AbstractAconitase decarboxylase 1 (ACOD1, also known as Immune Response Gene or IRG1) is a mitochondrial enzyme responsible for the synthesis of the metabolite itaconate in the TCA cycle of pro-inflammatory macrophages. Utilizing Acod1-/- mice and Acod1 KO cells, recent studies have assigned a cancer-promoting role for ACOD1 and demonstrated its expression in immunosuppressive macrophages, found in the TME of syngeneic tumors (Chen et al, Sci. Adv 2023), and in anti-PD-1 (aPD1)-resistant prostate cells (Schofield et al., Cell Rep 2024). To explore the druggability of ACOD1, we synthesized a series of small MW inhibitors and selected two compounds (ERG344 and its derivative ERG350) for further study. Here, we report that, while both compounds suppress synthesis of itaconate in vitro, ERG350 exhibited a 1000-fold improvement in inhibiting ACOD1 enzymatic activity (IC50 of ∼200 nM) compared to ERG344. Furthermore, both molecules exhibited acceptable pharmacokinetic profiles with half-lives of 8h for ERG344 and 11h for ERG350. Administration of 3 mpk ERG344 as a monotherapy in mice bearing CT26 colon tumors led to complete tumor regression in ∼20% of the animals and partial tumor regression in ∼40% of the animals. Immunophenotyping of ERG344-treated CT26 tumors revealed an increase in the frequency of tumor infiltrating lymphocytes (TILs), especially those expressing the CX3C chemokine receptor 1 (CX3CR1), and an increase in the frequency of mature dendritic cells DC (CD3-CD11b+F4/80-MHCII+CD206-) suggesting that ACOD1 inhibition promotes initiation of an anti-tumor immune response. Increased probability of survival was also observed in the CT26 colon cancer model after daily administration of ERG350 in doses ranging from 0.25 to 3 mpk. The study further reports the effect of ACOD1 inhibition in additional syngeneic models including models of hepatocellular carcinomasCitation Format:Adonia E. Papathanassiu, Weixing Li, Yajie Zhong, Carmen Chak-Lui Wong. Drugging of ACOD1 is associated with tumor regression in syngeneic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4251.

15 Jun 2022·Cancer Research

Abstract 4236: Temporal inhibition of BCAT1 alters metal homeostasis leading to reversal of terminal exhaustion of CD8 T cells, increased cytotoxicity, and increased efficacy of checkpoint inhibition in cancer

Author: Vu, Hong A. ; Li, Weixing ; Papathanassiu, Adonia E.

AbstractWe have previously demonstrated that BCAT1, the enzyme responsible for the reversible transamination of leucine in the cytosol, is a druggable target in immune-oncology: the small molecule inhibitor ERG245 dramatically increases the efficacy of anti-PD-1 treatment in the moderately immunogenic CT26 colon cancer model. We have also shown that Bcat1 gene expression is enriched in exhausted CD4+ and CD8+ intratumoral cells in cancer patients from diverse cancers. Here, we illustrate that the adoptive cell transfer (ACT) of murine CD8+ T cells treated with ERG245 increased the median survival of CT26 tumor-bearing mice from 25 days, observed with the ACT of untreated CD8+ T cells, to 32 days. This suggested that inhibition of BCAT1 prevented the known exhaustion of adoptively transferred CD8+ T cells, induced by the tumor microenvironment of CT26 tumors. To confirm this hypothesis, we developed an in vitro model of generating terminally exhausted (PD-1+TIM-3+GZMB+CXCL13+) CD8+ T cells by subjecting the cells to consecutive cycles of αCD3/αCD28 activation in the presence of TGF-β. Addition of ERG245 in the last activation cycle decreased terminal exhaustion of the cells. Mechanistically, bulk RNAseq experiments indicated and ICP analysis confirmed that inhibition of BCAT1 interfered with metal homeostasis leading to increased concentrations of Fe in the mitochondria and decreased concentrations of Zn in the nucleus of newly activated CD8+ T cells. The immediate impact of ERG245 treatment on the cells included a general decrease in the genes of processes depending on proper metal equilibrium such as cholesterol biosynthesis and ribosome biogenesis. Withdrawal of BCAT1 restored or reversed the cell phenotype leading to epigenetically altered CD8+ T cells with decreased histone acetyltransferase and histone demethylase presence, increased cytotoxicity, and increased ribosome biogenesis. Collectively, the data suggest that temporal inhibition of BCAT1 inhibition induces profound effects on CD8+ T cells including increased cytotoxicity and suppression of terminal exhaustion, thus rendering the cells rescuable by anti-PD-1 therapy.Citation Format: Adonia E. Papathanassiu, Weixing Li, Hong A. Vu. Temporal inhibition of BCAT1 alters metal homeostasis leading to reversal of terminal exhaustion of CD8 T cells, increased cytotoxicity, and increased efficacy of checkpoint inhibition in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4236.

