Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis.

Autor:	Wang VE; Department of Medicine, University of California, San Francisco, San Francisco, California.; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., Blaser BW; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Patel RK; CoLabs, University of California, San Francisco, San Francisco, Califoria., Behbehani GK; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Rao AA; CoLabs, University of California, San Francisco, San Francisco, Califoria., Durbin-Johnson B; Bioinformatics Core, Genome Center, University of California, Davis, Davis, California., Jiang T; Department of Medicine, University of California, San Francisco, San Francisco, California.; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., Logan AC; Department of Medicine, University of California, San Francisco, San Francisco, California.; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., Settles M; Bioinformatics Core, Genome Center, University of California, Davis, Davis, California., Mannis GN; Department of Medicine, University of California, San Francisco, San Francisco, California., Olin R; Department of Medicine, University of California, San Francisco, San Francisco, California.; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., Damon LE; Department of Medicine, University of California, San Francisco, San Francisco, California.; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., Martin TG; Department of Medicine, University of California, San Francisco, San Francisco, California.; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., Sayre PH; Department of Medicine, University of California, San Francisco, San Francisco, California.; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., Gaensler KM; Department of Medicine, University of California, San Francisco, San Francisco, California.; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., McMahon E; Department of Medicine, University of California, San Francisco, San Francisco, California.; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., Flanders M; Department of Medicine, University of California, San Francisco, San Francisco, California.; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., Weinberg V; Department of Medicine, University of California, San Francisco, San Francisco, California., Ye CJ; Department of Medicine, University of California, San Francisco, San Francisco, California., Carbone DP; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Munster PN; Department of Medicine, University of California, San Francisco, San Francisco, California.; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., Fragiadakis GK; CoLabs, University of California, San Francisco, San Francisco, Califoria.; Bakar ImmunoX Initiative, University of California, San Francisco, San Francisco, California.; Department of Medicine, Division of Rheumatology, University of California, San Francisco, San Francisco, California., McCormick F; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California., Andreadis C; Department of Medicine, University of California, San Francisco, San Francisco, California. charalambos.andreadis@ucsf.edu.; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
Jazyk:	angličtina
Zdroj:	Blood cancer discovery [Blood Cancer Discov] 2021 Sep; Vol. 2 (5), pp. 434-449. Date of Electronic Publication: 2021 Jul 16.
DOI:	10.1158/2643-3230.BCD-21-0055
Abstrakt:	Acute myeloid leukemia patients refractory to induction therapy or relapsed within one year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in pre-clinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single cell RNA sequencing using prospectively acquired patient specimens identified interferon response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well-tolerated with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies. Competing Interests: Conflict of Interests: The authors declare no potential conflicts of interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu