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Trabectedin

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https://www.readbyqxmd.com/read/28095394/loss-of-cul4a-expression-is-underlying-cisplatin-hypersensitivity-in-colorectal-carcinoma-cells-with-acquired-trabectedin-resistance
#1
B Englinger, M Mair, W Miklos, C Pirker, T Mohr, S van Schoonhoven, D Lötsch, W Körner, F Ferk, S Knasmüller, P Heffeter, B K Keppler, M Grusch, W Berger
BACKGROUND: Colorectal carcinoma (CRC) is the third most common cancer worldwide. Platinum-based anticancer compounds still constitute one mainstay of systemic CRC treatment despite limitations due to adverse effects and resistance development. Trabectedin has shown promising antitumor effects in CRC, however, again resistance development may occur. In this study, we aimed to develop strategies to circumvent or even exploit acquired trabectedin resistance in novel CRC treatment regimens...
January 17, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28072764/antitumour-activity-of-trabectedin-in-myelodysplastic-myeloproliferative-neoplasms
#2
Michela Romano, Matteo Giovanni Della Porta, Anna Gallì, Nicolò Panini, Simonetta Andrea Licandro, Ezia Bello, Ilaria Craparotta, Vittorio Rosti, Elisa Bonetti, Richard Tancredi, Marianna Rossi, Laura Mannarino, Sergio Marchini, Luca Porcu, Carlos M Galmarini, Alberto Zambelli, Marco Zecca, Franco Locatelli, Mario Cazzola, Andrea Biondi, Alessandro Rambaldi, Paola Allavena, Eugenio Erba, Maurizio D'Incalci
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...
January 10, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/27958379/a-systems-biology-approach-to-investigate-the-mechanism-of-action-of-trabectedin-in-a-model-of-myelomonocytic-leukemia
#3
L Mannarino, L Paracchini, I Craparotta, M Romano, S Marchini, R Gatta, E Erba, L Clivio, C Romualdi, M D'Incalci, L Beltrame, L Pattini
This study was designed to investigate the mode of action of trabectedin in myelomonocytic leukemia cells by applying systems biology approaches to mine gene expression profiling data and pharmacological assessment of the cellular effects. Significant enrichment was found in regulons of target genes inferred for specific transcription factors, among which MAFB was the most upregulated after treatment and was central in the transcriptional network likely to be relevant for the specific therapeutic effects of trabectedin against myelomonocytic cells...
December 13, 2016: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/27918201/the-importance-of-treating-by-histological-subtype-in-advanced-soft-tissue-sarcoma
#4
Javier Martín Broto, Axel Le Cesne, Peter Reichardt
While surgical resection (±radiotherapy) is standard treatment for localized soft tissue sarcomas (STS), chemotherapy is the mainstay for managing locally advanced and metastatic disease. Expanding knowledge of the biologies and sensitivities of STS histotypes, in conjunction with results from a growing collection of retrospective reviews and prospective randomized studies, point to the importance of treating in consideration of histological subtype. Doxorubicin ± ifosfamide continues to be standard first-line therapy for most STS subtypes...
