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9,754 results on '"Asparaginase"'

24. LBL-2016 for Children or Adolescents in China

Author

Shanghai Children's Medical Center, Tongji Hospital, West China Second University Hospital, Qilu Hospital of Shandong University, Tianjin Medical University Cancer Institute and Hospital, Children's Hospital of Soochow University, Nanjing Children's Hospital, and Xiangya Hospital of Central South University

Published
2024

36. Targeting Asparagine Metabolism in Well-Differentiated/Dedifferentiated Liposarcoma

Author

Klingbeil, Kyle D, Wilde, Blake R, Graham, Danielle S, Lofftus, Serena, McCaw, Tyler, Matulionis, Nedas, Dry, Sarah M, Crompton, Joseph G, Eilber, Fritz C, Graeber, Thomas G, Shackelford, David B, Christofk, Heather R, and Kadera, Brian E

Subjects
Medical Biochemistry and Metabolomics, Biomedical and Clinical Sciences, Cancer, Rare Diseases, 5.1 Pharmaceuticals, Good Health and Well Being, well-differentiated/dedifferentiated liposarcoma, asparagine metabolism, mTORC1 signaling, ATF4, asparaginase, complex I inhibitor, electron transport chain, patient-derived organoids, patient-derived xenograft, Oncology and Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundmTORC1 activity is dependent on the presence of micronutrients, including Asparagine (Asn), to promote anabolic cell signaling in many cancers. We hypothesized that targeting Asn metabolism would inhibit tumor growth by reducing mTORC1 activity in well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS).MethodsHuman tumor metabolomic analysis was utilized to compare abundance of Asn in WD vs. DD LPS. Gene set enrichment analysis (GSEA) compared relative expression among metabolic pathways upregulated in DD vs. WD LPS. Proliferation assays were performed for LPS cell lines and organoid models by using the combination treatment of electron transport chain (ETC) inhibitors with Asn-free media. 13C-Glucose-labeling metabolomics evaluated the effects of combination treatment on nucleotide synthesis. Murine xenograft models were used to assess the effects of ETC inhibition combined with PEGylated L-Asparaginase (PEG-Asnase) on tumor growth and mTORC1 signaling.ResultsAsn was enriched in DD LPS compared to WD LPS. GSEA indicated that mTORC1 signaling was upregulated in DD LPS. Within available LPS cell lines and organoid models, the combination of ETC inhibition with Asn-free media resulted in reduced cell proliferation. Combination treatment inhibited nucleotide synthesis and promoted cell cycle arrest. In vivo, the combination of ETC inhibition with PEG-Asnase restricted tumor growth.ConclusionsAsn enrichment and mTORC1 upregulation are important factors contributing to WD/DD LPS tumor progression. Effective targeting strategies require limiting access to extracellular Asn and inhibition of de novo synthesis mechanisms. The combination of PEG-Asnase with ETC inhibition is an effective therapy to restrict tumor growth in WD/DD LPS.

Published
2024

46. ALL Adult Consortium Trial: Adult ALL Trial

Author

Massachusetts General Hospital, Boston Children's Hospital, NCIC Clinical Trials Group, and Daniel J. DeAngelo, MD, PhD, Principal Investigator

Published
2024

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