sirpiglenastat (DRP-104) / Dracen Pharma - LARVOL DELTA

A DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Glutamine Antagonist DRP-104, Nivolumab, and Ipilimumab in Patients With Advanced Stage Fibrolamellar Carcinoma (FLC) (clinicaltrials.gov) - P1 | N=27 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

A DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Glutamine Antagonist DRP-104, Nivolumab, and Ipilimumab in Patients With Advanced Stage Fibrolamellar Carcinoma (FLC) (clinicaltrials.gov) - P1 | N=27 | Not yet recruiting | Sponsor: 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

Trial completion date • Trial initiation date • Trial primary completion date • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

A DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Glutamine Antagonist DRP-104, Nivolumab, and Ipilimumab in Patients With Advanced Stage Fibrolamellar Carcinoma (FLC) (clinicaltrials.gov) - P1 | N=27 | Not yet recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

New P1 trial • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

A Phase 2 Study of DRP-104, a Glutamine Antagonist, in Patients withNFE2L2/KEAP1-altered Non-Small Cell Lung Cancer (IASLC-WCLC 2026) - "Sci Adv. 2022."

Clinical • IO biomarker • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCND1 • KEAP1 • NFE2L2

70 Years of DON and Beyond: Glutaminase Inhibition as a Synergistic Strategy in Cancer Combination Therapy. (PubMed, Pharmaceutics) - "This review provides a historical-to-translational overview of glutamine-targeted therapies, with particular emphasis on glutaminase inhibitors, including compound 968, BPTES, CB-839, and next-generation inhibitors, as well as DON-derived prodrugs. We discuss their mechanisms of action and their integration with chemotherapy, targeted therapies, radiotherapy, and immunotherapy, highlighting how glutamine metabolism targeting influences tumor metabolic adaptation, redox homeostasis, therapy resistance, and tumor-immune interactions. Finally, we examine current clinical developments, emerging therapeutic combinations, and the challenges that must be addressed for the incorporation of glutamine metabolism targeting into precision oncology."

Journal • Review • Oncology

Glutamine Metabolic Blockade Reprograms the Tumor Immune Microenvironment in Triple-Negative Breast Cancer (SNMMI 2026) - "DRP-104 (Sirpiglenastat), a prodrug of 6-diazo-5-oxo-L-norleucine (DON) with markedly reduced GI toxicity, is a potent glutamine antagonist currently being tested in clinical trials...Using a newly developed immuno-PET probe – [89Zr]-deferoxamine (DFO)-H1.2F3 (anti-murine-CD69 monoclonal antibody, Edwards KJ, et al... Our data strongly suggest that glutamine metabolic blockade differentially impacts MDSC vs. T cells, changing both the abundance and functional state of immune cells. In particular, JHU083 treatment depletes MDSCs and restores effector T-cell activity, shifting immune populations from an immunosuppressive, pro-tumor state to an immune-active, anti-tumor state."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD69 • CD8 • GZMB • IFNG

Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer. (PubMed, bioRxiv) - "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."

Journal • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KEAP1 • KRAS

Defining a molecular signature for KEAP1-NRF2 mediated resistance to KRAS inhibition in KRAS-mutant pancreatic and lung cancer (AACR 2026) - "We determined that loss of KEAP1 and activation of the transcription factor NRF2 drove resistance to the KRASG12D-selective inhibitor MRTX1133 and the RAS(ON) multi-selective inhibitor RMC-7977. Finally, we observed that KEAP1-deficient cells exhibited elevated glutamine metabolism, and combination treatment with the clinical candidate glutamine antagonist DRP-104 (sirpiglenastat) strongly enhanced KRAS inhibitor-mediated growth suppression in KRAS-mutant PDAC and NSCLC tumors in vivo. In summary, our studies established a gene signature for KEAP1 loss-driven resistance and validated a therapeutic strategy to overcome KEAP1-NRF2-driven RAS inhibitor resistance."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KEAP1 • KRAS

Targeting DCLK1-mediated glutamine addiction in chemoresistant ovarian cancer (AACR 2025) - "Targeted gene expression profiling and pathway analysis revealed DCLK1 inhibition in cisplatin resistant (CPR) OC spheroids upregulated genes involved in glutamine metabolism. Collectively, our findings establish DCLK1 as a key regulator of metastasis and demonstrate that its inhibition induces glutamine dependency in chemoresistant tumor cells. Thus, the combined use of DCLK1 inhibitors (e.g., DCLK1-IN-1) with glutamine metabolism inhibitors (e.g., DRP-104) represents a rational therapeutic approach to mitigate peritoneal metastases in a chemoresistant setting."

Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor

Metabolic profiling of MEKi-treated fusion-negative rhabdomyosarcoma cell lines suggests a role for glutamine antagonism as a preclinical therapeutic approach (AACR 2025) - "We investigated the effects of DRP-104 on markers of tumor growth, DNA damage, and cell death by western blotting. As our own and other data support a role for MEKi and glutamine antagonism in RAS-active tumor models [5], future investigations will seek to combine DRP-104 with trametinib in cell-based and in vivo RAS-RMS models."

Preclinical • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • FGFR1 • PAX3 • PAX7

Cyanobacteria-derived RNA aptamer supports prostate cancer hormone sensitivity (AACR 2025) - "On the other hand, non-metabolizable L-Gln analogues like 6-Diazo-5-oxo-l-norleucine (DON) and DRP104 have shown promising antitumor effects...The L-Gln-depleting aptamer, with demonstrated serum stability, limited the proliferation, and lineage plasticity of the castrate resistant prostate tumors alone and in combination therapy with AR antagonists, enzalutamide and apalutamide in subcutaneous and orthotopic mouse models...Superiority of the functionalized nanoparticle targeting was demonstrated in an orthotopic PCa model over the un-targeted aptamer in reducing tumor weight. The studies demonstrated elevated L-Gln can be necessary and sufficient for castrate resistance, as its depletion sensitizes prostatic tumors to AR inhibition."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • FGF8 • FOXM1

PHGDH is a targetable driver of PDAC progression. (PubMed, bioRxiv) - "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."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PHGDH • SLC1A5

Positron emission tomography imaging detected enhanced anti-tumor immunity in triple-negative breast cancer mediated by glutamine antagonism (SABCS 2025) - "Our prior study has shown that TNBC tumors are enriched with myeloid-derived suppressor cells (MDSCs), which were significantly reduced by a pan-glutamine metabolic inhibitor JHU083, a pool compound of DRP-104/ Sirpiglenastat being evaluated in clinical trials. By selectively disrupting metabolism in cancer cells and MDSCs while sparing T cells that provide anti-tumor control, glutamine antagonism has immediate translational relevance for adoptive immunotherapies. Although ICI therapy removes PD-1 and CTLA4 mediated inhibition on T cells, it fails to inhibit tumor growth likely due to predominant presence of MDSCs which suppress CD8+ T cells as demonstrated by co-culture data. Combining JHU083 with ICI reduces MDSC infiltration to the tumor, leading to enhanced anti-tumor immunity detected by [89Zr]CD69 PET."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD69 • CD8 • GZMB • ITGAM • PTPRC

DRP-104 in Patients With NFE2L2/KEAP1-altered Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=37 | Recruiting | Sponsor: NYU Langone Health

New P2 trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Defining a molecular basis and therapeutic approach for KEAP1-NRF2 mediated resistance to KRAS inhibition in KRAS-mutant pancreatic ductal adenocarcinoma Free (AACRPanCa 2025) - "Recent clinical observations with the approved KRASG12C selective inhibitors sotorasib and adagrasib support the therapeutic value of targeting KRAS in PDAC...This gene set was distinct from transcriptional changes associated with other transcriptional signatures driving resistance to KRAS inhibitors (ERK, MYC and YAP/TAZ-TEAD). Finally, analysis of KEAP1-loss associated genes also identified the activation of glutamine metabolism, and we found the combination treatment with the glutamine antagonist DRP-104 enhanced KRAS inhibitor-mediated growth suppression in PDAC patient-derived organoids. In summary, our studies have established the molecular mechanisms underlying KEAP1-NRF2 pathway-driven resistance to KRAS inhibition and validated a potential therapeutic strategy to overcome this resistance."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KEAP1 • KRAS

Resilience and vulnerabilities of tumor cells under purine shortage stress. (PubMed, Clin Cancer Res) - "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."

Journal • Brain Cancer • Genito-urinary Cancer • Glioma • Oncology • Prostate Cancer • Solid Tumor • MTAP

Beyond the tumor: Enhancing pancreatic cancer therapy through glutamine metabolism and innovative drug delivery. (PubMed, J Cell Commun Signal) - "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."

