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Study Shows how a New Delivery Strategy may Improve Chemotherapy for Acute Myeloid Leukemia

Despite the availability of several new therapeutic options for the treatment of acute myeloid leukemia (AML), disease relapse remains a significant challenge.

New research published in The FASEB Journal shows that delivering a cellular metabolite via tiny particles called nanolipisomes may help augment the beneficial effects of certain anti-leukemia drugs.[1]

Nanoliposomes, also referred to as bilayer lipid vesicles, possess and maintain nanometric size ranges during both storage and applications. Due to their bilayer structure, composed of lipidic and aqueous sections, these nano-systems can, at the same time, encapsulate hydrophilic and hydrophobic compounds.

Ceramide
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 of care chemotherapy regimen of venetoclax (Venclexta® and Venclyxto®; AbbVie and Genentech) plus cytarabine (Cytosar-U®; Pfizer/Hospira [Pharmacia UpJohnn], known as the Ara-C regimen, in models of acute myeloid leukemia.

Novasep PharmaZell Group

The researchers also uncovered several mechanisms behind these effects.

Approach
Using a nanoscale delivery system for ceramide (ceramide nanoliposomes or CNL), the investigators studied the effect of CNL within a standard of care regimen. Based on the outcome, they demonstrate that CNL augmented the efficacy of venetoclax + cytarabine in in vitro, ex vivo, and in vivo models of AML.

The researchers noted that the CNL treatment induced non-apoptotic cytotoxicity, and augmented cell death induced by Ara-C and venetoclax. Interestingly, there observed that CNL reduced both venetoclax (Mcl-1) and cytarabine (Chk1) drug-resistant signaling pathways. In addition, venetoclax and Ara-C augmented the generation of endogenous pro-death ceramide species, which was intensified with CNL.

“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,” noted Todd Fox, Ph.D., the article’s corresponding author of the University of Virginia.

“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,” Fox concluded.

Clinical trials
Ceramide NanoLiposome in Patients With Advanced Solid Tumors – NCT02834611
Study of C6 Ceramide NanoLiposome (CNL) in Patients With Relapsed/Refractory Acute Myeloid Leukemia (KNAN2001) – NCT04716452

Highlights of prescribing information
Venetoclax (Venclexta® and Venclyxto®; AbbVie and Genentech) [Prescribing Information]
Cytarabine (Cytosar-U®; Pfizer [Pharmacia UpJohnn]) [Prescribing Information]

Reference
[1] Khokhlatchev AV, Sharma A, Deering TG, Shaw JJP, Costa-Pinheiro P, Golla U, Annageldiyev C, Cabot MC, Conaway MR, Tan SF, Ung J, Feith DJ, Loughran TP Jr, Claxton DF, Fox TE, Kester M. Ceramide nanoliposomes augment the efficacy of venetoclax and cytarabine in models of acute myeloid leukemia. FASEB J. 2022 Oct;36(10):e22514. doi: 10.1096/fj.202200765R. PMID: 36106439.

Featured image: AML Acute Myeloid Leukemia. Photo courtesy: © 2018 – 2022. Fotolia/Adobe. Used with permission.

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