Pro-905, a novel purine antimetabolite, combines with glutamine amidotransferase inhibition to suppress growth of malignant peripheral nerve sheath tumor.
Kathryn M LembergEunus S AliMarcela KrecmerovaJoanna Marie H AguilarJesse AltDiane E PetersLiang ZhaoYing WuNaziba NuhaJohn M AsaraVerena StaedtkeChristine A PratilasPavel MajerRana RaisIssam Ben-SahraBarbara S SlusherPublished in: Molecular cancer therapeutics (2023)
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 (GA) 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. Based on prior studies showing enhanced efficacy when GA 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 well-tolerated 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. Additionally, Pro-905 inhibited MPNST growth and was well-tolerated in both human patient-derived xenograft 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.
Keyphrases
- endothelial cells
- peripheral nerve
- poor prognosis
- induced apoptosis
- induced pluripotent stem cells
- cell cycle arrest
- anti inflammatory
- pluripotent stem cells
- long non coding rna
- gene expression
- stem cells
- emergency department
- cell death
- soft tissue
- small molecule
- signaling pathway
- insulin resistance
- mesenchymal stem cells
- high grade
- bone marrow
- cell proliferation
- cell therapy
- skeletal muscle
- single cell
- metabolic syndrome
- electronic health record