- |||||||||| Xospata (gilteritinib) / Astellas, IACS-010759 / UT MD Anderson Cancer Center
The Role and Mechanism of NDUFS2 in FLT3-Mutated Acute Myeloid Leukemia () - Dec 7, 2024 - Abstract #ASH2024ASH_7814;
Additionally, the inhibition of mitochondrial complex I by the inhibitor IACS-010759 can synergize with Gilteritinib to combat FLT3-mutated AML. This indicates that NDUFS2 may serve as a potential target for the treatment of FLT3-mutated AML and enhance the sensitivity of targeted drugs to FLT3-mutated AML.
- |||||||||| Novel Promising Therapeutic Strategies for Advancing the Treatment of KMT2A-Rearranged AML (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_2713;
We support the use of pediatric AML-PDXs in preclinical testing for their ability to mimic the heterogeneity of drug response, aiding in the identification of tailored second-line treatments. VEN+ASPN combination represents a novel promising therapeutic strategy for advancing the treatment of KMT2A-rearranged AML.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Pursuing Leukemia Stem Cells Definition in Pediatric Acute Myeloid Leukemia (Seaport Ballroom EFGH (Manchester Grand Hyatt San Diego)) - Nov 6, 2024 - Abstract #ASH2024ASH_1337;
Additionally, a 72-hour treatment with the chemotherapy agent cytarabine in 3D showed that RL cells were insensitive to this treatment, supporting the RL fraction being chemo-resistant...This result was corroborated by treating 3D scaffolds seeded with RL or RH cells with the complex I inhibitor IACS-010759, which was only effective in reducing RL viability (p<0.05)...This novel strategy of RL cell recognition allows to identify a LSCs population that needs to be targeted to reduce relapse events. Novel mitochondrial vulnerabilities and nutrient dependences are under evaluation to improve AML eradication.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Inhibition of OXPHOS reduces tumor hypoxia and induces metabolic rewiring as measured by [18F]FDG (e-Poster Area) - Sep 27, 2024 - Abstract #EANM2024EANM_1506;
Furthermore, we show tumor cells are metabolically plastic and switch their metabolism from OXPHOS to glycolysis when OXPHOS is pharmacologically inhibited, resulting in increased glucose uptake in tumor cell spheroids. In vivo we observed increased serum lactate levels and increased [18F] FDG uptake in several healthy tissues, but not in the tumor.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Review, Journal, Immune cell: Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759. (Pubmed Central) - Jul 4, 2024
However, IACS-01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS-01075.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Journal: Using Gaussian accelerated molecular dynamics combined with Markov state models to explore the mechanism of action of new oral inhibitors on Complex I. (Pubmed Central) - Jun 11, 2024
We selected the ND1, NDUFS2, and NDUFS7 subunits of Mitochondrial Complex I as the receptor proteins and established three systems for comparative analysis: protein-IACS-010759, protein-lead compound 10, and protein-HP661...Notably, key roles were identified for Met37, Phe53, and Pro212 in the binding of various inhibitors. In conclusion, we delved into the potential molecular mechanisms of triazole derivative HP661 in inhibiting Complex I. These research outcomes provide crucial information for a deeper understanding of the mechanisms underlying OXPHOS inhibition, offering valuable theoretical support for drug development and disease treatment design.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Journal: Characterizing OXPHOS inhibitor-mediated alleviation of hypoxia using high-throughput live cell-imaging. (Pubmed Central) - May 4, 2024
We successfully developed a high-throughput spheroid model in which hypoxia dynamics can be quantified over time. Using this model, we showed that the mitochondria-targeted OXPHOS inhibitors Mito-ATO, Mito-PEG-ATO and MitoTam reduce hypoxia in tumor cells in a dose-dependent manner, potentially sensitizing hypoxic tumor cells for radiotherapy.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Therapeutic modulation of rock overcomes metabolic adaption to oxphos inhibition and suppresses tumor growth (Section 27) - Mar 5, 2024 - Abstract #AACR2024AACR_7970;
Steady-state metabolomics and C13-glucose isotope tracing confirmed downregulation of multiple glycolytic metabolites and reduced glycolytic flux by the combination of ROCK inhibition and IACS-10759 and was associated with severe reduction in glucose uptake. In summary, our study identified a key role of ROCK kinases in metabolic adaptation of cancer cells and provides a strong rationale for pursuing ROCK inhibitors as novel combination agents with OXPHOS inhibition and lay the foundation for future clinical investigation in genetically defined subtypes of lung cancer.