01 Jul 2021·Cancer Research

Abstract 1202: ERG344: A novel IRG1 inhibitor for the treatment of colon cancer

Author: Lambrechts, Diether ; Vu, Hong A. ; Lodi, Francesca ; Papathanassiu, Adonia E.

AbstractImmune responsive gene 1 (Irg1) is an LPS-inducible gene within macrophages (MF) whose protein product is responsible for the synthesis of itaconate from aconitate through a break in the TCA cycle. Although primarily present in proinflammatory macrophages, IRG1 expression has been linked with certain cancers (glioblastoma, ovarian carcinoma) and its tumor-driven upregulation in peritoneal resident macrophages (pResMF) has been shown to contribute to peritoneal tumor growth. Here, we report Irg1 gene expression at the single cell level (scRNAseq) in samples obtained from colorectal cancer patients (n=7; ~11,000 single cells). Transcriptomic analysis showed that Irg1 was primarily expressed by cancer cells, although other tumoral cell types also showed substantial levels of the gene. To determine if IRG1 is a druggable target in cancer, we synthesized a series of small MW inhibitors and selected ERG344 for in vivo testing based on its ability to inhibit itaconate synthesis in a rat glioblastoma cell line (C6) engineered to stably express Irg1. The IC50 value of inhibition was ~150 μM. In vivo, ERG344 suppressed tumor growth and increased survival probability in a syngeneic colon cancer model (CT26). Drug administration was initiated when the tumors reached an average tumor volume of ~100 mm3 and involved daily ERG344 doses of 0.2 mg/kg ip or 0.3 mg/kg po. Complete tumor regressions (~17%) were observed in the same model when ERG344 was administered ip at 3 mg/kg. Immunophenotyping of CT26 tumors treated with either vehicle or 0.2 mg/kg ERG344 ip indicated that IRG1 inhibition renders the tumor microenvironment less immunosuppressive by decreasing the frequency of monocytic myeloid suppressor cells (m-MDSCs), increasing the frequency of cytotoxic CD8+ T cells, and decreasing the CD8+ expression of the negative co-stimulatory molecule PD-1. To determine if ERG344 is also able to reduce pResMF-driven peritoneal tumor growth, murine melanoma B16F15 cells were injected into the peritoneal cavity of C57BL/6 mice treated with vehicle or 1 mg/kg ERG344 (n=8/group). Seven days after tumor inoculation, mice treated with ERG344 showed reduced tumor growth in the peritoneal cavity, which led to increased survival probability of the animals. The studies collectively suggest that IRG1 is a novel target for the treatment of primary and metastatic tumor growth in colorectal cancer and highlight the therapeutic potential of ERG344.Citation Format: Adonia E. Papathanassiu, Francesca Lodi, Hong A. Vu, Diether Lambrechts. ERG344: A novel IRG1 inhibitor for the treatment of colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1202.

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Drug(Targets)	Indications	Global Highest Phase

ERG-344 ( IRG1 )	Colonic Cancer More	Preclinical
ERG350 ( IRG1 )	Colonic Cancer More	Preclinical
ERG-245 ( BCAT1 )	Neoplasms More	Pending

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