Lurbinectedin: First Approval

Markham, Anthony

doi:10.1007/s40265-020-01374-0

Cited by 55 publications

(42 citation statements)

References 17 publications

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“…Nonetheless, plitidepsin (Aplidin R ), also known as dehydrodidemnin B, isolated from Aplidium albicans, has been recently approved by the ATGA (Australian Therapeutics Goods Administration) for treatment of hematological cancers in association with dexamethasone 3 (Sakai et al, 1996;Alonso-Álvarez et al, 2017;Therapeutic Goods Administration, 2020), and is now under clinical trials for COVID-19 (White et al, 2021). Additionally, trabectedin, an alkaloid isolated from Ecteinascidia turbinata, and its synthetic derivative, lurbinectedin, make up for the three tunicate-sourced anticancer drugs approved for clinical use 4 1 https://oceanservice.noaa.gov/facts/ocean-species.html 2 www.midwestern.edu/departments/marinepharmacology.xml 3 www.ebs.tga.gov.au 4 www.fda.gov/drugs (Rinehart et al, 1990;Markham, 2020). Both didemnin B and trabectedin are recognized as products of the metabolism of symbiotic bacteria, emphasizing the importance of the associated microbiota on the chemical versatility previously attributed to tunicates (Tsukimoto et al, 2011;Xu et al, 2012;Schofield et al, 2015;Bauermeister et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

et al. 2021

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Marine natural products have emerged as an important source for drug development, notably in the field of anticancer therapy. Still, the limited effectiveness of current therapies for central nervous system tumors indicates the need to identify new therapeutic targets and also novel pharmacological agents. In this context, proteasome inhibitors are appearing as a promising new treatment for these diseases. Herein, cytotoxic extracts produced by four marine bacteria recovered from the Brazilian endemic ascidian Euherdmania sp. were screened to evaluate their potential as proteasome inhibitors. The extract from marine Streptomyces sp. BRA-346 was selected for further investigation due to the potent proteasome inhibitory activity it displayed. Bioassay-guided fractionation led to an enriched fraction (proteasome inhibition IC50 = 45 ng/mL), in which the presence of dihydroeponemycin (DHE), known for its proteasome inhibitory effect, and related compounds were annotated by mass spectrometry and further confirmed by comparison with DHE standard. Both DHE and the epoxyketone-containing fraction were evaluated in glioma cell lines, displaying high cytotoxicity in HOG and T98G cells (GI50 of 1.6 and 1.7 ng/mL for DHE, and 17.6 and 28.2 ng/mL for the BRA-346 fraction, respectively). Additional studies showed that the epoxyketone-containing fraction (at GI50 levels) led to an accumulation of ubiquitinated proteins and up-regulation of genes related to ER-stress response, suggesting treated cells are under proteasome inhibition. DHE induced similar effects in treated cells but at concentrations 25 times its GI50, suggesting that the other epoxyketone compounds in the bacteria extract derived fraction may contribute to enhance proteasome inhibition and further cellular effects in glioma cells. These findings revealed the molecular pathways modulated by this class of compounds in glioma cells and, moreover, reinforced the potential of this marine bacteria in producing a cocktail of structurally-related compounds that affect the viability of glioma cells.

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Section: Introductionmentioning

confidence: 99%

Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

et al. 2021

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“…Lurbinectedin (Zepzelca™), also known as PM01183, is a highly selective inhibitor of oncogenic transcription, with in vitro activity in the low nanomolar range [1]. Lurbinectedin was approved in June 2020 by the U.S. Food and Drug Administration (FDA) to treat adult patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy [2]. Lurbinectedin inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis [3].…”

Section: Introductionmentioning

confidence: 99%

Effect of lurbinectedin on the QTc interval in patients with advanced solid tumors: an exposure–response analysis

