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Phase ? Study of 64Cu-ATSM Therapy in Malignant Brain Tumors: Safety, Pharmacokinetics, and Preliminary Outcomes (Science Pavilion; Screen 14; Hall B-C (Convention Center)) - Jun 13, 2025 - Abstract #SNMMI2025SNMMI_1877;
Among them, 9 had glioblastoma, 4 had anaplastic astrocytoma, 1 had anaplastic oligodendroglioma, 2 had malignant meningioma, and 2 had metastatic brain tumors. Intravenously administered 64Cu-ATSM was well tolerated, with an MTD of 99 MBq/kg and no serious adverse events reported.
- |||||||||| ebselen (SPI-1005) / Sound Pharma, Cu(II)ATSM / Collaborative Medicinal Development, Tyzeka (telbivudine) / Novartis
Journal: A polytherapy approach demonstrates therapeutic efficacy for the treatment of SOD1 associated amyotrophic lateral sclerosis. (Pubmed Central) - May 17, 2025
Given the parallelism with other metals, this ABC transporter regulation appears to be a general defense mechanism of teleosts to react on metallic pollutants. These findings support CET polytherapy as an advantageous alternative compared to CuATSM monotherapy and highlight the potential of utilising small molecules targeting SOD1 as a polytherapy avenue for the treatment of SOD1-associated ALS.
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Review, Journal: Clinical characterization of IRF2BPL mutation: Case series and review of the literature. (Pubmed Central) - Apr 4, 2025
CuII (atsm) (copper II diacetylbis(4-methylaminouracil)) (CuATSM) is a small-molecular-weight drug that can be administered orally and then used in the human body. The literature suggests that the underlying mechanism of CuATSM involves the restoration of mitochondrial function, including correction of the mitochondrial differentiation and mislocalization observed in cells from NEDAMSS patients, but extensive trials are needed to demonstrate its efficacy in IFR2BPL-related diseases.
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Journal: Additive Effects of Cu-ATSM and Radiation on Survival of Diffuse Intrinsic Pontine Glioma Cells. (Pubmed Central) - Jan 8, 2025
Cu-ATSM toxicity in DIPG cells was also inhibited by overexpression of mitochondrial-targeted catalase. These results support the hypothesis that Cu-ATSM is selectively cytotoxic to DIPGs by a mechanism involving H2O2 generation and copper and being additively cytotoxic with ionizing radiation.
- |||||||||| Cu(II)ATSM / Collaborative Medicinal Development, liproxstatin-1 / Jilin University
Journal: Ligand-Based Radical Reactivity of Metal Thiosemicarbazones Prompts the Identification of Platinum(II)-Based Cytoprotectants. (Pubmed Central) - Nov 13, 2024
The RTA activity determined in organic solution largely translates to phospholipid bilayers and mammalian cells, where most complexes inhibited lipid peroxidation and associated ferroptotic cell death. A preliminary structure-activity study revealed Pt complexes with potencies eclipsing those of archetype ferroptosis inhibitors ferrostatin-1 and liproxstatin-1, suggesting that Pt (and to a lesser extent Ni) bis(thiosemicarbazone)s may be better suited to optimization for therapeutic development than those based on Cu.
- |||||||||| elesclomol (STA-4783) / Madrigal Pharma, Cu(II)ATSM / Collaborative Medicinal Development
Journal: Copper's dual role: unravelling the link between copper homeostasis, cuproptosis, and cardiovascular diseases. (Pubmed Central) - May 6, 2024
Therapeutic interventions include copper chelators (e.g., ammonium tetrathiomolybdate), and oxidative phosphorylation inhibitors like elesclomol and copper ionophores (CuII(atsm), CuII(gtsm), and disulfiram). These interventions modulate intracellular copper, elevate NO, and reduce inflammatory cytokines, contributing to decreased cardiovascular diseases.
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Phase I clinical trial of 64 Cu-ATSM for malignant brain tumors. (Hall A; Poster Bd #: 351) - Apr 24, 2024 - Abstract #ASCO2024ASCO_3158;
The recommended dose for future trials is 99 MBq/kg. The initial efficacy outcomes obtained in this study warrant more clinical evaluation of this new treatment approach for brain tumors with no currently available treatment options.
