Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models

Belgiovine, Cristina; Bello, Ezia; Liguori, Manuela; Craparotta, Ilaria; Mannarino, Laura; Paracchini, Lara; Beltrame, Luca; Marchini, Sergio; Galmarini, Carlos M.; Mantovani, Alberto; Frapolli, Roberta; Allavena, Paola; D’Incalci, Maurizio

doi:10.1038/bjc.2017.205

Cited by 130 publications

(120 citation statements)

References 44 publications

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“…Not only do hTAMs contribute to avoiding immunosuppression, but they also participate in other tumor-supporting functions, such as neovascularization and the spread of tumor cells. Several previous works have analyzed the role of TRB and LUR in macrophage function [ 31 , 38 , 40 , 44 , 45 , 46 , 47 ]; however, after analyzing hMFs from monocyte-derived blood cells from nearly 200 different donors, we were surprised by the fact that ca. a quarter of hMFs were extremely sensitive to these drugs at the therapeutic doses used.…”

Section: Discussionmentioning

confidence: 96%

“…This effect was more evident in both M1 and M2 hMF-R cells and was paralleled by the expression of HIF-1α transcription-dependent genes, such as PFKFB3 and the genes encoding for PD-L1 and PD-L2. The ability of TRB to interfere in the transcription machinery had been previously described [ 2 , 8 , 46 , 53 ]. However, regardless of the hMF-S or hMF-R phenotype, all hMFs exhibited a time-dependent dephosphorylation of RNA polymerase II, suggesting a rapid action of TRB at the transcription level, but also that this effect is per se unable to promote hMF cell death [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

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Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights

Povo‐Retana

Mojena

Stremtan

et al. 2020

Cancers

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Background: Tumor-associated macrophages (TAMs) play a crucial role in suppressing the immunosurveillance function of the immune system that prevents tumor growth. Indeed, macrophages can also be targeted by different chemotherapeutic agents improving the action over immune checkpoints to fight cancer. Here we describe the effect of trabectedin and lurbinectedin on human macrophage cell viability and function. Methods: Blood monocytes from healthy donors were differentiated into macrophages and exposed to different stimuli promoting functional polarization and differentiation into tumor-associated macrophages. Cells were challenged with the chemotherapeutic drugs and the effects on cell viability and function were analyzed. Results: Human macrophages exhibit at least two different profiles in response to these drugs. One-fourth of the blood donors assayed (164 individuals) were extremely sensitive to trabectedin and lurbinectedin, which promoted apoptotic cell death. Macrophages from other individuals retained viability but responded to the drugs increasing reactive oxygen production and showing a rapid intracellular calcium rise and a loss of mitochondrial oxygen consumption. Cell-membrane exposure of programmed-death ligand 1 (PD-L1) significantly decreased after treatment with therapeutic doses of these drugs, including changes in the gene expression profile of hypoxia-inducible factor 1 alpha (HIF-1α)-dependent genes, among other. Conclusions: The results provide evidence of additional onco-therapeutic actions for these drugs.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights

Povo‐Retana

Mojena

Stremtan

et al. 2020

Cancers

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“…3). Recently, TAMs were selectively targeted by the anticancer drugs trabectedin (Yondelis®) and lurbinectedin (Zepsyre®), respectively, inducing caspase-8-mediated apoptosis [57]. These drugs affect both (1) the primary tumor growth by binding to DNA, inducing double strand breaks, preventing DNA repair, and inhibiting the active transcription through structural changes of DNA and degradation of RNA polymerase II through the ubiquitin-proteasome pathway [58], and (2) the TME via modulation of the cytokine expression in the cancer cells through regulation of their transcription and depletion of TAMs by inducing overexpression of TRAIL receptors, their recruitment in lipid rafts, ligand-independent activation, and subsequent caspase-8-mediated apoptosis.…”