- |||||||||| Welireg (belzutifan) / Merck (MSD), IACS-010759 / UT MD Anderson Cancer Center, Sutent (sunitinib) / Pfizer
Investigating metabolic sensitivity and organization of renal cell carcinoma: To enhance effective therapies and patient survival (Section 13) - Mar 5, 2024 - Abstract #AACR2024AACR_7389;
Our biosensor single cell data show that even genetically homogeneous cell populations can vary in their usage of OXPHOS and glycolysis to supply ATP for cell growth. Tumor gene expression profile coupled with biosensor data, will address mechanism behind this metabolic shift in RCC tumors in primary cells isolated from primary and metastatic sites.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Investigating the significance of OXPHOS activity in non-small cell lung cancer brain metastases (Section 18) - Mar 5, 2024 - Abstract #AACR2024AACR_4392;
This elevated OXPHOS activity may be necessary for NSCLC brain metastasis growth, as OXPHOS inhibition reduced metastasis in the brain. NSCLC cells may undergo mitochondrial biogenesis to support survival in this unique metabolic environment, and this may represent an area of therapeutic vulnerability for brain metastases.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Journal: Oxidative phosphorylation is a pivotal therapeutic target of fibrodysplasia ossificans progressiva. (Pubmed Central) - Feb 21, 2024
Furthermore, IACS-010759 inhibited the muscle injury-induced enrichment of fibro/adipogenic progenitor genes and HO in transgenic mice carrying the mutated human ACVR1. These data indicated that OXPHOS is a critical downstream mediator of mTORC1 signaling in chondrogenesis and therefore is a potential FOP therapeutic target.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Journal: Pharmaco-phosphoproteomic analysis of cancer-associated KIT mutations D816V and V560G. (Pubmed Central) - Feb 9, 2024
Pathway analysis identified increased oxidative phosphorylation in D816V- and V560G-mutant KIT cells, which was targetable using the inhibitor IACS010759...Phosphoproteome analysis further revealed active kinases such as EGFR, ERK and PKC, which were targetable using pharmacological inhibitors. This study provides a pharmaco-phosphoproteomic profile of D816V- and V560G-mutant KIT cells, which reveals novel therapeutic strategies that may be applicable to a range of cancers.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Minimal Residual Disease in Acute Myeloid Leukemia Following Induction Chemotherapy Can be Effectively Eradicated By Targeting Mitochondrial Metabolism (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_3906;
Acute myeloid leukemia (AML) stem cells (AMLSCs) AMLSCs and residual cytarabine (AraC)-resistant AML cells (constituting minimal residual disease, MRD) thought to be responsible for chemoresistance and treatment failure, were shown to be highly dependent on mitochondrial function for survival and thus are vulnerable to pharmacological blockade of the oxidative phosphorylation (OXPHOS) (Farge et al...Here we evaluated OXPHOS dependency of AML MRD cells and determined impact of OXPHOS blockade on residual AML cells surviving standard chemotherapy (Doxorubicin/AraC, DA)...Next, the efficacy of IACS-010759 together with DA chemotherapy was evaluated in several chemotherapy-sensitive and -resistant animal models in vivo...Nat Med 2023) showed toxicities impeding its clinical utility, our data advocate for combining mitochondrial targeting strategies with chemotherapy as a part of induction and consolidation treatment for improved control of MRD, eradication of AMLSC and extended response duration. Thus, further studies to identify compounds with improved safety profile are warranted.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Journal: Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC-driven lymphoma. (Pubmed Central) - Jun 8, 2023
In these conditions, ascorbate synergized with IACS-010759 to kill MYC-overexpressing cells in vitro and reinforced its therapeutic action against human B-cell lymphoma xenografts. Hence, complex I inhibition and high-dose ascorbate might improve the outcome of patients affected by high-grade lymphomas and potentially other MYC-driven cancers.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
TARGETING DNA2 OVERCOMES METABOLIC REPROGRAMMING IN 1Q21 MULTIPLE MYELOMA (Hall Symann) - May 12, 2023 - Abstract #EHA2023EHA_918;
Given that metabolic reprogramming is a hallmark of cancer progression, further studies will clarify whether therapeutically targeting DNA2 has a broad spectrum of anti-cancer applications. Multiple myeloma, DNA repair, Resistance, DNA damage
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Review, Journal: Recent advances of mitochondrial complex I inhibitors for cancer therapy: Current status and future perspectives. (Pubmed Central) - Apr 4, 2023
Moreover, drug repurposing represents an effective and prospective strategy for CI inhibitor discovery. In this review, we mainly elaborate the biological function of CI in tumor progression, summarize the CI inhibitors reported in recent years and discuss the further perspectives for CI inhibitor application, expecting this work may provide insights into innovative discovery of CI-targeting drugs for cancer treatment.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Functional antibodies against multi span transmembrane proteins - revisiting the Warburg effect in cancer cells (Section 11; Poster Board #9) - Mar 14, 2023 - Abstract #AACR2023AACR_8678;
This is the first study to provide highly specific antibodies bocking the function of SLC2A1 transporter and demonstrate the proof of principle for inhibiting complex muti-pass membrane transporters with antibody therapeutics. While the developed anti-SLC2A1 antibodies could be efficacious in some indications as single agents, appreciable clinical activity could be obtained by the combined use with OXPHOS inhibitors.