IO biomarker • Journal • Review • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ASNS • HIF1A • KRAS • MYC • SLC1A5

Resilience and vulnerabilities of tumor cells under purine shortage stress. (PubMed, bioRxiv) - "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."

Journal • Brain Cancer • CNS Tumor • Genito-urinary Cancer • Glioma • Oncology • Prostate Cancer • Solid Tumor • MTAP

DRP-104 (Glutamine Antagonist) in Combination With Durvalumab in Patients With Advanced Stage Fibrolamellar Carcinoma (FLC) (clinicaltrials.gov) - P1/2 | N=27 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Aug 2029 ➔ Sep 2033

Trial completion date • Hepatocellular Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

Addressing Clinical Limitations of Glutaminase Inhibitors: Novel Strategies for Osimertinib-Resistant Lung Cancer by Exploiting Glutamine Metabolic Dependency. (PubMed, Adv Sci (Weinh)) - "This prodrug demonstrates superior safety compared to natural DON and greater antitumor activity against resistant tumors compared to the clinical phase II drug DRP104. These findings may address the clinical limitations of GLS1 allosteric inhibitors and underscore prodrug strategies in effectively treating Osimertinib-resistant lung cancer, providing a foundation for future clinical trials."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NQO1 • SLC1A5

DRP-104 (Glutamine Antagonist) in Combination With Durvalumab in Patients With Advanced Stage Fibrolamellar Carcinoma (FLC) (clinicaltrials.gov) - P1/2 | N=27 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Feb 2027 ➔ Aug 2029 | Trial primary completion date: Feb 2027 ➔ Aug 2028

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Hepatocellular Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

Exploiting a critical vulnerability to glutamine antimetabolite therapy in fibrolamellar hepatocellular carcinoma (FLC) (CRI-ENCI-AACR ICIC 2024) - P1/2 | "Our preliminary data using preclinical models of FLC and human biospecimens from FLC patients shows that the DNAJB1-PRKACA fusion results in a metabolic rewiring of the tumor cell characterized by glutamine dependence...Furthermore, the combination of JHU-083, a glutamine antagonist, in combination with checkpoint inhibitor therapy dramatically improved antitumor effects and enhanced survival in a preclinical model of FLC...Patients will receive DRP-104 (145 mg s.c. twice weekly) in combination with a fixed dose of durvalumab (1500 mg i.v. every 28 days)...Secondary objectives include progression free survival (PFS), overall survival (OS), and immunological correlates (NCT06027086). Through this trial, we will test the hypothesis that glutamine antagonism in FLC reverses resistance to immune checkpoint inhibitor (ICI) therapy through modulating the TiME."

CNS Disorders • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Metabolic Disorders • Oncology • Psychiatry • Solid Tumor • DNAJB1 • PRKACA

A genome-wide CRISPR screen reveals that antagonism of glutamine metabolism sensitizes head and neck squamous cell carcinoma to ferroptotic cell death. (PubMed, Cancer Lett) - "Finally, our analysis demonstrated that GPX4 mediates the protection of HNSCC cells from accumulating toxic lipid peroxides; hence, glutamine blockade sensitizes HNSCC cells to ferroptosis cell death upon GPX4 inhibition. These findings demonstrate the therapeutic potential of sirpiglenastat in HNSCC and establish a novel link between glutamine metabolism and ferroptosis, which may be uniquely translated into targeted glutamine-ferroptosis combination therapies."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • GPX4

Unveiling therapeutic frontiers: DON/DRP-104 as innovative Plasma kallikrein inhibitors against carcinoma-associated hereditary angioedema shocks - a comprehensive molecular dynamics exploration. (PubMed, Cell Biochem Biophys) - "Utilizing structure-based in silico methods, we conducted a comparative analysis with berotralstat, a clinically approved HAE prophylactic, and sebetralstat, an investigational HAE therapeutic agent, in Phase 3 clinical trials. The results revealed favorable binding kinetics of DON/DRP-104, showing thermodynamic profiles that were either superior or comparable to those of the reference drugs. These findings support their consideration for clinical investigations into the management of carcinoma-associated HAE."

Journal • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema • Oncology • Pain

DRP-104 with durvalumab in fibrolamellar hepatocellular carcinoma (YouTube) - "Marina Baretti, MD...gives an overview of a new Phase I/II trial (NCT06027086) using DRP-104 with durvalumab to treat fibrolamellar hepatocellular carcinoma (FLC)."

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