- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Modulation of OXPHOS and pharmacological response in ovarian cancer (Poster Area) - Jun 28, 2022 - Abstract #EACR2022EACR_321;
The combination of DDP with the OXPHOS inhibitor IACS-010759 (respiratory chain complex I inhibitor) significantly improved the survival of mice, indicating that the effect of DDP was enhanced by the impairment of the oxidative metabolism...HR-D OC-PDXs and ovarian cancer cell lines rely on oxidative metabolism for energy requirements and are very sensitive to OXPHOS inhibition. Further studies are needed to assess whether alterations of OXPHOS influence the response to PARP inhibition.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Subtype-specific Hypersensitivity to Oxidative Phosphorylation Inhibition in Small Cell Lung Cancer (Exhibit Hall - Hall B) - Jun 24, 2022 - Abstract #IASLCWCLC2022IASLC_WCLC_1586;
In this study, we demonstrate significant overactivation of OXPHOS in the SCLC-A subtype. Furthermore, our data show hypersensitivity of SCLC-A cells to specific inhibitors, suggesting targeting of upregulated oxidative phosphorylation as a potential new therapeutic approach in SCLC.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Journal: Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia. (Pubmed Central) - May 29, 2022
We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center, Tibsovo (ivosidenib) / Servier
Journal: Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia. (Pubmed Central) - May 21, 2022
We propose that the IDH1 mutation limits the flexibility for citrate utilization in the presence of impaired complex I activity to a degree that is not apparent in IDH2 mutant cells, exposing a mutation-specific metabolic vulnerability. This reduced metabolic plasticity explains the epistatic relationship between the germline complex I variants and oncogenic IDH1 mutation underscoring the utility of genomic data in revealing metabolic vulnerabilities with implications for therapy.
- |||||||||| Preclinical, Journal, PARP Biomarker: Preclinical evaluation of targeted therapies in Sdhb-mutated tumors. (Pubmed Central) - May 18, 2022
1H-MRS, but not DCE-MRI, enabled monitoring response to sunitinib, which was the best treatment in this study, promoting a decrease in succinate levels detected in vivo. This study paves the way for new therapeutic options and reveals a potential new early biomarker of response to treatment in SDHB-dependent PPGL.
- |||||||||| Journal: Targeting mitochondrial metabolism in acute myeloid leukemia. (Pubmed Central) - Apr 15, 2022
Other mitochondrial inhibitors including CPI-613, CB-839, dihydroorotate dehydrogenase inhibitors, IACS-010759, and mubritinib, have shown encouraging preclinical efficacy and are currently being evaluated in clinical trials. In this review, we summarize recent metabolism-based therapies and their ability to target altered cancer metabolism in AML.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, S63845 / Servier, Novartis, Ligand, IACS-010759 / UT MD Anderson Cancer Center
Journal, IO biomarker: Targeting mitochondrial respiration and the BCL2 family in high-grade MYC-associated B-cell lymphoma. (Pubmed Central) - Apr 9, 2022
In BCL2-negative lymphoma cells, instead, killing by IACS-010759 was potentiated by the Mcl-1 inhibitor S63845. Thus, combining an OxPhos inhibitor with select BH3-mimetic drugs provides a novel therapeutic principle against aggressive, MYC-associated DLBCL variants.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Journal: PGC1α/β EXPRESSION PREDICTS THERAPEUTIC RESPONSE TO OXIDATIVE PHOSPHORYLATION INHIBITION IN OVARIAN CANCER. (Pubmed Central) - Apr 6, 2022
Treatment with the respiratory chain complex I inhibitor IACS-010759 caused mitochondrial swelling and ATP depletion that consequently delayed malignant progression and prolonged the lifespan of high PGC1α/β-expressing OC-PDX-bearing mice...The clinical relevance of these findings was substantiated by analysis of ovarian cancer patient datasets, which showed that 25% of all cases displayed high PGC-1α/β expression along with an activated mitochondrial gene program. This study endorses the use of OXPHOS inhibitors to manage ovarian cancer and identifies the high expression of both PGC-1α and β as biomarkers to refine the selection of patients likely to benefit most from this therapy.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Morphological and functional plasticity of mitochondria promotes chemotherapy resistance in triple negative breast cancer (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_6195;
Blocking oxphos with an inhibitor of electron transport chain Complex I (IACS010759; PMID:29892070) was significantly more efficacious against residual than pre-treated tumors (PMID:30996079), providing evidence that dynamic metabolic phenotypes represent targetable therapeutic vulnerabilities for TNBC...These findings provide evidence that modulating mitochondrial fission and fusion may be a promising strategy to overcome metabolic states contributing to chemoresistance in TNBC. Our ongoing investigations are aimed at rational targeted therapies and scheduling approaches to overcome chemoresistance in in vivo models of TNBC.
- |||||||||| Avastin (bevacizumab) / Roche, IACS-010759 / UT MD Anderson Cancer Center, Fotivda (tivozanib) / Kyowa Kirin, AVEO, Jazz
Angiogenesis inhibitors strongly synergize with therapeutics targeting tumor metabolism (Section 14) - Mar 9, 2022 - Abstract #AACR2022AACR_5709;
The same results were recapitulated with the VEGFR inhibitor Tivozanib and HEX and the enolase inhibitor could be substituted with the Oxphos inhibitor IACS-010759, with similar effects...Together, these results suggest that angiogenesis inhibitors synergize broadly with cancer therapies targeting metabolism, allowing the realization of the full potential of these previously disappointing drugs. Our results warrant systematic combination clinical trials between angiogenesis inhibitors and established, as well as emerging anti-metabolic cancer therapies.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Clinical, Journal: Patient-derived iPSCs link elevated mitochondrial respiratory complex I function to osteosarcoma in Rothmund-Thomson syndrome. (Pubmed Central) - Feb 17, 2022
Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies.
- |||||||||| Cabometyx (cabozantinib tablet) / Takeda, Exelixis, Ipsen
Journal: Oxidative phosphorylation is a metabolic vulnerability in chemotherapy-resistant triple negative breast cancer. (Pubmed Central) - Jan 12, 2022
We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo...In addition, the combination of IACS-10759 and multi-kinase inhibitor cabozantinib had improved antitumor efficacy compared to either single agent. Taken together, these data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Journal: Metabolic regulation of RA macrophages is distinct from RA fibroblasts and blockade of glycolysis alleviates inflammatory phenotype in both cell types. (Pubmed Central) - Dec 16, 2021
2-DG treatment showed a more robust impact on impairing the RA M1 MΦ-mediated inflammatory phenotype than IACS-010759 (IACS, complexli), by reversing ERK, AKT and STAT1 signaling, IRF8/3 transcription and CCL2 or CCL5 secretion...Surprisingly, IACS treatment was inconsequential on CIA swelling, cell infiltration, M1 and Th1/Th17 cytokines (IFN-γ/IL-17) and joint glycolytic mediators. Collectively, our results indicate that blockade of glycolysis is more effective than inhibition of complex 1 in CIA, in part due to its effectiveness on the MΦ inflammatory phenotype.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
TARGETING ASPARAGINE METABOLISM INHIBITS TUMOR GROWTH IN LIPOSARCOMA ([VIRTUAL]) - Nov 26, 2021 - Abstract #CTOS2021CTOS_189;
Targeting Asn results in energy stress and cell cycle arrest. High ATF4 protein expression in WD LPS is associated with a decreased overall survival, serving as a potential prognostic indicator and biomarker for Asn-targeted therapy.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Ninlaro (ixazomib) / Takeda, IACS-010759 / UT MD Anderson Cancer Center
Mitochondrial Electron Transport Chain Inhibition Promotes Resistance to Proteasome Inhibitors in Multiple Myeloma (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_3190;
P=N/A
RESULTS We find that mitochondrial ETC (complex I-V) inhibition antagonizes bortezomib (BTZ) and carfilzomib (CFZ) induced cell death in MM in contrast to promoting sensitivity to venetoclax...The ensuing metabolic rewiring in mitochondrially suppressed MM induces several metabolic vulnerabilities including sensitivity to the SLC7A11 inhibitor, erastin...These ETC-inhibited cells are however sensitive to BCL-2 antagonists and afford additional metabolic vulnerabilities that can be capitalized upon to target metabolic heterogeneity in MM. Our study underscores the need for implementing combinatorial regimens in MM cognizant of mitochondrial metabolic heterogeneity-mediated resistance.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Targeting DNA2 Overcomes Myeloma Cells’ Metabolic Reprogramming in Response to DNA Damage (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_3152;
ILF2-ASO-resistant MM cells were significantly more sensitive to the OXPHOS inhibitor IACS-010759 than ILF2-ASO-sensitive cells were...In conclusion, our study has revealed a novel mechanism through which MM cells can overcome DNA damage activation. Further studies will clarify whether targeting DNA2 is synthetically lethal in tumors with increased demand of mitochondrial metabolism.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Journal: Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition. (Pubmed Central) - Nov 4, 2021
We further demonstrated that cytarabine, a commonly used antileukemia agent, increased OxPhos inhibition-triggered mitochondrial transfer from MSCs to AML cells. Our findings indicate an important role of exogenous mitochondrial trafficking from BM stromal cells to AML cells as well as endogenous mitochondrial fission and mitophagy in the compensatory adaptation of leukemia cells to energetic stress in the BM microenvironment.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Oxidative phosphorylation and NRF2 activation mediate resistance to estrogen deprivation in ER+ breast cancer (Hall 1) - Oct 26, 2021 - Abstract #SABCS2021SABCS_1101;
The therapeutic potential of targeting mitochondrial function in DTPs was tested with the Complex I inhibitor IACS-010759...Decreased DTP survival was concomitant with an increase in ROS. These findings establish the scope of metabolic reprogramming in DTPs and offer Mitochondrial Complex I and NRF2 inhibition as novel therapeutic strategies for eradicating DTPs in ER+ breast cancer.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
[VIRTUAL] Exogenous Mitochondrial Transfer and Endogenous Mitochondrial Fission Facilitate Resistance to OxPhos Inhibition in AML () - Sep 6, 2021 - Abstract #SOHO2021SOHO_406;
In summary, we identified a novel drug combination, AC220 and IACS-010759, which synergistically inhibits cell growth in AML cells due to a major disruption of cell metabolism, regardless of FLT3 mutation status. Our findings indicate an important role of exogenous mitochondrial trafficking from BM stromal cells to AML cells and of endogenous mitochondrial fission and mitophagy in the compensatory adaptation of leukemia cells to energetic stress in the BM microenvironment.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
[VIRTUAL] Targeting DNA2 overcomes myeloma cells’ metabolic reprogramming in response to DNA damage () - Aug 28, 2021 - Abstract #IMW2021IMW_356;
Consistent with these results, ILF2-ASO- resistant MM cells were significantly more sensitive to the OXPHOS inhibitor IACS-010759 than ILF2-ASO-sensitive cells were... In conclusion, our study has revealed a novel mechanism through which MM cells counteract oxidative DNA damage and maintain mitochondrial respiration after metabolic reprogramming.