- |||||||||| Avastin (bevacizumab) / Roche, IACS-010759 / UT MD Anderson Cancer Center, Lynparza (olaparib) / Merck (MSD), AstraZeneca
Exploiting mitochondrial metabolism to enhance the response to standard of care treatments in ovarian cancer (Section 12; Poster Board #11) - Mar 14, 2023 - Abstract #AACR2023AACR_7594;
Targeting these OXPHOS-dependent cells with the respiratory chain complex I inhibitor IACS-010759 improved the survival of mice. These results indicate that the metabolic profile of ovarian cancer cells is associated with the response to cisplatin and olaparib and lay the ground for the rational combination with OXPHOS inhibition to prolong therapies efficacy and eventually delay the development of recurrent disease.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Exploring metabolic vulnerabilities of metastatic prostate cancer to bone (Section 7; Poster Board #19) - Mar 14, 2023 - Abstract #AACR2023AACR_6389;
Metabolic in vitro analyses showed that C4-2B cells depended on aerobic respiration, while PC3 cells relied more heavily on glycolysis, as further confirmed by pharmacological interference using IACS-010759, a clinical grade inhibitor of oxidative phosphorylation tested in patients...Such metabolic vulnerabilities may be exploited to either introduce further lines of treatments or in combination with the existing therapies. These findings also underscore the important role that the tumor microenvironment can play in reprogramming prostate cancer metabolism and thus, influence the efficacy of metabolically targeted therapies.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Small cell lung cancer predominantly expressing ASCL1 shows a distinct oxidative phenotype (Section 8; Poster Board #5) - Mar 14, 2023 - Abstract #AACR2023AACR_4063;
The current standard treatment, a combination of a platinum-based chemotherapy and etoposide, does not consider the underlying molecular profiles and, therefore, displays limited success...Differential responses to inhibitors of complex 1 (metformin, IACS-010759), the CPT1 inhibitor perhexiline, the glutaminolysis inhibitor BPTES and the aerobic glycolysis inhibitor UK5099 were tested using MTT-based cell viability assays...Specifically, our data show upregulated oxidative phosphorylation as a potential therapeutic target. Understanding the variances in the metabolic phenotype between the molecular subtypes is integral to achieving precision medicine and advancing SCLC patient treatment.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Metabolic reprogramming driven by IGF2BP3-COX6B2 axis promotes acquired resistance to EGFR-TKIs in non-small lung cancer (Section 15; Poster Board #10) - Mar 14, 2023 - Abstract #AACR2023AACR_2512;
Inhibition of OXPHOS with IACS-010759, a small-molecule inhibitor, resulted in remarkable growth inhibition in vitro and in vivo in a gefitinib-resistant patient-derived xenograft model. Collectively, our findings suggest that metabolic reprogramming directed by the IGF2BP3-COX6B2 axis plays a critical role in TKI resistance, and targeting the metabolic pathway provides a new therapeutic strategy to overcome EGFR-TKI resistance in lung cancer.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
P1 data, Journal, Metastases: Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials. (Pubmed Central) - Jan 20, 2023
P1
Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Disruption of nucleotide homeostasis confers cancer cell susceptibility to oxidative phosphorylation inhibition independently of energy depletion () - Jan 13, 2023 - Abstract #LCC2023LCC_220;
A panel of metabolically flexible glycolysis-competent cancer cell lines along with those deficient in glycolysis were tested using OXPHOS inhibitors, including the mitochondrial complex I inhibitor IACS-010759... 1) Disruption of nucleotide homeostasis is a major determinant of cancer cell susceptibility to OXPHOS inhibition; 2) OXPHOS inhibition is a promising avenue for the treatment of cancers that are metabolic flexible and glycolysis competent, and 3) GOT1 targeting is potentially a useful approach to improve the therapeutic efficacy of OXPHOS inhibition for cancer treatment.
- |||||||||| ibrutinib / Generic mfg.
Journal: CD52 and OXPHOS-potential targets in ibrutinib-treated mantle cell lymphoma. (Pubmed Central) - Jan 1, 2023
In primary mantle cell lymphoma cells, a higher toxic effect with CD52 mAb was obtained, when cells were pretreated with ibrutinib, but only in an ibrutinib-sensitive cohort. Given the challenge of treating multi-resistant mantle cell lymphoma patients, this work highlights the potential use of anti-CD52 therapy as consolidation after ibrutinib treatment in patients who responded to the BTK inhibitor to achieve MRD negativity and prolong progression-free survival.
