RESUMEN
Selinexor is the first oral selective inhibitor of nuclear export compound tested for cancer treatment. Selinexor has demonstrated a safety therapy profile with broad antitumor activity against solid and hematological malignancies in phases 2 and 3 clinical trials (#NCT03071276, #NCT02343042, #NCT02227251, #NCT03110562, and #NCT02606461). Although selinexor shows promising efficacy, its primary adverse effect is high-grade thrombocytopenia. Therefore, we aimed to identify the mechanism of selinexor-induced thrombocytopenia to relieve it and improve its clinical management. We determined that selinexor causes thrombocytopenia by blocking thrombopoietin (TPO) signaling and therefore differentiation of stem cells into megakaryocytes. We then used both in vitro and in vivo models and patient samples to show that selinexor-induced thrombocytopenia is indeed reversible when TPO agonists are administered in the absence of selinexor (drug holiday). In sum, these data reveal (1) the mechanism of selinexor-induced thrombocytopenia, (2) an effective way to reverse the dose-limiting thrombocytopenia, and (3) a novel role for XPO1 in megakaryopoiesis. The improved selinexor dosing regimen described herein is crucial to help reduce thrombocytopenia in selinexor patients, allowing them to continue their course of chemotherapy and have the best chance of survival. This trial was registered at www.clinicaltrials.gov as #NCT01607905.
Asunto(s)
Hidrazinas/efectos adversos , Megacariocitos/metabolismo , Megacariocitos/patología , Transducción de Señal/efectos de los fármacos , Trombocitopenia/inducido químicamente , Trombocitopenia/metabolismo , Trombopoyesis/efectos de los fármacos , Trombopoyetina/metabolismo , Triazoles/efectos adversos , Animales , Apoptosis/efectos de los fármacos , Plaquetas/efectos de los fármacos , Plaquetas/patología , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Recuento de Células , Diferenciación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Feto/patología , Hígado/embriología , Megacariocitos/efectos de los fármacos , Megacariocitos/ultraestructura , Ratones Noqueados , Activación Plaquetaria/efectos de los fármacos , Células Madre/citología , Trombocitopenia/sangreRESUMEN
We present a low-resolution density-based scoring scheme for selecting high-quality models from a large pool of lesser quality models. We use pre-configured decoy data sets that contain large numbers of models with different degrees of correctness to evaluate the performance of the strategy. We find that the scoring scheme consistently identifies one of the highest quality models for a wide variety of target structures, resolution ranges, and noise models. Tests with experimental data yield similar results.