P1, N=27, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: May 2030 --> Aug 2030 | Initiation date: May 2026 --> Aug 2026 | Trial primary completion date: May 2026 --> Aug 2030

KEAP1 loss is associated with reduced response to KRAS inhibitor therapy. We demonstrate that KEAP1 loss-associated resistance can be overcome by pharmacologic inhibition of the KEAP1 loss-induced glutamine dependency, establishing a combination to enhance RAS inhibitor clinical efficacy.

Leveraging this metabolic liability, we demonstrated that PHGDH-deficient tumors exhibited selective sensitivity to the glutamine antagonist DRP-104, whereas PHGDH-intact tumors were resistant...PHGDH supports PDAC progression not primarily through serine provision, but by maintaining glutamine metabolism and mTOR signaling. This unanticipated metabolic crosstalk creates a synthetic lethal vulnerability to glutamine antagonism in PHGDH-deficient tumors, providing a rationale for combining serine synthesis pathway inhibitors with glutamine-targeting therapies in pancreatic cancer.

P1, N=27, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

HB023 successfully addresses the challenge of glutamine deprivation-induced immune escape by integrating metabolic inhibition with immune checkpoint blockade. This dual-modulatory approach reprograms the tumor immune microenvironment and improves immunotherapeutic efficacy, representing a promising strategy for advancing cancer treatment.

P2, N=37, Recruiting, NYU Langone Health

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.

Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.

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.

While this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug Docetaxel. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced anti-tumor immunity. Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.