telaglenastat (CB-839) / Cornerstone Pharma, Synhale Therapeutics - LARVOL DELTA

BEGIN: A Basket Trial of Glutaminase inhibition with Telaglenastat in NF1, KEAP1/NRF2, and STK11/LKB1-Altered Tumors (AACR-NCI-EORTC 2025) - P2 | "While the clinical development of the agent was discontinued, these findings demonstrate preliminary clinical activity of GLS inhibition in NF1-mutant melanoma and MPNST, providing proof-of-concept and supporting further investigation with biomarker-driven combination strategies."

IO biomarker • Late-breaking abstract • Pan tumor • Brain Cancer • Melanoma • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • KEAP1 • NF1 • NFE2L2 • STK11

Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma: The CANTATA Randomized Clinical Trial. (PubMed, JAMA Oncol) - P2 | "A total of 276 (62%) patients had received prior immune checkpoint inhibitors, including 128 with prior nivolumab plus ipilimumab, 93 of whom had not received prior antiangiogenic therapy...Tela + Cabo was well tolerated with AEs consistent with the known risks of both agents. ClinicalTrials.gov Identifier: NCT03428217."

Clinical • Journal • Cardiovascular • Genito-urinary Cancer • Hypertension • Immune Modulation • Inflammation • Oncology • Renal Cell Carcinoma • Solid Tumor

CB-839 HCl in Combination With Carfilzomib and Dexamethasone in Treating Patients With Recurrent or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=36 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jan 2026 ➔ Jun 2026 | Trial primary completion date: Jan 2026 ➔ Jun 2026

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Momordin Ic suppresses breast cancer growth by targeting ACTL8‑dependent glutamine metabolism and PI3K/AKT/mTOR-MYC. (PubMed, Biochem Pharmacol) - "Together, these findings establish ACTL8 as a key oncogenic driver of BC progression. Targeting ACTL8 offers a novel strategy to disrupt glutamine-dependent metabolic reprogramming, and Momordin Ic represents a promising lead agent to combat ACTL8-driven BC."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • MYC • SLC1A5

A phase I/II study of the safety and efficacy of telaglenastat (CB-839) in combination with nivolumab in patients with metastatic melanoma, renal cell carcinoma, and non-small-cell lung cancer. (PubMed, ESMO Open) - "Telaglenastat in combination with nivolumab was generally well tolerated. The combination did not show a pattern of efficacy across different study cohorts."

Journal • P1/2 data • Clear Cell Renal Cell Carcinoma • Fatigue • Genito-urinary Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

A Dual Glutathione-Depleting Nanoparticle Loaded with Porcine Pancreatic Elastase for Neoadjuvant Chemotherapy of Triple Negative Breast Cancer. (PubMed, ACS Nano) - "To address the limited therapeutic potential of PPE, we constructed PMC@HA nanoparticles by coencapsulating PPE within a bimetallic Cu/Zn nanocarrier and integrating the glutaminase inhibitor CB-839...When applied as a neoadjuvant regimen in conjunction with surgery, PMC@HA significantly decreases postoperative recurrence and distant metastasis in TNBC. This combinatorial approach may improve chemosensitivity and limit metastatic progression, thereby potentially extending long-term survival in patients with TNBC."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ELANE • FAS

Telaglenastat Plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase 2 ENTRATA Trial. (PubMed, Clin Cancer Res) - P2 | "TelaE was well tolerated and improved PFS vs PboE in patients with mRCC previously treated with TKIs and checkpoint inhibitors."

