AGI-5198 / Agios Pharma - LARVOL DELTA

Metformin attenuates myocardial ischemia/reperfusion-induced ferroptosis through the upregulation of Nur77-mediated IDH1. (PubMed, Biochim Biophys Acta Mol Cell Res) - "Catalytic site inhibitor IDH1 Inhibitor 5 (compound 2 AGI-5198) negated the protective effects of metformin. Collectively, these data reveal that metformin prevents myocardial I/R injury and ferroptosis through its effects on Nur77, IDH1 expression and inhibition of the JNK/P38 pathway. This highlights the novel therapeutic value of targeting ferroptosis with metformin to improve cardiac protection."

Journal • Cardiovascular • Fibrosis • Immunology • Myocardial Ischemia • Reperfusion Injury • IDH1 • PACERR • PTGS2

IDH1 mutation inhibits differentiation of astrocytes and glioma cells with low oxoglutarate dehydrogenase expression by disturbing α-ketoglutarate-related metabolism and epigenetic modification. (PubMed, Life Metab) - "Finally, we found that l-glutamine increased α-KG levels and augmented the differentiation-promoting effects of AGI5198, an IDH1-mutant inhibitor, in IDH1-mutant glioma cells. Collectively, this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas, providing a potential strategy for the treatment of IDH-mutant gliomas by targeting α-KG homeostasis."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • IDH1

Discovery of Aloperine as a Potential Antineoplastic Agent for Cholangiocarcinoma Harboring Mutant IDH1. (PubMed, Int J Mol Sci) - "In addition, aloperine preferentially resensitizes RBE cells to 5-fluorouracil, AGI-5198 and olaparib. This article demonstrates that aloperine shows preferential antitumor effects in intrahepatic cholangiocarcinoma cells harboring the mutant IDH1 by decreasing D-2-hydroxyglutarate, suggesting that aloperine could be used as a lead compound or adjuvant chemotherapy drug to treat ICC harboring the mutant IDH."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • IDH1

Zinc Finger MYND-Type Containing 8 (ZMYND8) is epigenetically regulated in mutant Isocitrate Dehydrogenase 1 (IDH1) glioma to promote radioresistance. (PubMed, Clin Cancer Res) - "These findings indicate the impact of ZMYND8 in the maintenance of genomic integrity and repair of IR-induced DNA damage in mIDH1 glioma."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • BRD4 • IDH1

Sphingosine kinase 1 as a therapeutic target for IDH1-R132H glioma (SNO 2021) - "RESULTS We probed the impact of decreasing D-2HG on the sphingolipid metabolism after treating a panel of IDH1 mut glioma cells with IDH1-R132H mut inhibitor, AGI5198...S1P production has been reported to be elevated particularly for malignant glioblastomas in prior studies; whereas our research revealed that it is relatively low in IDH mut by comparison with IDH WT tumor cells. These findings suggest targeting the sphingolipid metabolism may present a promising strategy to improve survival for patients diagnosed with IDH1 mut gliomas."

Brain Cancer • Glioblastoma • Glioma • Metabolic Disorders • Oncology • Solid Tumor • IDH1

IDH1-mutated cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity (AACR 2018) - "These effects were abolished by the IDH1MUT inhibitor AGI-5198 and were recapitulated by treatment with D-2HG. Thus, our study shows that altered oxidative stress responses due to a vulnerable oxidative metabolism underlie the sensitivity of IDH1MUT cancer cells to cisplatin. Furthermore, our data offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and imply that administration of IDH1MUT inhibitors in these patients limit efficacy of cisplatin treatment."

Oncology

Beyond the Influence of IDH Mutations: Exploring Epigenetic Vulnerabilities in Chondrosarcoma. (PubMed, Cancers (Basel)) - "Furthermore, class I HDAC inhibition sensitized chondrosarcoma to glutaminolysis and Bcl-2 family member inhibitors, suggesting that HDACs define the metabolic state and apoptotic threshold in chondrosarcoma. Taken together, HDAC inhibition may represent a promising targeted therapeutic strategy for chondrosarcoma patients, either as monotherapy or as part of combination treatment regimens."

IO Biomarker • Journal • Lymphoma • Oncology • Sarcoma • Solid Tumor • BCL2 • IDH1 • IDH2

Metabolic plasticity of IDH1-mutant glioma cell lines is responsible for low sensitivity to glutaminase inhibition. (PubMed, Cancer Metab) - "Major metabolic adaptations involved pathways that can generate glutamate by using alternative substrates from glutamine, such as alanine or aspartate. Indeed, asparagine synthetase was upregulated both in vivo and in vitro revealing a new potential therapeutic target for a combinatory approach with CB839 against IDH1 gliomas."

Journal • Preclinical • Glioma • Metabolic Disorders • Oncology • Solid Tumor • ASNS • IDH1

Extracellular glutamate and IDH1 inhibitor promote glioma growth by boosting redox potential. (PubMed, J Neurooncol) - "3D culture is more relevant to IDH1 glioma biology. The importance of redox homeostasis in IDH1 glioma suggests that metabolic pathway(s) can be explored for therapeutic targeting, whereas IDH1 inhibitors may have counterproductive consequences in patient treatment."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • Transplantation

Sphingolipid Pathway as a Source of Vulnerability in IDH1n n Glioma. (PubMed, Cancers (Basel)) - "inhibitor, AGI5198...To our knowledge, this is the first study that shows how altering the sphingolipid pathway in IDH1gliomas elucidates susceptibility that can arrest proliferation and initiate subsequent cellular death."

