Reference Detail

Ref Type

Journal Article

PMID

(18519791)

Authors

Tran MA, Smith CD, Kester M, Robertson GP

Title

Combining nanoliposomal ceramide with sorafenib synergistically inhibits melanoma and breast cancer cell survival to decrease tumor development.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	14	11	2008 Jun 01	3571-81	Clin Cancer Res

URL

Abstract Text

Deregulation of phosphatidylinositol 3-kinase/Akt and Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathways occurs in melanoma and breast cancer, deregulating normal cellular apoptosis and proliferation. Therapeutic cocktails simultaneously targeting these pathways could promote synergistically acting tumor inhibition. However, agents with manageable toxicity and mechanistic basis for synergy need identification. The purpose of this study is to evaluate the preclinical therapeutic efficacy and associated toxicity of combining sorafenib with nanoliposomal ceramide.Effects of sorafenib and nanoliposomal ceramide as single and combinatorial agents were examined on cultured cells using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt assays and CalcuSyn software used to assess synergistic or additive inhibition. Western blotting measured cooperative effects on signaling pathways. Rates of proliferation, apoptosis, and angiogenesis were measured in size- and time-matched tumors to identify mechanistic basis for inhibition. Toxicity was evaluated measuring animal weight, blood toxicity parameters, and changes in liver histology.Sorafenib and nanoliposomal ceramide synergistically inhibited cultured cells by cooperatively targeting mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling. A 1- to 2-fold increase in cellular apoptosis and 3- to 4-fold decrease in cellular proliferation were observed following combination treatment compared with single agents, which caused synergistically acting inhibition. In vivo, an approximately 30% increase in tumor inhibition compared with sorafenib treatment alone and an approximately 58% reduction in tumor size compared with nanoliposomal ceramide monotherapy occurred by doubling apoptosis rates with negligible systemic toxicity.This study shows that nanoliposomal ceramide enhances effectiveness of sorafenib causing synergistic inhibition. Thus, a foundation is established for clinical trials evaluating the efficacy of combining sorafenib with nanoliposomal ceramide for treatment of cancers.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
C6-ceramide nanoliposome	C6-ceramide nanoliposome	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
C6-ceramide nanoliposome				C6-ceramide nanoliposome is a liposomal formulation of C6-ceramide, which potentially reduces cell viability, and inhibits proliferation and migration, and may inhibit tumor growth (PMID: 25792190, PMID: 18519791).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	melanoma	sensitive	C6-ceramide nanoliposome + Sorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Nexavar (sorafenib) treatment in combination with C6-ceramide nanoliposome inhibited Mek and Akt phosphorylation, led to enhanced apoptosis and inhibition of proliferation, and synergistically reduced viability of melanoma cells harboring BRAF V600E in culture, and enhanced inhibition of tumor growth in a cell line xenograft model (PMID: 18519791).	18519791