Selective Inhibitor of Nuclear Export (SINE), Selinexor (KPT-330), Shows Remarkable Activity Against AML Leukemia-Initiating Cells
Notice bibliographique
Résumé
Abstract Currently available combination chemotherapy for acute myeloid leukemia (AML) often fails to induce long-term remissions, prompting the need to develop novel therapies. The frequent disease relapse that is observed in patients with AML is thought to occur because of the inability of the existing drugs to target the self-renewing leukemia-initiating (LICs) in AML. An attractive new strategy for AML therapy is inhibition of the nuclear export protein exportin 1 (XPO1), also called CRM1. A member of the karyopherin b family, XPO1 mediates nuclear export of proteins that contain leucine-rich nuclear export signals (NES), including protein adaptors that transport RNA molecules. XPO1 regulates nuclear export of ~220 eukaryotic proteins, including the tumor suppressor proteins p53, p73, p21, Rb, FOXO3A, BRCA1, and PP2A, cell cycle regulators, and apoptotic proteins. Indeed, nuclear-cytoplasmic transport by XPO1 is required for the survival of several types of solid tumors and hematologic malignancies. Recently, novel selective small molecule inhibitors of nuclear export (SINE) that inhibit the export function of XPO1 by targeting Cys528 in its NES-binding groove, were developed using an in silico molecular modeling strategy. The orally bioavailable SINE compound, selinexor (KPT-330), is in Phase 1 and 2 studies in patients with adult AML (NCT01607892 and NCT02088541) and in a Phase 1 study for relapsed childhood ALL and AML that was initiated in March, 2014 (NCT02091245). To determine the anti-leukemic activity of selinexor against primary AML blasts and LICs in a clinically relevant setting, we established mouse xenograft models of human leukemia, in which leukemic blast cells from patients with different subtypes of AML were transplanted into immunodeficient NOD-SCID-IL2Rcgnull (NSG) mice. Engrafted mice were treated with selinexor or a vehicle control. Selinexor was highly active against blast cells from two of the three patients with poor-prognosis disease (cytogenetically normal AML with an internal tandem duplication of FLT3 (AML-CN) and complex karyotype AML (AML-CK1 and AML-CK2)) as evidenced by a reduction in leukemic engraftment in primary mice. Importantly, serial dilution transplantation assays indicate that selinexor therapy greatly reduced the frequency of LICs in xenografts derived from all three patients (6 - to 434- fold reduction compared to controls), indicating that this agent not only targets the bulk leukemic cells, but also eliminates LICs. Interestingly, in mice bearing AML grafts derived from one of the patients with complex karyotype, selinexor dramatically decreased LIC frequency despite exhibiting only modest anti-leukemic activity against bulk disease in primary mice. These findings show that selinexor has potent activity against self-renewing LIC in poor-prognosis AML, even when it has only moderate activity against the bulk AML cell population. Moreover, bone marrow biopsies of selinexor-treated mice showed normal hematopoietic cell morphology and cellularity following four weeks of treatment. These findings demonstrate that inhibition of nuclear export with selinexor addresses the primary remaining problem in the therapy of AML, which is to destroy the very critical self-renewing LIC compartment while sparing normal hematopoietic cells. Disclosures Etchin: Leukemia and Lymphoma Society, Alex's Lemonade Stand, Luck2Tuck Foundation, Karyopharm Therapeutics, Inc: Research Funding. McCauley:Karyopharm Therapeutics, Inc: Employment, Equity Ownership. Kauffman:Karyopharm Therapeutics, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Shacham:Karyopharm Therapeutics, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
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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 | 0,000 | 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 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| 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 ».