JHU395 / Dracen Pharma - LARVOL DELTA

Metabolic cell competition in the glioblastoma tumour microenvironment: glucose, glutamine, and lactate as determinants of immune exclusion and targets for pharmacological reprogramming. (PubMed, Front Oncol) - "Glioblastoma (GBM) remains the most lethal primary brain tumour, with median overall survival of 14 to 16 months despite maximal safe surgical resection, concurrent chemoradiotherapy, and adjuvant temozolomide...Disrupting glucose and glutamine metabolism through glutamine antagonism (DON and prodrugs JHU083/JHU395), dichloroacetate (DCA)-mediated PDK inhibition, intravenous pharmacological ascorbate-mediated GAPDH inactivation and HIF-1alpha destabilisation, systemic glucose restriction (SGLT2 inhibitors), sodium phenylbutyrate-mediated glutamine depletion, and monocarboxylate transporter inhibition can invert this competitive hierarchy, reprogramming the immunosuppressive myeloid compartment while preserving T cell fitness; mebendazole is additionally reviewed as a multi-target anti-parasitic repurposing candidate with demonstrated GBM preclinical survival benefit...GBM cells and immunosuppressive myeloid cells are proposed to constitute a substrate-dependent..."

Journal • Review • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • GAPDH • HIF1A • NLRP3

Pro-905, a novel purine antimetabolite, combines with glutamine amidotransferase inhibition to suppress growth of malignant peripheral nerve sheath tumor. (PubMed, Mol Cancer Ther) - "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. 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."

Journal • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

[VIRTUAL] Comprehensive metabolic profiling of high MYC medulloblastoma revealed key differences between in vitro and in vivo in glucose and glutamine usage (AACR 2021) - "Twice weekly 15mg/kg dosing of JHU395 significantly extended the survival of the mice with D425 MED orthotopic xenografts (p<0.001 by log-rank test comparing treated vs vehicle control). Glutamine antagonists exploit MYC-amplified medulloblastoma's reliance on glutamine metabolism and may have therapeutic applications in human patients."

Preclinical • Medulloblastoma • Oncology • Solid Tumor • MYC

[VIRTUAL] A novel protide purine antimetabolite combines with the prodrug glutamine antagonist JHU395 in preclinical models of Ras-driven sarcomas (AACR 2021) - "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."

Preclinical • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • NF1

Novel Glutamine Antagonist JHU395 Suppresses MYC-Driven Medulloblastoma Growth and Induces Apoptosis. (PubMed, J Neuropathol Exp Neurol) - "Treatment of mice bearing orthotopic xenografts of human MYC-amplified medulloblastoma with JHU395 increased median survival from 26 to 45 days compared with vehicle control mice (p < 0.001 by log-rank test). These data provide preclinical justification for the ongoing development and testing of brain-targeted DON prodrugs for use in medulloblastoma."

Journal • Medulloblastoma • Oncology • Pediatrics • Solid Tumor • MYC