期刊
SCIENCE ADVANCES
卷 8, 期 46, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abq5925
关键词
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资金
- Bloomberg Kimmel Institute for Cancer Immunotherapy
- CureSearch for Children's Cancer Young Investigator Award
- Czech of Sciences [RVO 61388963]
- Ministry of Education, Youth, and Sports of the Czech Republic [LTAUSA18166]
- [R01CA193895]
- [R01CA229451]
- [R01NS103927]
- [R01 CA226765]
6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism while enhancing the metabolic fitness of tumor CD8+ T cells. The development of DON was halted due to dose-limiting gastrointestinal toxicities. In order to overcome this, a DON peptide prodrug, DRP-104, was designed and showed improved tolerability and enhanced efficacy in tumor regression. The effect of DRP-104 is dependent on CD8+ T cells and results in strong immunologic memory.
6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8+ T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104's effect was CD8+ T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.
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