A Metabolomics Pilot Study on Desmoid Tumors and Novel Drug Candidates

Abstract

Desmoid tumors (aggressive fibromatosis) are locally invasive soft tissue tumors that lack the ability to metastasize. There are no directed therapies or standard treatment plan, and chemotherapeutics, radiation, and surgery often have temporary effects. The majority of desmoid tumors are related to T41A and S45F mutations of the beta-catenin encoding gene (CTNNB1). Using broad spectrum metabolomics, differences were investigated between paired normal fibroblast and desmoid tumor cells from affected patients. There were differences identified, also, in the metabolomics profiles associated with the two beta-catenin mutations, T41A and S45F. Ongoing drug screening has identified currently available compounds which inhibited desmoid tumor cellular growth by more than 50% but did not affect normal fibroblast proliferation. Two drugs were investigated in this study, and Dasatinib and FAK Inhibitor 14 treatments resulted in unique metabolomics profiles for the normal fibroblast and desmoid tumor cells, in addition to the T41A and S45F. The biochemical pathways that differentiated the cell lines were aminoacyl-tRNA biosynthesis in mitochondria and cytoplasm and signal transduction amino acid-dependent mTORC1 activation. This study provides preliminary understanding of the metabolic differences of paired normal and desmoid tumors cells, their response to desmoid tumor therapeutics, and new pathways to target for therapy.

Longitudinal Pharmacometabonomics for Predicting Malignant Tumor Patient Responses to Anlotinib Therapy: Phenotype, Efficacy, and Toxicity

“…The most obviously disturbed metabolic pathways were aminoacyl-tRNA biosynthesis, alanine, aspartate and glutamate metabolism, steroid hormone biosynthesis, citrate cycle, tyrosine metabolism, and arginine and proline metabolism ( Table S4 ). According to the report of Kelly and coworkers, dasatinib treatment caused significant metabolomics variations in the desmoid tumor cell line T219 ( 26 ). All the disturbed metabolites, including asparagine, aspartate, dimethylamine, glucose-1-phosphate, glutamate, glutathione, isoleucine, leucine, proline, uridine, and valine were significantly upregulated after dasatinib treatment.…”

Furosine, a Maillard Reaction Product, Triggers Necroptosis in Hepatocytes by Regulating the RIPK1/RIPK3/MLKL Pathway

“…The overall changes in the levels of endogenous small-molecule metabolites in cells or organisms can be analyzed by metabonomics. Compared with proteomics and genomics, metabonomics analyzes the physiological and pathological changes in an organism or cells by a more comprehensive method [23,24,25,26]. In the present study, the metabolism of liver tissue, serum, and RBC was analyzed.…”

Metabolomic Strategies in Biomarker Research–New Approach for Indirect Identification of Drug Consumption and Sample Manipulation in Clinical and Forensic Toxicology?

“…In general, metabolomics is a valuable tool in different disciplines such as drug discovery (Lu and Chen, 2017; Mercier et al, 2018), biomarker research (Klein and Shearer, 2016; Wang et al, 2016b; Zhang et al, 2016; Ambati et al, 2017), studies of diseases (Klein and Shearer, 2016; Ren et al, 2016; Wurtz et al, 2016), and metabolic pathways confirmation (Ren et al, 2016; Zhang et al, 2016). It involves both the identification of endogenous substances in different biological samples as well as the statistical analysis of differences between two or more conditions.…”