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Background: Myxoid liposarcoma is a histological subtype of liposarcoma particularly sensitive to trabectedin. In clinical use this drug does not cause cumulative toxicity, allowing prolonged treatment, generally until disease progression. No other effective therapies are available for trabectedin-resistant patients.Methods: Through repeated in vivo treatment in athymic nude mice, we have obtained a patient-derived xenograft with acquired resistance to trabectedin.Results: At basal level, the morphology of the resistant and sensitive models did not differ, in keeping with the finding that the transcriptional profiles of the resistant and sensitive tumours were very similar. After trabectedin treatment adipogenesis was induced in the parental xenograft but not in the resistant one, as assessed by pathological and molecular analysis. A defective transcription-coupled-nucleotide excision repair in the resistant tumour due to mutation of the UVSSA gene may be implicated in the mechanism of resistance.Conclusions: This is the first in vivo model of myxoid liposarcoma with acquired resistance to trabectedin. Although further studies are necessary to characterise the resistance mechanisms, this is a useful tool for studying new therapeutic strategies to overcome trabectedin resistance in patients. [ABSTRACT FROM AUTHOR]

Background: Lurbinectedin is a novel anticancer agent currently undergoing late-stage (Phase II /III) clinical evaluation in platinum-resistant ovarian, BRCA1/2-mutated breast and small-cell lung cancer. Lurbinectedin is structurally related to trabectedin and it inhibits active transcription and the DNA repair machinery in tumour cells.Methods: In this study we investigated whether lurbinectedin has the ability to modulate the inflammatory microenvironment and the viability of myeloid cells in tumour-bearing mice.Results: Administration of lurbinectedin significantly and selectively decreased the number of circulating monocytes and, in tumour tissues, that of macrophages and vessels. Similar findings were observed when a lurbinectedin-resistant tumour variant was used, indicating a direct effect of lurbinectedin on the tumour microenviroment. In vitro, lurbinectedin induced caspase-8-dependent apoptosis of human purified monocytes, whereas at low doses it significantly inhibited the production of inflammatory/growth factors (CCL2, CXCL8 and VEGF) and dramatically impaired monocyte adhesion and migration ability. These findings were supported by the strong inhibition of genes of the Rho-GTPase family in lurbinectedin-treated monocytes.Conclusions: The results illustrate that lurbinectedin affects at multiple levels the inflammatory microenvironment by acting on the viability and functional activity of mononuclear phagocytes. These peculiar effects, combined with its intrinsic activity against cancer cells, make lurbinectedin a compound of particular interest in oncology. [ABSTRACT FROM AUTHOR]

The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening, we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells. Accordingly, KPT-6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo. [ABSTRACT FROM AUTHOR]

Background: Juvenile myelomonocytic leukaemia (JMML) and chronic myelomonocytic leukaemia (CMML) are myelodysplastic myeloproliferative (MDS/MPN) neoplasms with unfavourable prognosis and without effective chemotherapy treatment. Trabectedin is a DNA minor groove binder acting as a modulator of transcription and interfering with DNA repair mechanisms; it causes selective depletion of cells of the myelomonocytic lineage. We hypothesised that trabectedin might have an antitumour effect on MDS/MPN.Methods: Malignant CD14+ monocytes and CD34+ haematopoietic progenitor cells were isolated from peripheral blood/bone marrow mononuclear cells. The inhibition of CFU-GM colonies and the apoptotic effect on CD14+ and CD34+ induced by trabectedin were evaluated. Trabectedin's effects were also investigated in vitro on THP-1, and in vitro and in vivo on MV-4-11 cell lines.Results: On CMML/JMML cells, obtained from 20 patients with CMML and 13 patients with JMML, trabectedin - at concentration pharmacologically reasonable, 1-5 nM - strongly induced apoptosis and inhibition of growth of haematopoietic progenitors (CFU-GM). In these leukaemic cells, trabectedin downregulated the expression of genes belonging to the Rho GTPases pathway (RAS superfamily) having a critical role in cell growth and cytoskeletal dynamics. Its selective activity on myelomonocytic malignant cells was confirmed also on in vitro THP-1 cell line and on in vitro and in vivo MV-4-11 cell line models.Conclusions: Trabectedin could be good candidate for clinical studies in JMML/CMML patients. [ABSTRACT FROM AUTHOR]

Innovative strategies that utilize nanoparticles (NPs) for a better delivery of drugs and to improve their therapeutic efficacy have been widely studied in many clinical fields, including oncology. To develop safe and reliable devices able to reach their therapeutic target, a hierarchical characterization of NP interactions with biological fluids, cells, and whole organisms is fundamental. Unfortunately, this aspect is often neglected and the development of standardized characterization methods would be of fundamental help to better elucidate the potentials of nanomaterials, even before the loading of the drugs. Here, we propose a multimodal in vitro/in vivo/ex vivo platform aimed at evaluating these interactions for the selection of the most promising NPs among a wide series of materials. To set the system, we used non-degradable fluorescent poly(methyl-methacrylate) NPs of different sizes (50, 100, and 200 nm) and surface charges (positive and negative). First we studied NP stability in biological fluids. Then, we evaluated NP interaction with two cell lines of triple-negative breast cancer (TNBC), 4T1, and MDA-MB231.1833, respectively. We found that NPs internalize in TNBC cells depending on their physico-chemical properties without toxic effects. Finally, we studied NP biodistribution in terms of tissue migration and progressive clearance in breast-cancer bearing mice. The use of highly stable poly(methyl-methacrylate) NPs enabled us to track them for a long time in cells and animals. The application of this platform to other nanomaterials could provide innovative suggestions for the development of a systematic method of characterization to select the most reliable nanodrug candidates for biomedical applications. [ABSTRACT FROM AUTHOR]

Taxanes, including docetaxel (DOCE), are severely neurotoxic, causing disabling peripheral neuropathy. Co-treatment with neuroprotective agents has been proposed to prevent or reverse this. Besides its hemopoietic effects, erythropoietin (EPO) has neuroprotective and neurotrophic properties and when administered systemically it has a wide range of neuroprotective action in animal models of nervous system damage, including cisplatin-induced peripheral neurotoxicity. The present study investigated the effects of EPO on chemotherapy-induced peripheral neurotoxicity (CINP) by DOCE in vivo and whether it interfered with tumor growth or antitumor activity. Female Fischer rats bearing 13762 mammary carcinoma were randomly divided into four groups: untreated, treated with EPO, DOCE, or DOCE + EPO. DOCE was given once a week (5 mg/kg, i.v.) and EPO three times a week (50 μg/kg i.p.), for 4 weeks. Three other groups of rats without tumors were left untreated or given DOCE or DOCE + EPO. The rats were observed for 4 weeks after treatment. CINP and neuroprotection were evaluated by measuring nociception, electrophysiological, and biochemical parameters. EPO protected against CINP, and tumor growth in EPO-treated rats was the same as in controls. EPO significantly improved the thermal threshold, tail nerve conduction velocity, and intra-epidermal nerve fiber density. These benefits lasted through the follow-up period and EPO speeded-up spontaneous recovery after treatment withdrawal. EPO did not impair DOCE antitumor activity. Since CINP induced by DOCE reproduces the clinical utility of taxane in humans, the findings reported might provide a basis for investigating EPO as a neuroprotective agent in patients receiving therapy with DOCE. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]