Abstract
Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft-tissue sarcomas that arise from neural tissues and carry a poor prognosis. Previously, we found that the glutamine amidotransferase inhibitor JHU395 partially impeded tumor growth in preclinical models of MPNST. JHU395 inhibits de novo purine synthesis in human MPNST cells and murine tumors with partial decreases in purine monophosphates. On the basis of prior studies showing enhanced efficacy when glutamine amidotransferase inhibition was combined with the antimetabolite 6-mercaptopurine (6-MP), we hypothesized that such a combination would be efficacious in MPNST. Given the known toxicity associated with 6-MP, we set out to develop a more efficient and welltolerated drug that targets the purine salvage pathway. Here, we report the discovery of Pro-905, a phosphoramidate protide that delivered the active nucleotide antimetabolite thioguanosine monophosphate (TGMP) to tumors over 2.5 times better than equimolar 6-MP. Pro-905 effectively prevented the incorporation of purine salvage substrates into nucleic acids and inhibited colony formation of human MPNST cells in a dose-dependent manner. In addition, Pro-905 inhibited MPNST growth and was well-tolerated in both human patient-derived xenograft (PDX) and murine flank MPNST models. When combined with JHU395, Pro-905 enhanced the colony formation inhibitory potency of JHU395 in human MPNST cells and augmented the antitumor efficacy of JHU395 in mice. In summary, the dual inhibition of the de novo and purine salvage pathways in preclinical models may safely be used to enhance therapeutic efficacy against MPNST.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1390-1403 |
| Number of pages | 14 |
| Journal | Molecular cancer therapeutics |
| Volume | 22 |
| Issue number | 12 |
| DOIs | |
| State | Published - 2023 |
Funding
This research was supported by a CureSearch for Children’s Cancer Young Investigator Award (to K.M. Lemberg), a Maryland Innovation Initiative Award (to K.M. Lemberg), an Allegheny Health Network Award (to K.M. Lemberg), R01NS103927 (to B.S. Slusher.), and R01CA229451 (to to B.S. Slusher). D.E. Peters was supported by an NIH T32 training grant (T32 OD011089). C.A. Pratilas and the JHU NF1 Biospecimen Repository were supported by a grant from the K.M. Lemberg reports grants from CureSearch for Children’s Cancer, grants from TEDCO Maryland Innovation Initiative, and grants from Allegheny Health Network during the conduct of the study; in addition, K.M. Lemberg has a patent for WO2022046910 issued. M. Krecmerova reports grants from The Czech National Node for Translational Medicine EATRIS-CZ, grant No. LM2023053 by the Ministry of Education, Youth and Sports of the Czech Republic during the conduct of the study; in addition, M. Krecmerova has a patent for The Johns Hopkins patent application PCT/US21/47555/WO2022046910 pending. D.E. Peters reports grants from NIH during the conduct of the study. V. Staedtke reports grants from NCI U01CA247576, NCI K08CA230179, NTAP, Sontag Family Foundation, and other support from Gilbert Family Foundation Gene Therapy Initiative outside the submitted work. C.A. Pratilas reports grants from Kura Oncology, Novartis Oncology, and personal fees from Day One Therapeutics outside the submitted work. P. Majer reports grants from Czech National Node to the European Infrastructure for Translational Medicine EATRIS-CZ, grant no. LM2023053 provided by the Ministry of Education, Youth, and Sports of the Czech Republic. During the conduct of the study; in addition, P. Majer has a patent for co-inventor on Johns Hopkins University/IOCB Prague patents covering novel glutamine antagonist prodrugs and their utility issued and a patent for PCT/US21/47555/WO2022046910 pending; and These patents have been licensed to Dracen Pharmaceuticals Inc. In addition, P. Majer is a cofounder of and hold equity in Dracen Pharmaceuticals Inc. R. Rais reports a patent for PCT/ US21/47555/WO2022046910 pending. B.S. Slusher reports grants from NINDS and grants from NCI during the conduct of the study; other support from Dracen Pharmaceuicals outside the submitted work; in addition, B.S. Slusher has a patent for patents covering glutamine antagonist prodrugs and their utility issued and licensed to Dracen Pharmaceuticals and a patent for patent covering purine antimetabolite protides and their utility pending. This research was supported by a CureSearch for Children's Cancer Young Investigator Award (to K.M. Lemberg), a Maryland Innovation Initiative Award (to K.M. Lemberg), an Allegheny Health Network Award (to K.M. Lemberg), R01NS103927 (to B.S. Slusher.), and R01CA229451 (to to B.S. Slusher). D.E. Peters was supported by an NIH T32 training grant (T32 OD011089). C.A. Pratilas and the JHU NF1 Biospecimen Repository were supported by a grant from the Neurofibromatosis Therapeutics Acceleration Program (NTAP). V. Staedtke was supported by the NTAP Francis S. Collins Scholar Program. Research in the I. Ben-Sahra lab was supported by grants from the NIH, R01GM135587, R01GM143334 (to I. Ben-Sahra), and by the LAM Foundation, United States, Established Investigator Award LAM0151E01-22 (to I. Ben-Sahra). The synthetic part of the research was supported by the Czech National Node to the European Infrastructure for Translational Medicine EATRIS-CZ, grant no. LM2023053 provided by the Ministry of Education, Youth, and Sports of the Czech Republic.
ASJC Scopus subject areas
- Oncology
- Cancer Research