Journal • Glioma • Immunology • Inflammation • Metabolic Disorders • Oncology • Solid Tumor • IDH1

[VIRTUAL] Mutant IDH1 alters epigenetic regulation to promote stemness in low grade glioma: Deciphering signaling pathways altered by mIDH1 inhibition (AACR-II 2020) - "Pharmacological inhibition of mIDH1 (AGI-5198) can restore expression of genes involved in neural differentiation...In future work, we will perform ChIP-seq to define enhancers and promoters that regulate stem cell-like characteristics. These findings will reveal novel genomic loci unique to mIDH1 glioma.SC is supported by the T32 Cancer Biology Training Grant, the work is supported by grants from NIH/NINDS to MGC and PRL."

Astrocytoma • Brain Cancer • Glioma • Oncology • Solid Tumor • ATRX • IDH1 • TP53

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas. (PubMed, J Neurooncol) - "Forced overexpression of the IDH1 R132H protein in glioma cells reduced Fn14 expression, while treatment of IDH1 R132H-overexpressing cells with the IDH1 R132H inhibitor AGI-5198 or the DNA demethylating agent 5-aza-2'-deoxycytidine increased Fn14 expression. These results support a role for Fn14 in the more aggressive and invasive phenotype associated with IDH1 WT tumors and indicate that the low levels of Fn14 gene expression noted in IDH1 R132H mutant gliomas may be due to epigenetic regulation via changes in DNA methylation."

Journal • Biosimilar • Oncology • Solid Tumor

Mutant (R132H) IDH1-driven cellular transformation makes cells dependent on continued wild type IDH1 expression in a model of in vitro gliomagenesis (WFNOS 2017) - "...We recently showed (Mol Cancer Res 14: 976-983, 2016) that although mutant IDH1 expression in hTERT-immortalized, p53/pRb-deficient astrocytes can drive cellular transformation and gliomagenesis, selective pharmacologic inhibition and elimination of 2-HG by the mutant IDH1 inhibitor AGI-5198 has little effect on the growth or clonagenicity of these transformed cells... These results show that the in vitro transformative events driven by expression of mutant IDH1 make cells dependent not on continued mutant IDH1 expression, but rather on continued WT IDH1 expression. The data also support the development and testing of agents that can inhibit both the WT and mutant forms of IDH1."

Biosimilar • Oncology

RNA-binding Protein HuR Regulates Both Mutant and Wild-type IDH1 in IDH1-mutated Cancer. (PubMed, Mol Cancer Res) - "HuR-deficient cells were especially sensitive to stress, including low glucose conditions or a mutant IDH1 inhibitor (AGI-5198)...IDH1 mutant cancer cells were rescued by WT.IDH1 overexpression to a greater extent than Mut.IDH1 overexpression under these conditions. This study reveals the importance of HuR's regulation of both mutant and wild-type IDH1 in tumors harboring a heterozygous IDH1 mutation with implications for therapy.  Implications: This study highlights the HuR-IDH1 (mutant and wild-type IDH1) regulatory axis as a critical, actionable therapeutic target in IDH1-mutated cancer, and incomplete blockade of the entire HuR-IDH1 survival axis would likely diminish the efficacy of drugs that selectively target only the mutant isoenzyme."

Journal

Suppression of Oncometabolite 2-Hydroxyglutrate Produced by Mutant IDH1 Glioma with AGI-5198 Enhances the Efficacy of Radiotherapy and Immune Checkpoint Blockade Eliciting Immunological Memory (SNO 2019) - "Our results also demonstrate that antitumor immunity induced by 2HG inhibition is enhanced when combined with standard of care (temozolomide and radiation) and anti-PDL1 immune checkpoint blockade. In addition, when the long-term survivors (>90 days) were rechallenged with mIDH1 tumor cells in the contralateral hemisphere, without further treatment, all the mice remained tumor free, indicating the development of anti-glioma immunological memory. Collectively, these findings support the clinical testing of AGI-5198 as an adjuvant therapy and a novel immunotherapeutic strategy for treating patients with mIDH1 glioma."

Checkpoint inhibition • Clinical • IO Biomarker • PD(L)-1 Biomarker • IDH1 • TP53

IDH1 Causes Resistance to HDAC Inhibitors by Increasing NANOG in Glioblastoma Cells. (PubMed, Int J Mol Sci) - "Based on cell viability and apoptosis assays, we found that IDH1-overexpressing U87MG and U373MG cells are resistant to the anti-cancer effect of histone deacetylase inhibitors (HDACi), such as trichostatin A (TSA), vorinostat (SAHA), and valproic acid. Furthermore, we found that AGI-5198, a selective inhibitor of IDH1, significantly attenuates HDACi resistance and NANOG expression IDH1-expressing glioblastoma cells. These results suggested that IDH1 is a potential molecular target for HDACi-based therapy for GBM."

Journal

Radiotherapy resistance in chondrosarcoma cells; a possible correlation with alterations in cell cycle related genes. (PubMed, Clin Sarcoma Res) - "...Proliferation and clonogenic assays were performed in chondrosarcoma cell lines after γ-radiation in combination with mutant IDH1 inhibitor AGI-5198...Chondrosarcoma cell lines as well as primary tumors are variably radioresistant, particularly in case of a defective Rb pathway. Whether selection for radiotherapy can be based upon an intact Rb pathway should be further investigated."

Biomarker • IO Biomarker • Journal

Isocitrate dehydrogenase 1-mutated cancers are sensitive to the green tea polyphenol epigallocatechin-3-gallate. (PubMed, Cancer Metab) - "Effects of EGCG in IDH-mutated cell lines were diminished by treatment with the IDH1 inhibitor AGI-5198. This work shows that glutamate can be directly processed into D-2-HG and that reduction of glutamatolysis may be an effective and promising new treatment option for IDH cancers."

Journal