Clinical • Journal • P2 data • Cough • Fatigue • Genito-urinary Cancer • Hematological Disorders • Oncology • Pulmonary Disease • Renal Cell Carcinoma • Respiratory Diseases • Solid Tumor

Targeting glutamine metabolism and EGFR in RAS wildtype colorectal cancer (ESMO-GI 2023) - P1/2 | "We would also like to acknowledge support from Calithera Biosciences who supplied CB-839 for the study.Background: Alterations in glutamine metabolism have been proposed to play critical roles in cancer cell growth and survival. Panitumumab and CB-389 was very tolerable with some efficacy in heavily pre-treated patients. Early analysis of PET imaging data suggests a potential relationship between 18F-FSPG uptake and response, but additional studies are needed. It is anticipated that RNA-seq will identify genes that are related to glutamine avidity and represent a key determinate of response to inhibitors of glutamine metabolism."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EGFR • RAS

Ampelopsin preserves glutamate homeostasis against cerebral ischemia. (PubMed, Biomed Pharmacother) - "Notably, Amp regulates GLS, which is also the established target of CB-839, a potent and specific inhibitor known to suppress tumorigenesis...Simultaneously, NMDAR expression was reduced, preventing excitatory neurotoxicity driven by excessive glutamatergic signaling. Overall, this study highlights the potential of Amp in providing neuroprotection in mice subjected to transient focal cerebral ischemia by promoting the dynamic Glu homeostasis."

Journal • Cardiovascular • CNS Disorders • Oncology

A novel pan class-I glucose transporter inhibitor DRB18 exhibits synergistic effects with paclitaxel in vitro and in vivo against human non-small cell lung cancer. (PubMed, bioRxiv) - "Combined with different clinical and pre-clinical anticancer compounds such as V9302, CB839, Sutent, Brigatinib, DRB18 significantly increased death of A549 and Panc1 cells. Mechanistically, DRB18 treatment with paclitaxel elevated the expression of Caspases 3 and 9, suggesting GLUT-inhibiting and apoptosis-inducing anticancer mechanisms of DRB18 with paclitaxel. Collectively, our results demonstrate anticancer efficacy of pan class-I GLUT inhibitor DRB18 in combination with paclitaxel, providing a potentially more efficacious therapeutic strategy for treating advanced NSCLC and other cancers."

Journal • Preclinical • Cervical Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CASP9 • SLC2A1 • SLC2A3

Multi-omics reveals immune features in immune and non-immune cells, an IFN-γ/IFN-α-B2M positive feedback loop, and targeted metabolic therapy in multiple myeloma (ASH 2025) - "This multi-omics study delineates the complex cellular architecture of the MM TME, uncovers a novel IFN-γ/IFN-α–B2M positive feedback loop central to immune evasion and disease progression, and identifies CB-839+EGCG as a promising metabolic therapy. Our atlas provides a comprehensive resource for elucidating MM pathogenesis and tailoring targeted immunometabolic interventions."

Immune cell • IO biomarker • Hematological Malignancies • Multiple Myeloma • B2M • BCL2 • CD8 • GLS1 • IFNA1 • IFNG • IL6 • KRAS • LDHA • STAT3

Immunotherapy resistant ALL cells exhibit selective dependence on glutamine and specific transporters for growth and survival (ASH 2025) - "Introduction: Acute lymphoblastic leukemia (ALL) needs newer therapeutic options, especially in patientsthat fail targeted immunotherapies such as CD19 CART and blinatumomab...Treatmentwith the glutaminase inhibitor CB-839 sensitized resistant cells, consistent with their enhanced relianceon glutamine for energy production... CD19 immunotherapy resistant ALL cells exhibit increased expression of both glutaminaseand specific glutamine transporter SLC38A1. Our findings suggest that CD19 immunotherapy resistantcells are dependent on glutamine as a source of cellular energy. Further, our data suggests thatglutamine is selectively utilized for cellular energy in resistant cells, while it is shunted toward additionalpathways in parental cells, including the formation of asparagine and glutathione."