- |||||||||| BAY 872243 / Bayer, IACS-010759 / UT MD Anderson Cancer Center
Journal: NDUFS3 knockout cancer cells and molecular docking reveal specificity and mode of action of anti-cancer respiratory complex I inhibitors. (Pubmed Central) - Nov 10, 2022
We compared the specificity and mode of action of CI inhibitors metformin, BAY 87-2243 and EVP 4593 using cancer cell models devoid of CI...Most of the amino acids involved in such interactions are conserved across species and only rarely found mutated in human. Our data make a case for caution when referring to metformin as a CI-targeting compound, and highlight the need for dosage optimization and careful evaluation of molecular interactions between inhibitors and the holoenzyme.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center, Idhifa (enasidenib) / BMS, Servier, Tibsovo (ivosidenib) / Servier
Targeting IDH1-Mutated Pre-Leukemic Hematopoietic Stem Cells in Myeloid Disease, Including CCUS and AML (ENMCC - 252-254) - Nov 4, 2022 - Abstract #ASH2022ASH_5333;
This effect is specific for IDH1 mutations and the same effect is not seen in IDH2-mutated pHSCs. These results have potential clinical implications when considering therapeutic options in AML as well as IDH1-mutated pre-leukemic conditions such as CCUS.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, IACS-010759 / UT MD Anderson Cancer Center, navitoclax (ABT 263) / AbbVie
LP-118, a Novel BCL2 Inhibitor, Shows Potent in Vitro Anti-Myeloma Activity (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_4548;
P1
However, best results were seen when targeting the compensatory upregulation of MCL-1 with S63845, an MCL-1 inhibitor...An ongoing phase 1 dose-escalation trial (NCT04771572) is underway evaluating safety and tolerability in patients with relapsed or refractory hematological malignancies. Future in vitro and in vivo animal studies will continue to evaluate drug combinations that best overcome drug resistance to anti-apoptotic treatment.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, IACS-010759 / UT MD Anderson Cancer Center
Generation of Richter Transformation Models throughout Chronic Lymphocytic Leukemia Patient-Derived Xenografts: A Clonal Evolution Model (ENMCC - R02-R05) - Nov 4, 2022 - Abstract #ASH2022ASH_3679;
Finally, we observed that RT cells were resistant to venetoclax, but this resistance could be circumvented by the incubation of cells in combination with the OXPHOS inhibitor IACS-010759...We propose that targeting OXPHOS in combination with venetoclax might be a potential targeted therapy in RT patients. Altogether, these models will facilitate the development of new therapeutic opportunities for patients with RT.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Investigating the role of mitochondrial protein translation in the metabolic adaptation of chemoresistant triple negative breast cancer (Hall 1) - Oct 10, 2022 - Abstract #SABCS2022SABCS_1589;
Pharmacologic inhibition of mitochondrial electron transport chain (ETC) complex I with IACS-010759 (PMID: 29892070) had enhanced efficacy in residual, rather than treatment-naïve, tumors of orthotopic patient- derived xenograft (PDX) models...While DNA-damaging chemotherapies (e.g.Adriamycin, carboplatin) induced mitochondrial fusion and oxphos, taxanes (e.g.paclitaxel, docetaxel) induced mitochondrial fragmentation and reduced oxphos (Baek et al., Biorxiv Doi 10.1101/2022.02.25.481996)... These data suggest targeting mitochondrial translation may be a promising approach to overcome pro-survival metabolic adaptations in residual TNBC cells not killed by conventional chemotherapies.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Astrocytoma cells harboring mutant IDH1 are uniquely sensitive to inhibition of oxidative phosphorylation (West/Central Hall) - Sep 28, 2022 - Abstract #SNO2022SNO_686;
In summary, IACS-010759-induced inhibition of oxidative phosphorylation elicited pronounced anti-neoplastic responses in vitro, especially in astrocytomas expressing mutant IDH1. IACS-010759 may be a promising therapy for both IDH1 wt and mutant gliomas, and we are currently evaluating the efficacy of this strategy in glioma mouse models.
- |||||||||| IACS-010759 / UT MD Anderson Cancer Center
Journal: Subtype and site specific-induced metabolic vulnerabilities in prostate cancer. (Pubmed Central) - Sep 20, 2022
In vitro, ARPC C4-2B cells depended on aerobic respiration, while AVPC PC3 cells relied more heavily on glycolysis, as further confirmed by pharmacological interference using IACS-10759, a clinical-grade inhibitor of OXPHOS...Implications: These vulnerabilities may be exploited with mechanistically novel treatments, such as those targeting OXPHOS alone or possibly in combination with existing therapies. In addition, our findings underscore the impact of the tumor microenvironment in reprogramming prostate cancer metabolism.
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