Fudio

Tabernero

Subbiah

et al. 2020

Cancer Chemother Pharmacol

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Purpose This study assessed the effect of lurbinectedin, a highly selective inhibitor of oncogenic transcription, on the change from baseline in Fridericia’s corrected QT interval (∆QTcF) and electrocardiography (ECG) morphological patterns, and lurbinectedin concentration–∆QTcF (C-∆QTcF) relationship, in patients with advanced solid tumors. Methods Patients with QTcF ≤ 500 ms, QRS < 110 ms, PR < 200 ms, and normal cardiac conduction and function received lurbinectedin 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks. ECGs were collected in triplicate via 12-lead digital recorder in treatment cycle 1 and 2 and analyzed centrally. ECG collection time-matched blood samples were drawn to measure lurbinectedin plasma concentration. No effect on QTc interval was concluded if the upper bound (UB) of the least square (LS) mean two-sided 90% confidence intervals (CI) for ΔQTcF at each time point was < 20 ms. C-∆QTcF was explored using linear mixed-effects analysis. Results A total of 1707 ECGs were collected from 39 patients (females, 22; median age, 56 years). The largest UB of the 90% CI of ΔQTcF was 9.6 ms, thus lower than the more conservative 10 ms threshold established at the ICH E14 guideline for QT studies in healthy volunteers. C-∆QTcF was better fit by an effect compartment model, and the 90% CI of predicted ΔQTcF at Cmax was 7.81 ms, also below the 10 ms threshold of clinical concern. Conclusions ECG parameters and C-ΔQTcF modelling in this prospective study indicate that lurbinectedin was not associated with a clinically relevant effect on cardiac repolarization.

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“…Lurbinectedin is an inhibitor of RNA polymerase II, an enzyme commonly hyperactivated in SCLC, and induces DNA breaks in cells that result in apoptosis ( Markham, 2020 ). The drug covalently binds to central guanine in trinucleotide triplets in the minor groove of DNA, forming adducts capable of inducing DNA double-strand breaks ( Markham, 2020 ). It may also induce immunogenic cell death and increase anti-tumor immunity.…”

Section: Lurbinectidin: a Novel Agent In Clinical Use In Sclcmentioning

confidence: 99%

“…It may also induce immunogenic cell death and increase anti-tumor immunity. Lurbinectedin also has an impact on the tumor microenvironment as it is associated with a reduction in tumor associated macrophages ( Markham, 2020 ). Lurbinectedin has been shown to downregulate ASCL1 and thus decrease the rapid growth rate that is characteristic of SCLC cells ( Markham, 2020 ).…”

Section: Lurbinectidin: a Novel Agent In Clinical Use In Sclcmentioning

confidence: 99%

Absence of Biomarker-Driven Treatment Options in Small Cell Lung Cancer, and Selected Preclinical Candidates for Next Generation Combination Therapies

et al. 2021

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Lung cancer is the second most common cancer in the United States, and small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. In SCLC, more than other malignancies, the standard of care is based on clinical demonstration of efficacy, and less on a mechanistic understanding of why certain treatments work better than others. This is in large part due to the virulence of the disease, and lack of clinically or biologically relevant biomarkers beyond routine histopathology. While first line therapies work in the majority of patients with extensive stage disease, development of resistance is nearly universal. Although neuroendocrine features, Rb and p53 mutations are common, the current lack of actionable biomarkers has made it difficult to develop more effective treatments. Some progress has been made with the application of immune checkpoint inhibitors. There are new agents, such as lurbinectedin, that have completed late-phase clinical testing while other agents are still in the pre-clinical phase. ONC201/TIC10 is an imipridone with strong in vivo and in vitro antitumor properties and activity against neuroendocrine tumors in phase 1 clinical testing. ONC201 activates the cellular integrated stress response and induces the TRAIL pro-apoptotic pathway. Combination treatment of lurbinectedin with ONC201 are currently being investigated in preclinical studies that may facilitate translation into clinical trials for SCLC patients.

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Lurbinectedin: First Approval

Cited by 55 publications

References 17 publications

Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

Effect of lurbinectedin on the QTc interval in patients with advanced solid tumors: an exposure–response analysis

Absence of Biomarker-Driven Treatment Options in Small Cell Lung Cancer, and Selected Preclinical Candidates for Next Generation Combination Therapies

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