Cristiana Stefan

Clinical impact of trabectedin (ecteinascidin-743) in advanced/metastatic soft tissue sarcoma

Background: Patients with advanced or metastatic non-gastrointestinal stromal tumour soft tissue sarcoma (STS) whose disease progresses during or after chemotherapy with doxorubicin or ifosfamide have few options and very limited life expectancy. In this setting, the DNA and transcription interacting agent trabectedin (ecteinascidin-743), isolated originally from the tunicate Ecteinascidia turbinata, has encouraging activity and is now approved in the European Union. Objective: To review evidence for the efficacy of trabectedin in STSs. Methods: This review includes material known to the authors through preclinical and clinical work with trabectedin, and information from relevant papers and abstracts. Results: Pooled analysis of Phase II studies suggests that around 50% of STS patients, failing conventional chemotherapy, experienced long lasting tumour control (either objective response or stabilization of disease) when treated with trabectedin. Twenty-nine per cent of patients were alive at 2 years, and median overall survival was 10.3 months. Leiomyosarcomas and liposarcomas appear particularly sensitive to the drug. In myxoid and round-cell liposarcomas trabectedin seems exceptionally active. A link between specific translocations underlying this disease and the drugs mechanism of action is being explored. Trabectedin is also active in synovial, ewing sarcoma and other translocation-related STSs. Trabectedin is not cardio- or neurotoxic. The neutropenia and hepatic toxicity that occur are non-cumulative, reversible, and lessened by steroid premedication. The lack of cumulative toxicities could make trabectedin appropriate for prolonged treatment. Conclusion: The potential of trabectedin should be further explored in STSs in general and in specific subtypes, both in combination with other cytotoxic agents and with modulators of intracellular signalling.

High Efficacy of Panobinostat Towards Human Gastrointestinal Stromal Tumors in a Xenograft Mouse Model

Purpose: Histone deacetylase inhibitors have emerged as potent anticancer compounds. Using a nude-mouse xenograft model, for the first time we evaluated the response of human gastrointestinal stromal tumors (GIST) carrying different oncogenic KIT mutations to panobinostat (LBH589), administered single or in combination with imatinib. Experimental Design: We grafted the human GIST882 cell line with KIT exon 13 mutation and two biopsies from patients radiologically progressing under imatinib showing KIT exon11 and KIT exon9 mutations, respectively. Our study included 4 groups: A (n = 9; control), B (n = 10; panobinostat 10 mg/kg daily, i.p.), C (n = 9; imatinib 150 mg/kg bidaily, p.o), and D (n = 8; combination panobinostat-imatinib, same dose/schedule as above). Treatment lasted 12 days. Tumor size was measured regularly using standard variables. Histopathological assessment was by H&E, and immunohistochemically with KIT, cleaved caspase-3, Ki-67, and histone acetylation staining. Results: Overall, GIST xenografts responded rapidly to panobinostat as indicated by tumor regression, necrosis, hemorrhages, fibrosis, and/or myxoid degeneration, remarkable apoptosis, and substantial decline of cell proliferation. H3 and H4 acetylation increased significantly from control level in all treated groups. The combination of panobinostat and imatinib further enhanced most of the assessed parameters. Conclusions: We show for the first time potential therapeutic activity of panobinostat in human GISTs, in vivo. Our results warrant further exploration of histone deacetylase inhibitors for the treatment of advanced GISTs. Our study is also the first one on human GIST mouse xenografts established using patient biopsies.

The Heat Shock Protein 90 Inhibitor IPI-504 Induces KIT Degradation, Tumor Shrinkage, and Cell Proliferation Arrest in Xenograft Models of Gastrointestinal Stromal Tumors

The activity of the receptor tyrosine kinase KIT is crucial for gastrointestinal stromal tumor (GIST) growth and survival. Imatinib and sunitinib are very effective in advanced GIST, but have no curative potential. The observation that heat shock protein 90 (HSP90) inhibition results in KIT degradation prompted us to assess the efficacy of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) alone or in combination with imatinib or sunitinib in two GIST xenografts with distinctive KIT mutations. Nude mice were grafted with human GIST carrying KIT exon 13 (GIST-882; n = 59) or exon 11 (GIST-PSW; n = 44) mutations and dosed with imatinib (50 mg/kg twice daily), sunitinib (40 mg/kg once daily), IPI-504 (100 mg/kg 3 times per week), IPI-504 + imatinib, or IPI-504 + sunitinib. We evaluated tumor volume, proliferation and apoptosis, KIT expression and activation, as well as adverse events during treatment. Treatment with IPI-504 alone resulted in tumor regression, proliferation arrest, and induction of tumor necrosis. We documented downregulation of KIT and its signaling cascade in IPI-504–treated animals. Treatment effects were enhanced by combining IPI-504 with imatinib or sunitinib. On histologic examination, liver damage was frequently observed in animals exposed to combination treatments. In conclusion, IPI-504 shows consistent antitumor activity and induces KIT downregulation in GIST, as a single agent, and is more potent in combination with imatinib or sunitinib. The sequence of drug administration in the combination arms warrants further studies. Mol Cancer Ther; 10(10); 1897–908. ©2011 AACR.

Trabectedin (ET-743): evaluation of its use in advanced soft-tissue sarcoma

Trabectedin (ET-743; Yondelis) is a novel DNA-binding agent, originally derived from the marine tunicate, Ecteinascidia turbinata, and now produced synthetically. The efficacy of trabectedin in patients with advanced soft-tissue sarcoma has been demonstrated in three Phase II studies involving 189 previously treated patients. A pooled analysis of data from these studies showed that trabectedin induced tumor control (objective responses plus disease stabilization) in approximately 50% of patients; median overall survival was 10.3 months and progression-free survival at 6 months was 19.8%, with 29.3% of patients alive at 2 years. Responses were achieved in patients who were resistant to both doxorubicin and ifosfamide. Trabectedin is generally well tolerated, with adverse events being non cumulative, reversible and manageable. Unlike other commonly used cytotoxic agents, trabectedin is not associated with cardiotoxicity or neurotoxicity and alopecia is rare. Trabectedin is an interesting new anticancer agent that offers much promise for the treatment of advanced soft-tissue sarcoma.