Zelenirstat Nmt Inhibitor in Patients with Relapsed/Refractory B-Cell Lymphoma and Acute Myelogenous Leukemia: Mechanistic Insights and Clinical Outcomes
Notice bibliographique
Résumé
Background Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, regulates numerous membrane-bound signal transduction pathways driving cancer cell biology, including B cell receptor and Bruton tyrosine kinase signaling in lymphoma, and FLT3, c-Kit and Jak/Stat signaling in AML. This modification is catalyzed by two N-myristoyltransferases (NMT), NMT1 and NMT2. Aberrant NMT expression has been identified in cancer cells and inhibition of myristoylation represents a novel anticancer treatment strategy. Zelenirstat (PCLX-001) is an oral, highly bioavailable, small molecule NMT inhibitor with strong affinity for both NMT1 and NMT2. In vitro, hematologic cancer cell lines were exquisitely sensitive to zelenirstat, and even more so to the combination of zelenirstat with the Bcl2 inhibitor Venetoclax. Zelenirstat regressed subcutaneous tumors in xenograft models derived from lymphoma and acute myeloid leukemia (AML) cell lines, as well as in refractory DLBCL patient (pt) derived xenograft models. We recently completed a first in human phase I dose escalation study in patients with refractory solid tumors and relapsed/refractory (R/R) B cell lymphomas (https://doi.org/10.1007/s10637-024-01448-w). The success of this phase I study has triggered additional mechanistic studies of zelenirstat, as well as a phase IIA study of zelenirstat in R/R B cell lymphoma, and a Phase I dose escalation study of zelenirstat in R/R acute myelogenous leukemia. Methods AML cell lines treated with zelenirstat were analyzed for metabolic impacts using western blot, luciferase, in-gel activity, and Seahorse assays. In the phase IIA study of zelenirstat in R/R B-cell lymphoma, patients are receiving zelenirstat with daily oral administration at the recommended phase II dose of 210 mg daily until progression. Response assessments occur every second 28-day cycle. We also will soon be opening the study “A Phase 1 Study of Oral PCLX-001 in (R/R) Acute Myeloid Leukemia (AML)” at the MD Anderson Cancer Center. In this study, previously treated AML patients are receiving daily oral zelenirstat with careful attention to pharmacokinetics, as zelenirstat metabolism, in which CYPD 3A4 dominates, is expected to be modulated by concurrent azole antifungals commonly used in this setting. The primary objectives are to determine the safety and tolerability of zelenirstat in patients with R/R AML, and to determine the minimum safe and biologically effective dose. Secondary endpoints are the estimates of ORR, CR, CRp, Cri, Crh, and PR, and duration of response, time to progression, and overall survival. Results In AML cell lines, in addition to promoting the loss of various Src family kinases involved in growth signaling, treatment drove loss of NDUFAF4, AMPKß, and complex I involved in energy metabolism. Zelenirstat impaired oxidative metabolism, glycolysis, and reduced cellular ATP. In the phase IIA lymphoma study, two patients with DLBCL have been dosed, one who experienced PD, and one patient with three prior lines of therapy who achieved PR and PET metabolic response and continues study medication after eleven 28-day cycles of continuous therapy. No dose limiting toxicities have occurred. In the Phase I study of zelenirstat in R/R AML, first patient on study is expected in 2024. Updated clinical results will be presented. Conclusions In pre-clinical studies, zelenirstat treatment significantly reduces key myristoylated metabolic proteins and regulators, leading to metabolic suppression and cell death. Zelenirstat is safe and well tolerated at the 210 mg OD dose in patients with R/R DLBCL, and objective responses of significant duration have been observed in heavily pre-treated patients. The absence of severe toxicities to date, the attainment of plasma concentrations highly active in preclinical models, and pre-clinical and clinical evidence of anticancer activity support the ongoing development of zelenirstat as an oral, daily therapy for patients with R/R B-cell lymphoma and R/R AML.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 source (Gemma direct ou Codex distillé), 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 ».