January 2017: Future Oncology
https://www.readbyqxmd.com/read/27902465/gene-and-microrna-modulation-upon-trabectedin-treatment-in-a-human-intrahepatic-cholangiocarcinoma-paired-patient-derived-xenograft-and-cell-line
#5
Caterina Peraldo Neia, Giuliana Cavalloni, Giovanna Chiorino, Paola Ostano, Massimo Aglietta, Francesco Leone
Intrahepatic cholangiocarcinoma (ICC) is an aggressive and lethal malignancy with limited therapeutic options. Trabectedin has a high antitumor activity in preclinical models of biliary tract carcinoma (BTC), being a promising alternative treatment. Here, we studied the effect of trabectedin at transcriptomic level on an ICC patient derived xenograft (PDX) and on the derived cell line, MT-CHC01. Further, putative targets of trabectedin were explored in the in vitro model. In vitro, trabectedin inhibited genes involved in protein modification, neurogenesis, migration, and motility; it induced the expression of genes involved in keratinization, tissues development, and apoptotic processes...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27895579/pharmacodynamic-modeling-of-cell-cycle-effects-for-gemcitabine-and-trabectedin-combinations-in-pancreatic-cancer-cells
#6
Xin Miao, Gilbert Koch, Sihem Ait-Oudhia, Robert M Straubinger, William J Jusko
Combinations of gemcitabine and trabectedin exert modest synergistic cytotoxic effects on two pancreatic cancer cell lines. Here, systems pharmacodynamic (PD) models that integrate cellular response data and extend a prototype model framework were developed to characterize dynamic changes in cell cycle phases of cancer cell subpopulations in response to gemcitabine and trabectedin as single agents and in combination. Extensive experimental data were obtained for two pancreatic cancer cell lines (MiaPaCa-2 and BxPC-3), including cell proliferation rates over 0-120 h of drug exposure, and the fraction of cells in different cell cycle phases or apoptosis...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27843394/trabectedin-followed-by-irinotecan-can-stabilize-disease-in-advanced-translocation-positive-sarcomas-with-acceptable-toxicity
#7
J Herzog, F von Klot-Heydenfeldt, S Jabar, A Ranft, C Rossig, U Dirksen, J Van den Brande, M D'Incalci, I von Luettichau, P J Grohar, W E Berdel, St Burdach
Background. Preclinical data indicate that trabectedin followed by irinotecan has strong synergistic effects on Ewing sarcoma. This is presumably due to hypersensitization of the tumor cells to the camptothecin as an effect of trabectedin in addition to synergistic suppression of EWS-FLI1 downstream targets. A strong effect was also reported in a human rhabdomyosarcoma xenograft. Procedure. Twelve patients with end-stage refractory translocation-positive sarcomas were treated with trabectedin followed by irinotecan within a compassionate use program...
2016: Sarcoma
https://www.readbyqxmd.com/read/27797624/factors-to-consider-and-questions-to-ask-in-the-management-of-recurrent-ovarian-cancer-a-focus-on-the-role-of-trabectedin-pegylated-liposomal-doxorubicin
#8
Antonio González-Martín, Andreas du Bois
Given the heterogeneity of both disease and clinical situation, recurrent ovarian cancer continues to be a considerable therapeutic challenge. While newer treatment options have led to improved clinical outcomes, treatment selection has become more complex. An increasing number of clinical questions must be addressed before the optimal strategy and sequence can be decided for an individual patient. Areas covered: In this review, evidence is examined to guide decision-making for the main treatment options of surgery, chemotherapy and targeted therapy...
November 2016: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/27797622/experience-with-trabectedin-pegylated-liposomal-doxorubicin-for-recurrent-platinum-sensitive-ovarian-cancer-unsuited-to-platinum-rechallenge
#9
Nicoletta Colombo, Anne-Claire Hardy-Bessard, Gabriella Ferrandina, Christian Marth, Ignacio Romero
As most patients with ovarian cancer experience multiple remissions and relapses, oncologists must prepare ahead for long-term treatment. While platinum-based regimens are standard of care for platinum-sensitive recurrence, there are circumstances in which platinum rechallenge is not the best approach. These situations include patients with limited sensitivity to platinum; patients with residual toxicity from previous platinum therapy; and patients at risk of developing hypersensitivity reactions. An alternative regimen for these patients is the non-platinum combination of trabectedin + pegylated liposomal doxorubicin (PLD)...
November 2016: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/27782906/trabectedin-in-advanced-desmoplastic-round-cell-tumors-a-retrospective-single-center-series
#10
Benjamin Verret, Charles Honore, Sarah Dumont, Philippe Terrier, Julien Adam, Andrea Cavalcanti, Isabelle Sourrouille, Guillaume Klausner, Marion Ahlenc-Gelas, Nicolas Kiavue, Gabriella Domitrescu, Lamiae El Amarti, Olivier Mir, Axel Le Cesne
Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive malignancy that occurs with unpredictable chemosensitivity and limited treatment options in the advanced setting. Prognosis is poor, and exploring new treatment options for such diseases is difficult because of its rarity. Clinical activity of trabectedin for advanced DSRCT was scarcely reported in the literature. Here, we report a series of six patients treated with trabectedin for an unresectable DSRCT. After receiving trabectedin, two patients had stable disease with a time to progression of 3 and 3...
