JHU083

In addition, we found that the glutamine metabolism inhibitor JHU083 promoted the infiltration of CD4 and CD8 T cells and T lymphocyte differentiation, and increased the efficacy of PD-1 inhibitors. Glutamine inhibitors can inhibit the apoptosis of immune cells in the tumor microenvironment, while promoting CD8 T cells activation and cytotoxicity increase. Inhibition of glutamine metabolism within the pancreatic cancer microenvironment results in reduced apoptosis of immune cells, heightened activation and cytotoxicity of CD8 T cells, and a substantial enhancement in the therapeutic efficacy of immunotherapy.

Ex vivo bone marrow-derived macrophage cultures further confirmed that M2 macrophages were more sensitive to glutamine antagonist than M1 macrophages. Together, our findings indicate that JHU083 exerted its anti-tumor activity not only through direct targeting of glutamine-addicted cancer cells but also by shifting the M1/M2 macrophage landscape in favor of an immune-stimulatory microenvironment.

Multiple strategies have emerged to disrupt this dependence: glutamine antagonists (DON and its prodrugs DRP-104, JHU-083), small-molecule glutaminase inhibitors (CB-839), antibody-drug conjugates targeting the ASCT2 transporter, and combination regimens pairing glutamine blockade with immune checkpoint inhibitors. Nanoparticle formulations-including pH-sensitive and PEGylated liposomes co-delivering DON and gemcitabine-enable targeted delivery and reduce off-target toxicity...To overcome these escape routes, future interventions must concurrently target compensatory pathways and integrate biomarker-driven patient selection. Combining glutamine-targeted agents with inhibitors of asparagine synthesis or lipid oxidation, guided by multi-omics profiling, promises a more durable therapeutic benefit and lays the groundwork for personalized treatment of PDAC.

Combining BSO with the glutamine antagonist JHU-083 is synthetically lethal in vitro and in vivo and significantly extends the survival of mice bearing intracranial GBM xenografts. Collectively, our studies advance our understanding of oncogene-induced metabolic vulnerabilities in GBMs.

Combination treatment of JHU083 and gefitinib reversed the up-regulation of PD-L1 in bladder cancer cells induced by prolonged glutamine blockade, resulting in the alleviation of T-cell immunosuppression and a significant improvement in therapeutic outcome. These preclinical findings show promise for glutamine metabolism targeting as a viable therapeutic strategy for bladder cancer, with the potential for further enhancement through combined treatment with gefitinib.

Inhibition of glutaminase aggravates oxidative stress by reducing glutathione level, thus leading to apoptotic-mediated cell death in cancer cells Therefore, inhibiting the glutaminase activity using glutaminase inhibitors such as BPTES, DON, JHU-083, CB-839, compound 968, etc. may answer many intriguing questions behind the uncontrolled proliferation of cancer cells and serve as a prophylactic treatment for cancer. Earlier reports neither discuss nor provide perspectives on exact signaling gene or pathway. Hence, the present review highlights the plausible role of glutaminase in cancer and the current therapeutic approaches and clinical trials to target and inhibit glutaminase enzymes for better cancer treatment.

Although the anti-tumor effect of glutamine antagonism on tumor-infiltrating T cells was moderate, JHU083 promoted a stem cell-like phenotype in CD8+ T cells and decreased Treg abundance. Finally, JHU083 caused a ubiquitous shutdown in glutamine utilizing metabolic pathways in tumor cells, leading to reduced HIF-1alpha, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key anti-tumor features.

Thyroid cancer exhibited enhanced glutamine metabolism, as evidenced by the glutamine dependence of thyroid cancer cells and high expression of multiple glutamine metabolism-related genes. Targeting glutamine metabolism with DON prodrug could be a promising therapeutic option for advanced thyroid cancer.

This effect is specific to TERT-expressing GBM cells because the combination of DON and BSO does not affect viability of normal astrocytes or astrocytomas that use the ALT pathway for telomere maintenance. Importantly, in vivo stable isotope tracing confirmed that combined treatment with JHU-083 (a brain-penetrant prodrug of DON) and BSO abrogates synthesis of GSH, aspartate, and pyrimidine nucleotides from [U-13C]-glutamine and induces apoptotic death in mice bearing intracranial GBM6 tumors.Collectively, our studies highlight the therapeutic potential of targeting metabolic vulnerabilities induced by TERT expression in GBMs in vivo.

Moreover, JHU-083, a specific pharmacologic inhibitor of glutaminase, killed ZFTA-RELAFUS tumor cells in vitro and in vivo. To summarize, our results suggest that the ZFTA-RELA fusion expressing tumor cells exhibit strong glutamine dependence, and targeting it has significant therapeutic relevance.

Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal form of liver cancer that primarily affects children and young adults. Systemic treatment of BALB/c mice bearing TIBx-FLC tumors with JHU-083, a glutamine antagonist, in combination with immune checkpoint inhibitor therapy enhanced survival as compared to vehicle or monotherapy. These data identify altered glutamine metabolism as a target in FLC, and may provide an explanation for immune suppression seen in the FLC tumor microenvironment.