receptor generally have a poor prognosis. Several tyrosine kinase/FLT3 inhibitors have been developed and tested clinically, but very few (midostaurin and gilteritinib) have thus far been FDA/EMA-approved for patients with newly diagnosed or relapse/refractory FLT3-ITD AML. Disappointingly, clinical responses are commonly partial or not durable, highlighting the need for new molecules targeting FLT3-ITD AML. Here, we tested EC-70124, a hybrid indolocarbazole analog from the same chemical space as midostaurin with a potent and selective inhibitory effect on FLT3. In vitro, EC-70124 exerted a robust and specific antileukemia activity against FLT3-ITD AML primary cells and cell lines with respect to cytotoxicity, CFU capacity, apoptosis and cell cycle while sparing healthy hematopoietic (stem/progenitor) cells. We also analyzed its efficacy in vivo as monotherapy using two different xenograft models: an aggressive and systemic model based on MOLM-13 cells and a patient-derived xenograft model. Orally disposable EC-70124 exerted a potent inhibitory effect on the growth of FLT3-ITD AML cells, delaying disease progression and debulking the leukemia. Collectively, our findings show that EC-70124 is a promising and safe agent for the treatment of AML with FLT3-ITD.
Ajuts:	Instituto de Salud Carlos III PI20/00822 Agencia Estatal de Investigación PID2019-108160
Nota:	Fundació Carreras
Nota:	Funding: We thank CERCA/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa for institutional support. This research was funded by the Spanish Ministry of Economy and Competitiveness (RTC-2016-4603-1 in collaboration with Entrechem, PID2019-108160RBI00/AEI/10.13039/501100011033), the Interreg V-A program (POCTEFA) 2014-2020 (grant PRO-TEOblood EFA360/19), Health Canada (H4080-144541) and Deutsche Josep Carreras Leukämie Stiftung in collaboration with I.J. to P.M. (15R/2021). P.M. and M.R.-O. also acknowledge the support from ISCIII-RICORS within the Next Generation EU program (plan de recuperación, transformación y resiliencia). Additional funding was provided by Consejería de Salud y Familia (PI-0119-2019) to RDG, the Health Institute Carlos III (FIS PI20/00822), Asociación Española Contra el Cáncer (PRYGN211192BUEN) and Ministerio de Ciencia e Innovacion (PLE2021-007518 and PI20/00822) to C.B. M.V. was supported by Juan de la Cierva fellowship (IJCI-2017-33172). B.L.-M. was supported by the Asociación Española Contra el Cáncer (INVES20011LÓPE) and Consejería de Salud y Familia (PEER-0028-2020).
Nota:	We thank CERCA/Generalitat de Catalunya and Fundaci? Josep Carreras-Obra Social la Caixa for institutional support. This research was funded by the Spanish Ministry of Economy and Competitiveness (RTC-2016-4603-1 in collaboration with Entrechem, PID2019-108160RB-I00/AEI/10.13039/501100011033), the Interreg V-A program (POCTEFA) 2014?2020 (grant PRO-TEOblood EFA360/19), Health Canada (H4080-144541) and Deutsche Josep Carreras Leuk?mie Stiftung in collaboration with I.J. to P.M. (15R/2021). P.M. and M.R.-O. also acknowledge the support from ISCIII-RICORS within the Next Generation EU program (plan de recuperaci?n, transformaci?n y resiliencia). Additional funding was provided by Consejer?a de Salud y Familia (PI-0119-2019) to RDG, the Health Institute Carlos III (FIS PI20/00822), Asociaci?n Espa?ola Contra el C?ncer (PRYGN211192BUEN) and Ministerio de Ciencia e Innovacion (PLE2021-007518 and PI20/00822) to C.B. M.V. was supported by Juan de la Cierva fellowship (IJCI-2017-33172). B.L.-M. was supported by the Asociaci?n Espa?ola Contra el C?ncer (INVES20011L?PE) and Consejer?a de Salud y Familia (PEER-0028-2020).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	AML ; EC-70124 multi-kinase inhibitor ; FLT3-ITD mutation ; FLT3 inhibitor ; AML preclinical mode
Publicat a:	Cancers, Vol. 14 Núm. 6 (3-2 2022) , p. 1593, ISSN 2072-6694

DOI: 10.3390/cancers14061593
PMID: 35326743

14 p, 1.7 MB

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