A novel protide purine antimetabolite combines with the prodrug glutamine antagonist JHU395 in preclinical models of Ras-driven sarcomas

0545193 - ÚOCHB 2022 US eng A - Abstract
Lemberg, K. M. - Aguilar, J. M. H. - Alt, J. - Krečmerová, Marcela - Majer, Pavel - Rais, R. - Slusher, B.
A novel protide purine antimetabolite combines with the prodrug glutamine antagonist JHU395 in preclinical models of Ras-driven sarcomas.
Cancer Research. American Association for Cancer Research. Roč. 81, č. 13 (2021). ISSN 0008-5472. E-ISSN 1538-7445.
[AACR Annual Meeting 2021. 10.04.2021-15.04.2021, online]
Institutional support: RVO:61388963
OECD category: Organic chemistry
https://doi.org/10.1158/1538-7445.AM2021-1293

Early clinical investigations of a glutamine antagonist in combination with a purine antimetabolite in pediatric cancers had promise but excessive gastrointestinal toxicity. We recently described that the well-tolerated glutamine antagonist prodrug JHU395 impeded tumor growth in Ras-driven sarcoma models with significant effects on nucleotide metabolites. We therefore investigated the combination of the purine antimetabolite 6-mercaptopurine (6-MP) with JHU395 in NF1-mutant malignant peripheral nerve sheath tumor (MPNST) models. 6-MP (10 micromolar) inhibited growth of human MPNST cells as a single agent and in combination with low dose JHU395 (1 micromolar). However, at previously published doses in mice, single agent 6-MP (20 mg/kg i.p. daily) resulted in weight loss and elevations in serum alanine aminotransferase (ALT), a marker of hepatotoxicity. To limit GI and hepatotoxicity from methylated side products of 6-MP, we developed Protide-TGMP-905 (Pro-905), a phosphoramidate protide of the 6-MP active metabolite 6-TGMP, which enables delivery of active monophosphorylated nucleotide antimetabolite with minimal formation of hepatotoxic methylated 6-MP (Me6-MP) metabolites. When administered at 20% of the 6-MP dose, Pro-905 treated mice (10 mg/kg i.p. daily) experienced similar myelosuppression, an indication of active metabolite formation, without elevation of ALT. One hour following Pro-905 administration (10 mg/kg i.p.) 6-TGMP was detectable in mouse plasma (0.25 nmol/ml), whereas one hour following 6-MP administration 6-TGMP in plasma was below the limit of detection. When administered to flank MPNST mice at this dose, Pro-905 inhibited tumor growth as a single agent and abrogated tumor growth in combination with JHU395 (Day 10 log2-fold change tumor volume: Vehicle = 2.81, Pro-905 = 1.66, JHU395 = 1.76, Combination = 0.31) and improved survival compared to vehicle (Median survival: Vehicle = 15 days, Combination = 23 days). Tumor metabolomics studies were performed to investigate metabolic differences between single agent JHU395, Pro-905, and combination treated mice. Protide purine antimetabolites in combination with glutamine antagonists are tolerated and efficacious in Ras-driven sarcoma models in preclinical studies.
Permanent Link: http://hdl.handle.net/11104/0321931