January 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/27775259/major-clinical-research-advances-in-gynecologic-cancer-in-2015
#11
REVIEW
Dong Hoon Suh, Miseon Kim, Hak Jae Kim, Kyung Hun Lee, Jae Weon Kim
In 2015, fourteen topics were selected as major research advances in gynecologic oncology. For ovarian cancer, high-level evidence for annual screening with multimodal strategy which could reduce ovarian cancer deaths was reported. The best preventive strategies with current status of evidence level were also summarized. Final report of chemotherapy or upfront surgery (CHORUS) trial of neoadjuvant chemotherapy in advanced stage ovarian cancer and individualized therapy based on gene characteristics followed...
November 2016: Journal of Gynecologic Oncology
https://www.readbyqxmd.com/read/27773933/targeting-transcription-coupled-nucleotide-excision-repair-overcomes-resistance-in-chronic-lymphocytic-leukemia
#12
G Lohmann, E Vasyutina, J Bloehdorn, N Reinart, J I Schneider, V Babu, G Knittel, G Crispatzu, P Mayer, C Prinz, J K Muenzner, B Biersack, D G Efremov, L Chessa, C D Herling, S Stilgenbauer, M Hallek, R Schobert, H C Reinhardt, B Schumacher, M Herling
Treatment resistance becomes a challenge at some point in the course of most patients with chronic lymphocytic leukemia (CLL). This applies to fludarabine-based regimens, and is also an increasing concern in the era of more targeted therapies. As cells with low-replicative activity rely on repair that triggers checkpoint-independent noncanonical pathways, we reasoned that targeting the nucleotide excision repair (NER) reaction addresses a vulnerability of CLL and might even synergize with fludarabine, which blocks the NER gap-filling step...
December 2, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27710871/trabectedin-as-a-chemotherapy-option-for-patients-with-brca-deficiency
#13
REVIEW
Bradley J Monk, Domenica Lorusso, Antoine Italiano, Stan B Kaye, Miguel Aracil, Adnan Tanović, Maurizio D'Incalci
Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin...
November 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/27698882/metastatic-extraskeletal-ewing-s-sarcoma-treated-with-trabectedin-a-case-report
#14
Jorge Hernando-Cubero, Pilar Sanz-Moncasi, Alba Hernández-García, Isabel Pajares-Bernard, Javier Martínez-Trufero
The Ewing's sarcoma family of tumors (ESFT) comprises a number of rare malignant tumors. Standard first-line treatment for patients with these tumors includes chemotherapy with a five-drug regimen of vincristine, doxorubicin (Adriamycin(®)) and cyclophosphamide, alternating with ifosfamide and etoposide (VAC/IE). In cases of inadequate response, there are a number of second-line regimens available. However, further treatment options are required for those patients with disease unresponsive to standard treatment...
October 2016: Oncology Letters
https://www.readbyqxmd.com/read/27697767/lurbinectedin-inactivates-the-ewing-sarcoma-oncoprotein-ews-fli1-by-redistributing-it-within-the-nucleus
#15
Matt L Harlow, Nichole Maloney, Joseph Roland, María José Guillén-Navarro, Matthew K Easton, Susan M Kitchen-Goosen, Elissa A Boguslawski, Zachary B Madaj, Ben K Johnson, Megan J Bowman, Maurizio D'Incalci, Mary E Winn, Lisa Turner, Galen Hostetter, Carlos M Galmarini, Pablo M Aviles, Patrick J Grohar
There is a great need to develop novel approaches to target oncogenic transcription factors with small molecules. Ewing sarcoma is emblematic of this need, as it depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. We have previously shown that the small molecule trabectedin interferes with EWS-FLI1. Here we report important mechanistic advances and a second-generation inhibitor to provide insight into the therapeutic targeting of EWS-FLI1. We discovered that trabectedin functionally inactivated EWS-FLI1 by redistributing the protein within the nucleus to the nucleolus...