- |||||||||| Ibrance (palbociclib) / Pfizer, IACS-010759 / UT MD Anderson Cancer Center
Journal: Metabolic adaptations to MEK and CDK4/6 co-targeting in uveal melanoma. (Pubmed Central) - Jun 3, 2021
IACS-010759, an OxPhos inhibitor, decreased UM cell survival in combination with MEKi + CDK4/6i. These data highlight adaptive upregulation of OxPhos in response to MEKi + CDK4/6i treatment in UM and suggest that suppression of this metabolic state may improve the efficacy of MEKi plus CDK4/6i combinations.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Journal: Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries. (Pubmed Central) - May 29, 2021
Significantly, preclinical testing of the complex I mitochondrial inhibitor IACS-010759 showed it extends overall survival in a preclinical model of ARID1A-mutated OCCC. These findings provide for the targeting mitochondrial activity in ARID1A-mutated OCCCs.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Journal: Cork-in-bottle mechanism of inhibitor binding to mammalian complex I. (Pubmed Central) - May 16, 2021
We combine structural and kinetic analyses to deconvolute cross-species differences in inhibition and identify the structural motif of a "chain" of aromatic rings as a characteristic that promotes inhibition. Our findings provide insights into the importance of π-stacking residues for inhibitor binding in the long substrate-binding channel in complex I and a guide for future biorational drug design.
- |||||||||| telaglenastat (CB-839) / Calithera, IACS-010759 / UT MD Anderson Cancer Center
[VIRTUAL] Exploiting oncogene-conferred glutamine addiction as a therapeutic vulnerability in resistant mantle cell lymphoma () - Mar 11, 2021 - Abstract #AACR2021AACR_3715;
In conclusion, we report that glutaminolysis and OXPHOS are upregulated in IBN-R MCL that could be partially due to high expression of GLS1. Our preliminary results revealed that the GLS inhibitor, CB-839, may present a clinical potential for a new indication and the combinatory treatment with our in-house inhibitor, IACS-010759, warrants more in-depth investigation as a novel therapeutic regimen.
- |||||||||| Review, Journal: Targeting mitochondrial respiration for the treatment of acute myeloid leukemia. (Pubmed Central) - Jan 23, 2021
The imipridone family (ONC201, ONC206, ONC212) of inhibitors target mitochondria through activation of ClpP mitochondrial protease and reduce function of essential pathways. These molecules offer a new mechanism for developing clinical therapies in AML and support novel strategies to target LSCs in parallel with conventional therapies.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Trial completion, Trial completion date, Trial primary completion date, Metastases: IACS-010759 in Advanced Cancers (clinicaltrials.gov) - Nov 24, 2020
P1, N=29, Completed,
These results highlight the importance of homeostatic balance between glycolysis and oxidative phosphorylation for proper microglial function in AD. Active, not recruiting --> Completed | Trial completion date: Feb 2024 --> Nov 2020 | Trial primary completion date: Feb 2024 --> Nov 2020
- |||||||||| telaglenastat (CB-839) / Calithera, IACS-010759 / UT MD Anderson Cancer Center
[VIRTUAL] Targeting Glutamine Metabolism Overcomes Resistance to Targeted Therapies in Refractory Mantle Cell Lymphoma () - Nov 5, 2020 - Abstract #ASH2020ASH_5069;
Our preliminary results revealed that the new GLS inhibitor, GCB-839, may present a clinical potential for a new indication and warrants more in-depth investigation. Deciphering the mechanisms involved in MCL metabolic heterogeneity and adaptability during drug resistance development would be crucial to identify key actors enabling MCL cells to escape from therapy.
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