Abstract 39: XPO1 inhibitor, KPT-8602, is well tolerated and highly active against AML blasts and LICs
Notice bibliographique
Résumé
Abstract Standard chemotherapy often induces remissions in AML patients, but the disease frequently relapses due to incomplete targeting of leukemia-initiating cells (LICs), emphasizing the need for novel effective treatments. An attractive target for AML therapy is nuclear exporter exportin 1 (XPO1), which mediates continuous nuclear export of a subset of proteins and RNAs. The orally bioavailable XPO1 inhibitor of the Selective Inhibitor of Nuclear Export (SINE) class of compounds, selinexor (KPT-330), is currently in phase 1 and 2 clinical trials in adult patients with AML and in phase 1 trials for relapsed childhood ALL and AML. The results of these trials are encouraging, as they have demonstrated that selinexor is active in inducing remission in patients with relapsed or refractory disease. Here we report the antileukemic efficacy and tolerability of KPT-8602, a second-generation XPO1 inhibitor. KPT-8602 demonstrates substantially reduced brain penetration compared to selinexor, with resultant attenuation of the CNS-mediated side effects of anorexia and weight loss. Due to its improved tolerability profile, KPT-8602 can be given daily compared to the two- or three-times-weekly regimen of selinexor. To define the antileukemia activity of KPT-8602 against primary AML blasts and LICs in a relevant preclinical setting, we established patient-derived xenograft (PDX) models, in which leukemic blasts from AML patients with poor-prognosis disease (cytogenetically normal AML with FLT3-ITD (AML-CN), AML with complex karyotype (AML-CK), and MDS-derived AML (MDS/AML) are transplanted into immunodeficient NOD-SCID-IL2Rcgnull (NSG) mice. Mice engrafted with leukemic blasts are treated with vehicle, selinexor (20 mg/kg three times per week), or KPT-8602 (15 mg/kg daily for 4 weeks). KPT-8602 exhibits superior antileukemic activity and better tolerability in the AML PDX models tested, with nearly complete elimination of human AML cells in AML-CN model. To determine the frequency of LICs in the vehicle control, selinexor or KPT-8602, we used a limiting dilution transplantation assay. Although both selinexor and KPT-8602 effectively targeted LICs, KPT-8602 is more potent in eliminating LICs, as evidenced by a more profound reduction of LIC frequency in the AML-CK and AML-CN PDX models (507-fold vs. 0.9-fold reduction in AML-CK, P<0.0001; and 437-fold vs. 111-fold reduction in AML-CN by KPT-8602 vs. selinexor, P=0.79). The impact on normal human hematopoietic stem and progenitor cell (HSPC) fractions by CD34/CD38 flow analysis and limiting dilution transplantation assays (performed by the same methodology as described for PDX models of AML) demonstrates that, in contrast to its profound effects against AML LIC, KPT-8602 does not preferentially kill normal HSPC, providing a therapeutic window for elimination of relapse-driving LICs while sparing normal HSPCs. KPT-8602 has entered a phase 1/2 trial in patients with relapsed/refractory multiple myeloma. Our preclinical results indicate that KPT-8602 should be tested in clinical trials to determine its toxicity and efficacy in patients with relapsed or refractory AML, with the hope that it can eventually be integrated into upfront combination chemotherapy regimens. To delineate the pathways that mediate the apoptotic signaling in response to the SINE compounds, we are conducting the RNA-seq, ChIP-seq and ATAC-seq studies on AML cell lines treated in vitro as well as AML cells isolated from PDX mice. The preliminary results of these studies will be presented at the meeting. Citation Format: Julia Etchin, Alla Berezovskaya, Amy S. Conway, Ilene A. Galinsky, Richard M. Stone, Erkan Baloglu, William Senapedis, Yosef Landesman, Michael Kauffman, Sharon Shacham, Jean CY Wang, A Thomas Look. XPO1 inhibitor, KPT-8602, is well tolerated and highly active against AML blasts and LICs [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 39.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».