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Journal: Patient-Derived Blood-Brain Barrier Model for Screening Copper Bis(thiosemicarbazone) Complexes as Potential Therapeutics in Alzheimer's Disease. (Pubmed Central) - Apr 4, 2024
To demonstrate its utility as a small molecule drug candidate screening platform, we investigated the effects of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuII(atsm)) and a library of metal bis(thiosemicarbazone) complexes?a class of compounds exhibiting antineuroinflammatory therapeutic potential in neurodegenerative disorders...Together, the presented model provides an effective and easily scalable in vitro BBB platform for screening AD drug candidates. Its improved translational potential makes it a valuable tool for advancing the development of metal-based compounds aimed at modulating neuroinflammation in AD.
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Preclinical, Journal: Evidence for decreased copper associated with demyelination in the corpus callosum of cuprizone treated mice. (Pubmed Central) - Jan 22, 2024
Treatment with the blood-brain barrier permeant copper compound CuII(atsm) increased brain copper levels and this was most pronounced in the soluble fraction of the corpus callosum...These results provide support for the involvement of decreased CNS copper availability in demyelination in the cuprizone model. Relevance to human demyelinating disease is discussed.
- |||||||||| ebselen (SPI-1005) / Sound Pharma, Cu(II)ATSM / Collaborative Medicinal Development, Tyzeka (telbivudine) / Novartis
A polytherapy approach demonstrates therapeutic efficacy in familial SOD1 ALS models (Event Halle, Messe Basel, Ground Floor) - Nov 7, 2023 - Abstract #ALSMND2023ALS_MND_476;
Furthermore, multiple different ratios of the CET treatment) were found to significantly improve survival compared to the highest concentration of CuATSM alone tested (0.5 mM) (p < 0.05), despite using less than half the concentration of CuATSM. In addition, CET treatment significantly reduced the percentage of cells containing inclusions compared to the highest concentration of CuATSM alone.
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Journal: Structural and Functional Diversity in Rigid Thiosemicarbazones with Extended Aromatic Frameworks: Microwave-Assisted Synthesis and Structural Investigations. (Pubmed Central) - May 14, 2023
The radiolabeling of these thiosemicarbazones with Cu was achieved under mild conditions for the first time: this cyclotron-available radioisotope of copper (t = 12.7 h; ?+ 17.8%; ?- 38.4%) is well-known for its proficiency in positron emission tomography (PET) imaging and for its theranostic potential, on the basis of the preclinical and clinical cancer research of established bis(thiosemicarbazones), such as the hypoxia tracer Cu-labeled copper(diacetyl-bis(N4-methylthiosemicarbazone)], [Cu]Cu(ATSM)...Tests showed that their IC levels are comparable to that of the clinical drug cis-platin, evaluated under similar conditions. The cellular internalizations of the selected ZnL-type compounds Zn(AN-Allyl), Zn(AA-Allyl), Zn(PH-Allyl), and Zn(PY-Allyl) were evaluated in living PC-3 cells using laser confocal fluorescent spectroscopy and these experiments showed exclusively cytoplasmic distributions.
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Journal: Ferroptotic stress facilitates smooth muscle cell dedifferentiation in arterial remodelling by disrupting mitochondrial homeostasis. (Pubmed Central) - Mar 2, 2023
Copper-diacetyl-bis-methylthiosemicarbazone (CuATSM), an agent used for clinical molecular imaging and that potently inhibits ferroptosis, prevented SMC phenotypic switch, neointimal formation and arterial inflammation in mice. These results indicate that pro-ferroptosis stress is likely to promote SMC phenotypic switch during neointimal formation and imply that inhibition of ferroptotic stress may be a promising translational approach to treat CVDs with SMC phenotype switch.
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Journal: Mechanisms of IRF2BPL-related disorders and identification of a potential therapeutic strategy. (Pubmed Central) - Dec 9, 2022
Moreover, flies harboring heterozygous truncations of the IRF2BPL ortholog (Pits) display progressive motor defects that are ameliorated by CuATSM treatment. Our findings provide insights into mechanisms involved in NEDAMSS and reveal a promising treatment for this severe disorder.
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Evaluation of Renal Blood Flow Using 64Cu-ATSM PET (W308, Orange County Convention Center, West Building) - Oct 15, 2022 - Abstract #KIDNEYWEEK2022KIDNEY_WEEK_3971;
The Bland-Altman analysis showed agreement with the RBF measured by ASL imaging and 64 Cu-ATSM imaging (Bias=-2.4, SD=24.9). Conclusion We report for the first time that 64 Cu-ATSM PET is useful for assessing RBF in healthy subjects and patients with various renal diseases, as well as ASL-MRI.
