RESUMO
Subsets of non-acute promyelocytic leukemia (APL) acute myelogenous leukemia (AML) exhibit aberrant retinoid signaling and demonstrate sensitivity to retinoids in vitro. We present the results of a phase 1 dose-escalation study that evaluated the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist, in patients with relapsed or refractory myelodysplastic syndrome (MDS) or AML. In this single center, single arm study, eleven patients with relapsed or refractory MDS/AML were enrolled and treated. Oral IRX195183 was administered at two dose levels: 50 mg daily or 75 mg daily for a total of two 28-day cycles. Patients with stable disease or better were allowed to continue on the drug for four additional 28-day cycles. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema. Three patients at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia. The maximally tolerated dose was not reached. Four of the eleven patients had (36%) stable disease or better. One had a morphological complete remission with incomplete hematologic recovery while on the study drug. Two patients had evidence of in vivo leukemic blast maturation, as reflected by increased CD38 expression. In a pharmacodynamics study, plasma samples from four patients treated at the lowest dose level demonstrated the capacity to differentiate leukemic cells from the NB4 cell line in vitro. These results suggest that IRX195183 is safe, achieves biologically meaningful plasma concentrations and may be efficacious in a subset of patients with MDS/AML. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02749708.
Assuntos
Antineoplásicos/farmacologia , Família 26 do Citocromo P450/genética , Resistencia a Medicamentos Antineoplásicos/genética , Retinoides/farmacologia , Tretinoína/farmacologia , Animais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/química , Receptores do Ácido Retinoico/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The hindbrain region of the vertebrate central nervous system (CNS) presents a complex regionalisation. It consists of 7-8 distinct morphological segments called rhombomeres, each with a unique identity provided by combinations of transcription factors. One class of signalling molecules, retinoids, have been shown to be crucial for hindbrain patterning through direct trans-activation of Hox genes in the neuroectoderm. However, how this morphogen acts is not yet fully understood. Here, we show that the retinoid receptor antagonist AGN193109 causes a posterior hindbrain defect in Xenopus, comparable to that seen in other vertebrates. We show that this defect arises during gastrulation. Blocking endogenous retinoid activity during gastrulation causes downregulation of the most 3' Hox genes (paralogues 1-5) in gastrula neuroectoderm, but their initial activation in gastrula non-organiser mesoderm is unaffected. Similar results were obtained in avian embryos: Vitamin A-deficient quail embryos have defective expression of 3 Hox genes (i.e. Hoxb1, Hoxb4 ) in the neural tube, but their early expression in the primitive streak and emerging paraxial and lateral mesoderm is not affected. In Xenopus, depletion of retinoids from mesoderm by targeted injection of mRNAs for the retinoic acid catabolising enzyme xCYP26 and the cellular retinoic acid binding protein xCRABP blocks 3 Hox gene expression in the overlying neuroectoderm. We propose that the gastrula non-organiser mesoderm and its later derivative, the paraxial mesoderm, is the source of a retinoid, which acts as a transforming (caudalising) signal for the future posterior hindbrain.
Assuntos
Mesoderma/metabolismo , Placa Neural/metabolismo , Retinoides/metabolismo , Transdução de Sinais/fisiologia , Animais , Comunicação Celular/genética , Sistema Nervoso Central/metabolismo , Gástrula/metabolismo , Gastrulação , Expressão Gênica , Genes Homeobox , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Retinoides/genética , Rombencéfalo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Vertebrados/genética , Vertebrados/metabolismo , Xenopus/genética , Xenopus/metabolismo , Xenopus laevis/genética , Xenopus laevis/metabolismoRESUMO
BAR is a nuclear bile acid receptor (BAR) (FXR) receptor that regulates gene networks involved in cholesterol and bile acid homeostasis. We have identified two classes of synthetic compounds that differentially modulate BAR activity. The first class activates BAR target genes in the predicted fashion and is 25-fold more potent than endogenous bile acids. The second class, represented by AGN34, antagonizes BAR in transient reporter assays. Surprisingly, this compound acts in a gene-selective manner in vivo: it is an agonist on CYP7A1, an antagonist on IBABP, and is neutral on SHP. These findings indicate that synthetic BAR modulators can be developed to regulate transcription in a gene-specific fashion. Given the ability of BAR to regulate several lipid homeostatic pathways, the identification of gene-selective BAR modulators have important implications for the development of improved cholesterol lowering agents.