Section: The Role Of Caspase-8 In Macrophage Differentiationmentioning

confidence: 99%

The role of caspase-8 in the tumor microenvironment of ovarian cancer

Kostova

Mandal

Becker

et al. 2020

Cancer Metastasis Rev

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Caspase-8 is an aspartate-specific cysteine protease, which is best known for its apoptotic functions. Caspase-8 is placed at central nodes of multiple signal pathways, regulating not only the cell cycle but also the invasive and metastatic cell behavior, the immune cell homeostasis and cytokine production, which are the two major components of the tumor microenvironment (TME). Ovarian cancer often has dysregulated caspase-8 expression, leading to imbalance between its apoptotic and non-apoptotic functions within the tumor and the surrounding milieu. The downregulation of caspase-8 in ovarian cancer seems to be linked to high aggressiveness with chronic inflammation, immunoediting, and immune resistance. Caspase-8 plays therefore an essential role not only in the primary tumor cells but also in the TME by regulating the immune response, B and T lymphocyte activation, and macrophage differentiation and polarization. The switch between M1 and M2 macrophages is possibly associated with changes in the caspase-8 expression. In this review, we are discussing the non-apoptotic functions of caspase-8, highlighting this protein as a modulator of the immune response and the cytokine composition in the TME. Considering the low survival rate among ovarian cancer patients, it is urgently necessary to develop new therapeutic strategies to optimize the response to the standard treatment. The TME is highly heterogenous and provides a variety of opportunities for new drug targets. Given the variety of roles of caspase-8 in the TME, we should focus on this protein in the development of new therapeutic strategies against the TME of ovarian cancer.

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“…PM01183 inhibits active transcription in tumor cells through binding to CG-rich sequences, irreversible stalling and degradation of elongating RNA polymerase II on the DNA template, generation of XPF-dependent single- and double-strand DNA breaks, and subsequent apoptosis [ 2 ]. PM01183 also has a selective apoptotic-inducing effect on mononuclear phagocytes, and inhibits the production of inflammatory cytokines by these cells [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study

et al. 2017

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BackgroundLurbinectedin (PM01183) has synergistic antitumor activity when combined with doxorubicin in mice with xenografted tumors. This phase I trial determined the recommended dose (RD) of doxorubicin (bolus) and PM01183 (1-h intravenous infusion) on day 1 every 3 weeks (q3wk), and obtained preliminary evidence of antitumor activity for this combination in small-cell lung cancer (SCLC).Patients and methodsPatients with advanced solid tumors received doxorubicin and PM01183 following a standard dose escalation design and expansion at the RD. Twenty-seven patients had relapsed SCLC: 12 with sensitive disease (platinum-free interval ≥90 days) and 15 with resistant disease (platinum-free interval <90 days).ResultsDoxorubicin 50 mg/m2 and PM01183 4.0 mg flat dose was the RD. In relapsed SCLC, treatment tolerance at the RD was manageable. Transient and reversible myelosuppression (including neutropenia, thrombocytopenia, and febrile neutropenia) was the main toxicity, managed with dose adjustment and colony-stimulating factors. Fatigue (79%), nausea/vomiting (58%), decreased appetite (53%), mucositis (53%), alopecia (42%), diarrhea/constipation (42%), and asymptomatic creatinine (68%) and transaminase increases (alanine aminotransferase 42%; aspartate aminotransferase 32%) were common, and mostly mild or moderate. Complete (n = 2, 8%) and partial response (n = 13, 50%) occurred in relapsed SCLC, mostly at the RD. Response rates at second line were 91.7% in sensitive disease [median progression-free survival (PFS)=5.8 months] and 33.3% in resistant disease (median PFS = 3.5 months). At third line, response rate was 20.0% (median PFS = 1.2 months), all in resistant disease.ConclusionDoxorubicin 50 mg/m2 and PM01183 4.0 mg flat dose on day 1 q3wk has shown remarkable activity, mainly in second line, with manageable tolerance in relapsed SCLC, leading to further evaluation of this combination within an ongoing phase III trial.

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Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models

Cited by 130 publications

References 44 publications

Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights

Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights

The role of caspase-8 in the tumor microenvironment of ovarian cancer

Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study

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