October 3, 2016: Cancer Research
https://www.readbyqxmd.com/read/27677742/b-cells-and-macrophages-pursue-a-common-path-toward-the-development-and-progression-of-chronic-lymphocytic-leukemia
#16
REVIEW
G Galletti, F Caligaris-Cappio, M T S Bertilaccio
The development and progression of chronic B-cell tumors depend on a complex microenvironmental network of cells that include monocyte-derived macrophages. In chronic lymphocytic leukemia (CLL) the survival of malignant cells is supported in vitro by nurse-like cells, which differentiate from CD14(+) monocytes and have been identified as tumor-associated macrophages (TAMs). The role of the monocyte/macrophage lineage in CLL has been extensively studied in vitro, but only recently has been investigated in in vivo models...
December 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27623022/tetrahydroisoquinolines-in-therapeutics-a-patent-review-2010-2015
#17
Inder Pal Singh, Purvi Shah
1,2,3,4-Tetrahydroisoquinoline (THIQ) is one of the 'privileged scaffolds', commonly found in nature. Initially, this class of compounds was known for its neurotoxicity. Later on, 1-methyl-1,2,3,4-tetrahydroisoquinoline was proved as an endogeneous Parkinsonism-preventing agent in mammals. The fused THIQs have been studied for their role as anticancer antibiotics. The US FDA approval of the trabectedin for the treatment of soft tissue sarcomas, is a milestone in the anticancer drug discovery. Areas covered: This review covers the patents on various therapeutic activities of the THIQ derivatives in the years between 2010 and 2015...
January 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/27615729/efficacy-of-trabectedin-for-the-treatment-of-liposarcoma
#18
Ritika Zijoo, Margaret von Mehren
INTRODUCTION: Trabectedin (ET-743) is a synthetic marine derived alkylating agent, extracted originally from a Caribbean Sea sponge. It is approved for the treatment of Soft Tissue sarcomas (STS) in Europe and recently by the FDA for liposarcomas and leiomyosarcomas. AREAS COVERED: Trabectedin has multiple mechanisms of action, including one targeting the FUS-CHOP oncogene in Myxoid/Round cell Liposarcomas. Numerous Phase I, II and III clinical trials have been conducted with Trabectedin...
October 2016: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/27574465/advanced-soft-tissue-sarcoma-and-treatment-options-critical-appraisal-of-trabectedin
#19
REVIEW
Ingrid M E Desar, Anastasia Constantinidou, Suzanne E J Kaal, Robin L Jones, Winette T A van der Graaf
Soft-tissue sarcomas (STS) are a heterogeneous group of rare solid tumors of mesenchymal origin. This paper reviews the current status of systemic treatment in advanced and metastatic soft tissue sarcomas, with an emphasis on trabectedin. Trabectedin is a unique type of chemotherapeutic agent with multiple potential mechanisms of action. We discuss the putative mechanisms, as well as the toxicity and administration schedules of trabectedin, followed by its efficacy in first-line systemic therapy and beyond first-line systemic therapy...
2016: Cancer Management and Research
https://www.readbyqxmd.com/read/27561088/association-of-the-germline-brca2-missense-variation-glu2663lys-with-high-sensitivity-to-trabectedin-based-treatment-in-soft-tissue-sarcoma
#20
Gianmaria Miolo, Alessandra Viel, Vincenzo Canzonieri, Tania Baresic, Angela Buonadonna, Davide Adriano Santeufemia, Della Puppa Lara, Giuseppe Corona
We report an interesting clinical case of a patient carrying a specific BRCA2 germline variant affected by bone and hepatic metastases from a high grade uterine stromal sarcoma who obtained a complete metabolic response after only 3 cycles of trabectedin treatment (1.5 mg/m(2) given intravenously over 24 hours every 21 days). Molecular investigations linked this outstanding positive pharmacological response with the loss of heterozygosity (LOH) of the mutated BRCA2 gene. These data support the hypothesis that the response to trabectedin may be positively conditioned by the different DNA repair defects present in the neoplasm and that BRCAness tumor genotype is important in determining the efficacy of trabectedin-based chemotherapy...
October 2, 2016: Cancer Biology & Therapy
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