IO biomarker • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • CD19 • CD22

TEPH: Telaglenastat Efficacy in Pulmonary Hypertension (clinicaltrials.gov) - P1/2 | N=28 | Not yet recruiting | Sponsor: Chan, Stephen, MD, PhD | Initiation date: Nov 2025 ➔ Feb 2026 | Trial primary completion date: Sep 2027 ➔ Sep 2028

Trial initiation date • Trial primary completion date • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Glutamine Promotes Myogenesis in Myoblasts Through Glutaminolysis-Mediated Histone H3 Acetylation That Enhances Myogenin Transcription. (PubMed, Nutrients) - " Glutamine, glutamate, and DM-α-KG promoted C2C12 myoblast differentiation in a concentration-dependent manner, whereas the glutaminase inhibitor CB-839 suppressed differentiation... This report demonstrates glutaminolysis-dependent histone H3 acetylation, which induces myogenin transcription in myoblasts. These results, connecting glutamine supplementation during resistance training, may make it an effective strategy to accelerate muscle regeneration."

Journal • Myogenin

Integrating biochemical and computational approaches to identify targeted therapeutic strategies for liver fibrosis: Effects of Telaglenastat (CB-839) on the glutaminase pathway. (PubMed, Biochem Biophys Res Commun) - "These findings demonstrate that CB-839 exhibits significant antifibrotic effects in a rat model of liver fibrosis, primarily by modulating glutamine metabolism and key fibrotic biomarkers. CB-839 has the potential to be a promising therapeutic approach for liver fibrosis."

Journal • Fibrosis • Gastroenterology • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Oncology • Solid Tumor • MMP2 • PPARA • PPARG • TGFB1 • TIMP1

Macropinocytosis and Vascularization Determine Response to mTOR Inhibitors in Lung Squamous Cell Carcinoma. (PubMed, Cancer Res) - "Moreover, prolonged treatment of LUSC PDXs with TAK228 and the glutaminase inhibitor CB-839 led to upregulation of vascularization, which coincided with a rebound in tumor growth despite continued therapeutic administration. These findings highlight adaptive resistance mechanisms to small molecule inhibitors that target key metabolic pathways, lending insight into potential future clinical strategies for the treatment of LUSC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma

Niosomal co-delivery of metformin and telaglenastat: A targeted nanotherapeutic strategy for breast cancer treatment and metastasis suppression in 2D and 3D models. (PubMed, Biomed Pharmacother) - "In conclusion, coordinated inhibition of GLUT-1- and GLS-1-driven metabolism via MET/TEL-loaded niosomes achieves enhanced cytotoxicity, durable spheroid penetration, and strong anti-migratory and metabolic modulatory effects. This stable co-delivery platform represents a promising nanotherapeutic strategy to overcome metabolic adaptability and treatment resistance in breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • SLC2A1

Stroma-driven horizontal transfer of TCA-related proteins mediates metabolic plasticity and imatinib resistance in chronic myeloid leukemia. (PubMed, Cell Commun Signal) - "This study describes a novel mechanism of direct bone marrow-mediated protection of leukemic cells from imatinib/TKI, related to transfer of metabolic proteins leading to higher activity of TCA cycle, metabolic plasticity and adaptation. Targeting the stroma-driven TCA cycle-related metabolism combined with imatinib presents a promising strategy to achieve therapeutic efficacy to overcome bone marrow microenvironment-mediated protection in CML."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34

Structure-enabled discovery of carboxylate esters prodrugs as potential potent inhibitors targeting Glutaminase C. (PubMed, Bioorg Chem) - "Herein, a series of acidic derivatives targeting the basic hotspot were designed based on the scaffold of CB839...Prodrug 16 showed pronounced antiproliferative activity in A549 cells (IC50 = 2.45 nM) alongside favorable stability, and additionally regulated cellular metabolites and increased reactive oxygen species by blocking glutamine metabolism. Ultimately, prodrug 16 exhibits strong in vivo antitumor activity in an A549 xenograft model, establishing it as a highly potent GAC inhibitor and suggesting a novel approach for the development of next-generation GAC-targeting therapeutics."

