by Wiley

CNL augments the efficacy of cytarabine/venetoclax treatment in in vivo AML models. (A–C) Bioluminescence images (A), their quantification (B) and survival of MOLM-13 Luc-YFP bearing NRG mice (C) treated for 12 days with control or CNL (30 mg/kg; intravenous; every other day), Ara-C (25 mg/kg; intraperitoneally), and venetoclax (100 mg/kg; oral gavage) both 5 days on/2 days off then 5 days on again alone or in combination. N = 5/group. B: *p < .05; **p < .01; ***p < .001; #p < .0001 versus control by two-way ANOVA (Dunnett's test); $p < .001 versus CNL + Ara-C by two-way ANOVA (Sidak's test). Shown are means +/− SD; C: *p < .005 between VEN/Ara-C and CNL/VEN/Ara-C by Kaplan–Meier analysis. CNL dose and dosage regimen was determined by previous PK and efficacy studies in solid and non-solid tumor models (D) Survival of C1498-bearing C57Bl/6J mice treated 11 days with alternative days dosing frequency with either Control (intravenous, similar volume equivalent to CNL formulation), CNL (intravenous, 31.2 mg/kg), Ara-C (intraperitoneally, 75 mg/kg) or CNL/Ara-C. The CNL/Ara-C group had median survival time of 55 days compared with 34 days for the CNL monotherapy group (p < .01), 41 days for the Ara-C monotherapy group (p < .05), and 31 days for control group (p < .001) by Kaplan–Meier analysis. Credit: The FASEB Journal (2022). DOI: 10.1096/fj.202200765R

Many drug-resistant tumors have dysfunctional metabolism of ceramide, a metabolite that promotes cell death.

Investigators who previously demonstrated that augmenting ceramide can counter tumors' drug resistance mechanisms have now shown that adding ceramide nanoliposomes can improve the efficacy of a standard chemotherapy regimen of venetoclax plus cytarabine in models of acute myeloid leukemia.

In their study published in The FASEB Journal, the researchers also uncovered several mechanisms behind these effects.

"Ceramide-based therapeutics had been a decades long passion for senior author Dr. Mark Kester, who sadly passed away this summer, and we will continue his legacy to assess the utility of the ceramide nanoliposome in the clinic. This publication is part of the basis for clinical trials testing the potential of the ceramide nanoliposome in acute myeloid leukemia, which are expected to begin in 2023," said corresponding author Todd Fox, Ph.D., of the University of Virginia.

More information: Andrei V. Khokhlatchev et al, Ceramide nanoliposomes augment the efficacy of venetoclax and cytarabine in models of acute myeloid leukemia, The FASEB Journal (2022). DOI: 10.1096/fj.202200765R

Journal information: FASEB Journal 

Provided by Wiley