- |||||||||| Cu(II)ATSM / Collaborative Medicinal Development, Lexiscan (regadenoson) / GE Healthcare, Astellas, Gilead
Journal: Biomimetic Dp44mT-nanoparticles selectively induce apoptosis in Cu-loaded glioblastoma resulting in potent growth inhibition. (Pubmed Central) - Oct 7, 2022
Co-loading Dp44mT with regadenoson (Reg), that transiently opens the blood-brain-barrier (BBB), yielded biomimetic Ang-MNPs@(Dp44mT/Reg) NPs that actively targeted and traversed the BBB delivering Dp44mT specifically to GBM cells...Oral dosing of U87MG-Luc tumor bearing mice with diacetyl-bis(4-methylthiosemicarbazonato)-copperII (Cu(II)-ATSM), significantly enhanced Cu-level in GBM tumor...Targeting Ang-MNPs@(Dp44mT/Reg) NPs also down-regulated antiapoptotic Bcl-2, but up-regulated pro-apoptotic Bax and cleaved-caspase-3, demonstrating the involvement of the apoptotic pathway in GBM suppression. Notably, Ang-MNPs@(Dp44mT/Reg) showed negligible systemic drug toxicity in mice, further indicating therapeutic potential that could be adapted for other central nervous system disorders.
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Preclinical, Journal: In vivo detection of hydrogen sulfide in the brain of live mouse: application in neuroinflammation models. (Pubmed Central) - Oct 5, 2022
Notably, Ang-MNPs@(Dp44mT/Reg) showed negligible systemic drug toxicity in mice, further indicating therapeutic potential that could be adapted for other central nervous system disorders. Our biosensor can be readily utilized to study brain HS function in live animal models and shows great potential as a novel imaging agent for diagnosing brain diseases.
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Journal: Novel Anti-Neuroinflammatory Properties of a Thiosemicarbazone-Pyridylhydrazone Copper(II) Complex. (Pubmed Central) - Oct 1, 2022
Copper(II) complexes of bis(thiosemicarbazones) (Cu(gtsm) and Cu(atsm)) have broad therapeutic actions in preclinical models of neurodegeneration, with Cu(atsm) demonstrating beneficial outcomes on neuroinflammatory markers in vitro and in vivo...These findings demonstrate that CuL can induce anti-neuroinflammatory effects in vitro and provide selective benefit in vivo. The outcomes provide further support for the development of copper-based compounds to modulate neuroinflammation in brain diseases.
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Journal: Cells Overexpressing ALS-Associated SOD1 Variants Are Differentially Susceptible to CuATSM-Associated Toxicity. (Pubmed Central) - Aug 22, 2022
Determination of the no-observed-adverse-effect level and the LC suggest that CuATSM-associated toxicity is dependent on the amount of copper-depleted SOD1 available as well as the mutant's ability to bind copper. Our results suggest that the particular variant of SOD1 mutant is crucial in not only determining the level of efficacy achieved but also potential adverse events.
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Journal: Copper bis(thiosemicarbazone) complexes modulate P-glycoprotein expression and function in human brain microvascular endothelial cells. (Pubmed Central) - Jul 28, 2022
However, only the Cu-ATSM complex enhanced P-gp expression and this was mediated partly through activation (1.4-fold) of the extracellular signal-regulated kinase 1 and 2, an outcome that was significantly attenuated in the presence of an inhibitor of the mitogen activated protein kinase regulatory pathway. Our findings suggest that Cu (ATSM) and Cu (GTSM) have the potential to modulate the expression and function of P-gp at the BBB to impact brain drug delivery and clearance of Aβ.
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Preclinical study of tumor hypoxia by multimodal MRI and PET imaging in brain metastases: interest of 64Cu-ATSM? (Poster Area) - Jun 28, 2022 - Abstract #EACR2022EACR_1266;
In vitro studies confirmed an increase of expression of HIFs and their target genes (TUBB3; VEGF, GLUT-1; CCDN1; CA-IX) by hypoxia in H2030-BrM3 cells Conclusion These results confirm our previous studies showing the existence of a hypoxic microenvironment of BM from lung cancer with an inter-metastasis heterogeneity and add a new angle on redox metabolism with 64 Cu-ATSM uptake. This study underlines that 64 Cu-ATSM imaging could be complementary to other hypoxia imaging modalities ( 18 F-FMISO, MRI oxygen saturation) to target and guide RT depending on the presence or not of tumoral hypoxia
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Biomarker, Journal: Correlation of hypoxia PET tracer uptake with hypoxic radioresistance in cancer cells: PET biomarkers of resistance to stereotactic radiation therapy? (Pubmed Central) - Jun 15, 2022
This study highlights an important mismatch in pO thresholds between these PET tracers and other markers of hypoxia: tracer uptake only occurred at oxygen levels that were well below levels that induced radioresistance, pimonidazole uptake and HIF1α expression. Although their pO thresholds do not match the threshold for resistance to conventionally fractionated radiotherapy (pO 2.5-10 mmHg), their specificity for extreme hypoxia (pO ≪ 1 mmHg) suggests these PET tracers may be of particular use to predict outcomes in stereotactic radiation therapy where these maximally resistant cells play a key role in determining the biological effect.
- |||||||||| ebselen (SPI-1005) / Sound Pharma, Cu(II)ATSM / Collaborative Medicinal Development
Journal: A copper chaperone-mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis. (Pubmed Central) - Apr 19, 2022
Measuring dismutase activity via zymography and immunoblotting for disulfide formation showed that polytherapy promoted more effective maturation of transfected SOD1 variants beyond either compound alone. Our data suggest that a polytherapy of CuATSM and ebselen may merit more study as an effective method of treating SOD1-associated ALS.
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Journal: Photoactivatable bis(thiosemicarbazone) derivatives for copper-64 radiotracer synthesis. (Pubmed Central) - Mar 31, 2022
Then, irradiation with UV light in the presence of a protein of interest in a pH buffered aqueous solution afforded the Cu-labelled protein conjugates in decay-corrected radiochemical yield of 86.9 ± 1.0% via the transmetallation method and 35.3 ± 1.7% from the direct radiolabelling method. This study successfully demonstrates the viability of photochemically induced conjugation methods for the development of copper-based radiotracers for potential applications in diagnostic positron emission tomography (PET) imaging and targeted radionuclide therapy.
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Trial completion date, Trial primary completion date: ALS Treatment Extension Study (clinicaltrials.gov) - Feb 17, 2022
P1/2, N=28, Active, not recruiting,
Experiments in mouse embryonic fibroblasts and hippocampal cells reveal that lipophilicity as well as inherent RTA activity contribute to the potency of ferroptosis rescue, and that one compound (CuATSP) is almost 20-fold more potent than CuATSM and among the most potent ferroptosis inhibitors reported to date. Trial completion date: Dec 2020 --> Dec 2022 | Trial primary completion date: Dec 2020 --> Dec 2022
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A Study on Antiproliferation Activity of Constitutional Isomers of Hybrid Thiosemicarbazone-Alkylthiocarbamate Copper Complexes (Room 20BCD Theater 3 (San Diego Convention Center)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_14039;
For example, CuATSM and CuGTSM are undergoing clinical trials as a hypoxia imaging agent and a potential anticancer drug, respectively...Results from this study suggest small differences in physical structure can have a profound effect on the biological activity of copper complexes. The larger therapeutic window of KB-L4-16 suggests it could be a useful agent against cancer due to its greater activity and selectivity against A549 compared to IMR-90.
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Linkage Isomers of a Bis(alkylthiocarbamato) Copper Complex with Antiproliferation Activity (Room 7B (San Diego Convention Center)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_2040;
Copper bis(thiosemicarbazone) (CuBTSC) complexes such as CuATSM and CuGTSM have received significant attention as diagnostic and therapeutic agents...The isomers CuL555 and CuL465 possessed GI50 values of 0.10 and 0.14 µM for A549 and 1.4 and 0.78 µM for IMR-90, respectively. Comparison with related complexes suggests that the biological activity may be related to pendent functional groups that influence shape, polarity, and potential interactions with cellular targets.
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Clinical, Journal: Cu-ATSM Predicts Efficacy of Carbon Ion Radiotherapy Associated with Cellular Antioxidant Capacity. (Pubmed Central) - Dec 27, 2021
These data suggest that the cellular activity of Nrf2-driven antioxidant systems is a possible determinant of carbon ion RBE predictable by Cu-ATSM uptake. These new findings highlight the potential clinical utility of Cu-ATSM imaging to identify high RBE tumors that will benefit from carbon ion radiotherapy.
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