Journal • Oncology

Targeting METTL3 Induces a Metabolic Vulnerability in ER+ Breast Carcinoma Cells. (PubMed, Endocr Relat Cancer) - "CB-839 increased the potency of STM2457 only in the LCC9 and ZR-75-1-4-OHT endocrine-resistant cells. Our collective findings suggest that METTL3 inhibition leads to selective glycolytic and oxidative metabolic changes between these endocrine-sensitive and resistant BC cells that can be exploited for combinatorial therapy."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • GLS1 • HK2 • METTL3 • SLC1A5

Testing of the Anti Cancer Drugs CB-839 HCl (Telaglenastat) and MLN0128 (Sapanisertib) in Advanced Stage Non-small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=22 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=85 ➔ 22 | Trial completion date: Jun 2026 ➔ Nov 2026 | Trial primary completion date: Jun 2026 ➔ Nov 2025

Enrollment change • Trial completion date • Trial primary completion date • Brain Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • KEAP1 • KRAS • NFE2L2 • ROS1

Metabolic nanoblockers for synergistic cancer treatment through glutaminase inhibition and sonodynamic therapy. (PubMed, Ultrason Sonochem) - "To address these challenges, we herein developed metabolic nanoblockers (CBE@AM NPs) by encapsulating a glutamine metabolism inhibitor CB839 and a sonosensitizer chlorin e6 (Ce6) into melanin-inspired nanoparticles...Concurrently, they inhibited the glutamine metabolism in the tumor, disrupting redox homeostasis and remodeling the immunosuppressive TME, thereby amplifying both SDT-generated oxidative stress and ICD-induced antitumor immunity. CBE@AM NPs demonstrated a potent tumor-inhibitory effect in tumor-bearing mice, highlighting their potential for immunometabolic reprogramming to enhance the therapeutic efficacy of SDT."

Journal • Oncology

Immune suppression in MTAP-deficient cancers via glutamate metabolism and CXCL10 downregulation. (PubMed, Front Immunol) - "Several glutamate pathway inhibitors, including the clinically tested glutaminase inhibitor CB-839, selectively impaired their growth...These findings uncover a novel link between glutamate metabolism and immune modulation in MTAP-deficient tumors. Our study provides mechanistic and preclinical support for targeting glutamate pathways to both suppress tumor growth and convert immune-cold tumors into more immunoresponsive states, offering a promising strategy to enhance ICI efficacy in this challenging cancer subtype."

IO biomarker • Journal • Immune Modulation • Immunology • Oncology • CXCL10 • MTAP • PTPRC

Targeting Glutamine Dependence through GLS1 Inhibition Suppress Multiple Myeloma and Phenomenon of Sars-Cov-2 Infectious Disease (ASH 2023) - "Combined treatment with panobinostat and telaglenastat caused more cytotoxicity. The GLS is involved myeloma progress and GLS inhibitor suppresses myeloma cells and enhance cytotoxic effects of HDAC inhibitor. We also provide the GLS inhibitor is effective to SARS-CoV-2 phenomenon and promising clinical relevance as a candidate drug for treatment of myeloma patients in COVID-19 pandemic."

Hematological Malignancies • Infectious Disease • Monoclonal Gammopathy • Multiple Myeloma • Oncology • Respiratory Diseases • CASP3 • CASP7 • GLS1 • TNFA

Rational Design of Non-Toxic Multidrug Combinations Demonstrates Durable and Hypoxia-Enhanced Efficacy Against Renal Cell Carcinoma. (PubMed, Pharmaceutics) - " From an initial panel of 10 drugs, either approved or undergoing clinical trial, the optimized drug combinations (ODCs) contained crizotinib, telaglenastat, U-104, and vismodegib at clinical and subtherapeutic doses. Moreover, chronic exposure of 786O and UOK276 cells led to durable responses, suggesting a prolonged effect in responders. Our findings demonstrate the potential of optimized, non-toxic drug combinations as a highly selective and effective strategy for accelerating the development of precision RCC treatment."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor