Interest in marine natural products has allowed the discovery of new drugs and trabectedin (ET-743, Yondelis), derived from the marine tunicate Ecteinascidia turbinata, was approved for clinical use in 2007. It binds to the DNA minor groove leading to interferences with the intracellular transcription pathways and DNA-repair proteins. In vitro antitumor activity was demonstrated against various cancer cell lines and soft tissue sarcoma cell lines. In phase I studies tumor responses were observed also in osteosarcomas and different soft tissue sarcoma subtypes. The most common toxicities were myelosuppression and transient elevation of liver function tests, which could be reduced by dexamethasone premedication. The efficacy of trabectedin was established in three phase II studies where it was administered at 1.5 mg/m2 as a 24 h intravenous infusion repeated every three weeks, in previously treated patients. The objective response rate was 3.7%–8.3% and the tumor control rate (which included complete response, partial response and stable disease) was obtained in half of patients for a median overall survival reaching 12 months. In nonpretreated patients the overall response rate was 17%. Twenty-four percent of patients were without progression at six months. The median overall survival was almost 16 months with 72% surviving at one year. Predictive factors of response are being explored to identify patients who are most likely to respond to trabectedin. Combination with other agents are currently studied with promising results. In summary trabectedin is an active new chemotherapeutic agents that has demonstrated its role in the armamentarium of treatments for patients with sarcomas.
soft tissue sarcoma; trabectedin; chemotherapy; DNA-minor groove binder
ET-743 (trabectedin; Yondelis) is approved in Europe for the treatment of soft tissue sarcomas. Emerging phase 1 and 2 clinical data have shown high response rates in myxoid liposarcoma in part owing to the inhibition of the FUS-CHOP transcription factor. In this report, we show that modulation of specific oncogenic transcription factors by ET-743 may extend to other tumor types. We demonstrate that, among a panel of pediatric sarcomas, Ewing sarcoma family of tumors (ESFTs) cell lines bearing the EWS-FLI1 transcription factor are the most sensitive to treatment with ET-743 compared with osteosarcoma, rhabdomyosarcoma, and synovial sarcoma. We show that ET-743 reverses a gene signature of induced downstream targets of EWS-FLI1 in two different ESFT cell lines (P = .001). In addition, ET-743 directly suppresses the promoter activity of a known EWS-FLI1 downstream target NR0B1 luciferase reporter construct without changing the activity of a constitutively active control in ESFT cells. Furthermore, the effect is specific to EWS-FLI1, as forced expression of EWS-FLI1 in a cell type that normally lacks this fusion protein, HT1080 cells, induces the same NR0B1 promoter, but this activation is completely blocked by ET-743 treatment. Finally, we used gene set enrichment analysis to confirm that other mechanisms of ET-743 are active in ESFT cells. These results suggest a particular role for ET-743 in the treatment of translocation-positive tumors. In addition, the modulation of EWS-FLI1 makes it a novel targeting agent for ESFT and suggests that further development of this compound for the treatment of ESFT is warranted.
Trabectedin is a new marine-derived compound that binds the DNA minor groove and interacts with proteins of the DNA repair machinery. Trabectedin has shown promising single-agent activity in pretreated patients with soft tissue sarcoma, and ovarian and breast cancer, and combination with various other chemotherapeutic drugs seems feasible. Toxicities are mainly hematologic and hepatic, with Grade 3–4 neutropenia and thrombocytopenia observed in approximately 50% and 20% of patients, respectively, and Grade 3–4 elevation of liver enzymes observed in 35%–50% of patients treated with trabectedin. The recently reported results of a large Phase III trial comparing pegylated liposomal doxorubicin (PLD) alone with a combination of PLD and trabectedin in patients with recurrent ovarian cancer showed improved progression-free survival with the combination of trabectedin and PLD, albeit at the price of increased toxicity. Current research focuses on the identification of predictive factors for patients treated with trabectedin, as well as the development of other combinations.
chemotherapy; ovarian cancer; combination; drug development; DNA repair
Soft tissue sarcoma (STS) comprises a large variety of rare malignant tumors. Development of distant metastasis is frequent, even in patients undergoing initial curative surgery. Trabectedin, a tetrahydroisoquinoline alkaloid isolated from the Caribbean marine tunicate Ecteinascidia turbinata, was approved in 2007 for patients with advanced STS after failure of anthracyclines and ifosfamide, or for patients unsuited to receive these agents. In this study, we retrospectively analyzed 25 patients who had been treated with trabectedin at our institution between 2007 and 2010. The majority (72%) had been heavily pre-treated with ≥2 previous lines of chemotherapy. Response assessed by conventional RECIST criteria was low, with only one patient achieving a partial remission (PR) and 10 stable disease (SD) after three cycles of treatment. However, median progression-free survival (PFS) and overall survival (OS) were significantly prolonged in this population compared to non-responders, with 7.7 months versus 2.1 months (p < 0.0001; HR 15.37, 95% CI 4.3 to 54.5) and 12.13 months versus 5.54 months (p = 0.0137; HR 3.7, 95% CI 1.3 to 10.5), respectively. PFS for all patients was 58% at three months and 37% at six months. Side effects, including neutropenia, elevation of liver transaminases/liver function tests, and nausea/vomiting, were usually mild and manageable. However, dose reductions due to side effects were necessary in five patients. We conclude that trabectedin is an effective and generally well tolerated treatment for STS even in a heavily pre-treated patient population.
trabectedin; soft tissue sarcoma; metastatic; advanced; chemotherapy
ET-743 (trabectedin, Yondelis®) and PM00104 (Zalypsis®) are marine derived compounds that have antitumor activity. ET-743 and PM00104 exposure over sustained periods of treatment will result in the development of drug resistance, but the mechanisms which lead to resistance are not yet understood.
Human chondrosarcoma cell lines resistant to ET-743 (CS-1/ER) or PM00104 (CS-1/PR) were established in this study. The CS-1/ER and CS-1/PR exhibited cross resistance to cisplatin and methotrexate but not to doxorubicin. Human Affymetrix Gene Chip arrays were used to examine relative gene expression in these cell lines. We found that a large number of genes have altered expression levels in CS-1/ER and CS-1/PR when compared to the parental cell line. 595 CS-1/ER and 498 CS-1/PR genes were identified as overexpressing; 856 CS-1/ER and 874 CS-1/PR transcripts were identified as underexpressing. Three zinc finger protein (ZNF) genes were on the top 10 overexpressed genes list. These genes have not been previously associated with drug resistance in tumor cells. Differential expressions of ZNF93 and ZNF43 genes were confirmed in both CS-1/ER and CS-1/PR resistant cell lines by real-time RT-PCR. ZNF93 was overexpressed in two ET-743 resistant Ewing sarcoma cell lines as well as in a cisplatin resistant ovarian cancer cell line, but was not overexpressed in paclitaxel resistant cell lines. ZNF93 knockdown by siRNA in CS-1/ER and CS-1/PR caused increased sensitivity for ET-743, PM00104, and cisplatin. Furthermore, ZNF93 transfected CS-1 cells are relatively resistant to ET-743, PM00104 and cisplatin.
This study suggests that zinc finger proteins, and ZNF93 in particular, are involved in resistance to ET-743 and PM00104.
Myxoid liposarcoma is a relatively common malignant soft tissue tumor, characterized by a (12;16) translocation resulting in a FUS-DDIT3 fusion gene playing a pivotal role in its tumorigenesis. Treatment options in patients with inoperable or metastatic myxoid liposarcoma are relatively poor though being developed and new hope is growing.
Using kinome profiling and subsequent pathway analysis in two cell lines and four primary cultures of myxoid liposarcomas, all of which demonstrated a FUS-DDIT3 fusion gene including one new fusion type, we aimed at identifying new molecular targets for systemic treatment. Protein phosphorylation by activated kinases was verified by Western Blot and cell viability was measured before and after treatment of the myxoid liposarcoma cells with kinase inhibitors. We found kinases associated with the atypical nuclear factor-kappaB and Src pathways to be the most active in myxoid liposarcoma. Inhibition of Src by the small molecule tyrosine kinase inhibitor dasatinib showed only a mild effect on cell viability of myxoid liposarcoma cells. In contrast, inhibition of the nuclear factor-kappaB pathway, which is regulated by the FUS-DDIT3 fusion product, in myxoid liposarcoma cells using casein kinase 2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) showed a significant decrease in cell viability, decreased phosphorylation of nuclear factor-kappaB pathway proteins, and caspase 3 mediated apoptosis. Combination of dasatinib and TBB showed an enhanced effect.
Kinases associated with activation of the atypical nuclear factor-kappaB and the Src pathways are the most active in myxoid liposarcoma in vitro and inhibition of nuclear factor-kappaB pathway activation by inhibiting casein kinase 2 using TBB, of which the effect is enhanced by Src inhibition using dasatinib, offers new potential therapeutic strategies for myxoid liposarcoma patients with advanced disease.
Trabectedin and thioglitazones have been documented to induce adipocytic maturation in myxoid liposarcoma; we have noted this in our experience as well. Intriguingly, we have also encountered this same phenomenon in myxoid liposarcomas exposed to various combinations of neoadjuvant doxorubicin and ifosfamide systemic chemotherapy with preoperative radiation, where the pathological effects have been less characterized. We examined the histological changes, including adipocytic maturation, associated with this treatment in patients with myxoid liposarcoma and evaluated for prognostic significance.
Twenty-two patients were identified with histologically confirmed myxoid liposarcomas (9 with variable hypercellular areas) who were treated with neoadjuvant doxorubicin (75-90 mg/m2/continous infusion over 72h every 3 week) and ifosfamide (2.5 g/m2 daily x 4 every 3 weeks) for 4-6 cycles. Twenty-one patients received pre-operative radiation including 5 with concurrent gemcitabine. Pre- and post-treatment MRI studies were compared for changes in tumor area, fat content and contrast uptake, with the latter two estimated as: none, <25%, 25-49% and >50%. Post-treatment specimens were evaluated for hyalinization, necrosis and adipocytic maturation. Clinical follow-up was obtained.
Median age was 45 (26-72) years with a median tumor size of 11 (2-18) cm. All occurred in the lower extremities except for one case in the neck. As is common in myxoid liposarcoma, all had extensive treatment changes (>90%) with extensive hyalinization (n = 16; >90%) or prominent adipocytic maturation (n = 6; >50%) including 2 cases composed almost entirely of mature-appearing adipose tissue. Variable necrosis was identified (5-30%). MRI revealed a decrease in tumor area in all but one tumor (median, 65%), an increase in fat content in 7 tumors (n = 2, >50%;n = 2, 25-50%;n = 3,<25%), and a decrease in contrast enhancement in most tumors (n = 5, >50%; n = 9, 25-49%; n = 7, <25%). Median follow-up was 57 (12-96) months with 17 alive with no disease/metastases, 3 alive with disease and 2 dead of disease. Six patients developed metastases with median interval of 26 (22-51) months post resection. Four of 6 tumors with increased adipocytic maturation >50% on histology had increased fat detected by MRI (>25%). All 6 are alive but 2 developed metastases. In the remaining patients, 4 developed metastases with 14 alive and 2 dead of disease.
Myxoid liposarcoma exposed to neoadjuvant doxorubicin and ifosfamide and pre-operative radiation can have prominent adipocytic maturation similar to trabectedin treatment. Myxoid liposarcomas exhibit extensive treatment changes with prominent hyalinization being the most common histological change. Despite this, patients develop metastases regardless of adipocytic maturation. While of unclear significance, no patient with fatty maturation died of disease.
Adipocytic maturation; Myxoid liposarcoma; Treatment
Myxoid round cell liposarcoma (MRCLS) is a common liposarcoma subtype characterized by a translocation that results in the fusion protein TLS:CHOP as well as by mixed adipocytic histopathology. Both the etiology of MRCLS and the mechanism of action of TLS:CHOP remain poorly understood. It was previously shown that ET-743, an antitumor compound with an unclear mechanism of action, is highly effective in patients with MRCLS. To identify the cellular origin of MRCLS, we engineered a mouse model in which TLS:CHOP was expressed under the control of a mesodermally restricted promoter (Prx1) in a p53-depleted background. This model resembled MRCLS histologically as well as functionally in terms of its specific adipocytic differentiation–based response to ET-743. Specifically, endogenous mesenchymal stem cells (MSCs) expressing TLS:CHOP developed into MRCLS in vivo. Gene expression and microRNA analysis of these MSCs showed that they were committed to adipocytic differentiation, but unable to terminally differentiate. We also explored the method of action of ET-743. ET-743 downregulated TLS:CHOP expression, which correlated with CEBPα expression and adipocytic differentiation. Furthermore, PPARγ agonists enhanced the differentiation process initiated by ET-743. Our work highlights how clinical observations can lead to the generation of a mouse model that recapitulates human disease and may be used to develop rational treatment combinations, such as ET-743 plus PPARγ agonists, for the treatment of MRCLS.
Soft tissue sarcomas (STS) are a rare group of malignancies with multiple different subtypes. Close to half of intermediate or high grade STS develop metastatic disease. Treatment of recurrent/metastatic sarcomas is quite challenging with only a few drugs showing measurable benefits. Trabectedin (ecteinascidin 743, ET-743, Yondelis) is a newly developed alkylating agent that has shown significant broad spectrum potential as a single agent second line drug alone or in combination particularly in the treatment of liposarcomas and leiomyosarcomas. Clinical benefit rates seem to favor its use especially in pretreated patients with recurrent/metastatic disease. The drug is well tolerated in general but hepatotoxicity and hematologic side effects are common. Approved in Europe, the currently ongoing Phase III trials along with the already existing clinical evidence may provide enough data for the Food and Drug Administration for an approval in the US.
trabectedin; liposarcoma; leiomyosarcoma; metastatic sarcoma; efficacy; side effects
Liposarcomas are separated into clinicopathological entities by a characteristic morphological spectrum and distinctive genetic changes. Myxoid liposarcoma (MLS) represents one such entity with specific chromosomal translocations leading to the generation of fusion genes, the human translocation liposarcoma (TLS)-CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) or the Ewing sarcoma (EWS)-CHOP. In the present study, four cases of liposarcoma with detection of TLS-CHOP or EWS-CHOP, whose postoperative diagnosis was other than MLS (one well-differentiated liposarcoma, two de-differentiated liposarcomas and one unclassified) were examined for medical records, imaging data and histopathology. Clinical records demonstrated that three of the four cases were considerably difficult to diagnose definitively, and histopathological re-examination pointed out areas of myxomatous change as a minor component (<10%). Their dominant components (>90%) resembled pleomorphic sarcoma, pleomorphic malignant fibrous histiocytoma and monophasic synovial sarcoma. The current cases may represent an extreme variant of the morphological spectrum within MLS. In cases of difficulty in making definitive diagnosis of soft tissue sarcoma by standard histopathological examination and identification of myxoid stroma even as a minor component, analyzing TLS-CHOP and EWS-CHOP fusion genes may aid the diagnosis of unusual MLS.
Ewing sarcoma-CCAAT/enhancer binding homologous protein; histopathology; myxoid liposarcoma; reverse transcription-polymerase chain reaction; human translocation liposarcoma-CCAAT/enhancer binding homologous protein; variation
Trabectedin is a new marine-derived compound that binds the DNA minor groove and interacts with proteins of the DNA repair machinery. Phase I trials have established the standard regimen as 1500 μg/m2 24-hour continuous infusion repeated every 3 weeks. Several phase II trials have shown response in 5%–10% of unselected patients with soft tissue sarcoma failing prior chemotherapy and disease stabilisation in 30%–40%. Furthermore, prolonged disease control has been described in 15%–20% of patients. Toxicities are mainly haematological and hepatic with grade 3–4 neutropenia and thrombocytopenia observed in approximately 50% and 20% of patients respectively, and grade 3–4 elevation of liver enzymes observed in 35%–50% of patients treated with trabectedin. Current research focuses on the identification of predictive factors for patients with soft tissue sarcoma treated with trabectedin.
chemotherapy; sarcoma; drug development; DNA repair
Liposarcomas are the most common class of soft tissue sarcomas, and myxoid liposarcoma is the second most common liposarcoma. EWSR1-DDIT3 is a chimeric fusion protein generated by the myxoid liposarcoma-specific chromosomal translocation t(12;22)(q13;q12). Current studies indicate that multipotent mesenchymal cells are the origin of sarcomas. The mechanism whereby EWSR1-DDIT3 contributes to the phenotypic selection of target cells during oncogenic transformation remains to be elucidated.
Reporter assays showed that the EWSR1-DDIT3 myxoid liposarcoma fusion protein, but not its wild-type counterparts EWSR1 and DDIT3, selectively repressed the transcriptional activity of cell lineage-specific marker genes in multipotent mesenchymal C3H10T1/2 cells. Specifically, the osteoblastic marker Opn promoter and chondrocytic marker Col11a2 promoter were repressed, while the adipocytic marker Ppar-γ2 promoter was not affected. Mutation analyses, transient ChIP assays, and treatment of cells with trichostatin A (a potent inhibitor of histone deacetylases) or 5-Aza-2′-deoxycytidine (a methylation-resistant cytosine homolog) revealed the possible molecular mechanisms underlying the above-mentioned selective transcriptional repression. The first is a genetic action of the EWSR1-DDIT3 fusion protein, which results in binding to the functional C/EBP site within Opn and Col11a2 promoters through interaction of its DNA-binding domain and subsequent interference with endogenous C/EBPβ function. Another possible mechanism is an epigenetic action of EWSR1-DDIT3, which enhances histone deacetylation, DNA methylation, and histone H3K9 trimethylation at the transcriptional repression site. We hypothesize that EWSR1-DDIT3-mediated transcriptional regulation may modulate the target cell lineage through target gene-specific genetic and epigenetic conversions.
This study elucidates the molecular mechanisms underlying EWSR1-DDIT3 fusion protein-mediated phenotypic selection of putative target multipotent mesenchymal cells during myxoid liposarcoma development. A better understanding of this process is fundamental to the elucidation of possible direct lineage reprogramming in oncogenic sarcoma transformation mediated by fusion proteins.
Myxoid soft-tissue sarcomas represent a heterogeneous group of mesenchymal tumors characterized by a predominantly myxoid matrix, including myxoid liposarcoma (MLS), low-grade fibromyxoid sarcoma (LGFMS), extraskeletal myxoid chondrosarcoma (EMC), myxofibrosarcoma, myxoinflammatory fibroblastic sarcoma (MIFS), and myxoid dermatofibrosarcoma protuberans (DFSP). Cytogenetic and molecular genetic analyses have shown that many of these sarcomas are characterized by recurrent chromosomal translocations resulting in highly specific fusion genes (e.g., FUS-DDIT3 in MLS, FUS-CREB3L2 in LGFMS, EWSR1-NR4A3 in EMC, and COL1A1-PDGFB in myxoid DFSP). Moreover, recent molecular analysis has demonstrated a translocation t(1; 10)(p22; q24) resulting in transcriptional upregulation of FGF8 and NPM3 in MIFS. Most recently, the presence of TGFBR3 and MGEA5 rearrangements has been identified in a subset of MIFS. These genetic alterations can be utilized as an adjunct in diagnostically challenging cases. In contrast, most myxofibrosarcomas have complex karyotypes lacking specific genetic alterations. This paper focuses on the cytogenetic and molecular genetic findings of myxoid soft-tissue sarcomas as well as their clinicopathological characteristics.
Background: To assess the cost-effectiveness of trabectedin compared with end-stage treatment (EST) after failure with anthracycline and/or ifosfamide in metastatic soft tissue sarcoma (mSTS).
Design: Analysis was carried out using a probabilistic Markov model with trabectedin → EST and EST arms, three health states (stable disease, progressive disease and death) and a lifetime perspective (3% annual discount rate). Finnish resources (drugs, mSTS, adverse events and travelling) and costs (year 2008) were used. Efficacy was based on an indirect comparison of the STS-201 and European Organisation for Research and Treatment of Cancer trials. QLQ-C30 scale scores were mapped to 15D, Short Form 6D and EuroQol 5D utilities. The outcome measures were the cost-effectiveness acceptability frontier, incremental cost per life year gained (LYG) and quality-adjusted life year (QALY) gained and the expected value of perfect information (EVPI).
Results: Trabectedin → EST was associated with 14.0 (95% confidence interval 9.1–19.2) months longer survival, €36 778 higher costs (€32 816 using hospital price for trabectedin) and €31 590 (€28 192) incremental cost per LYG with an EVPI of €3008 (€3188) compared with EST. With a threshold of €50 000 per LYG, trabectedin → EST had 98.5% (98.2%) probability of being cost-effective. The incremental cost per QALY gained with trabectedin → EST was €42 633–47 735 (€37 992–42 819) compared with EST. The results were relatively insensitive to changes.
Conclusion: Trabectedin is a potentially cost-effective treatment of mSTS patients.
cancer; economic evaluation; leiomyosarcoma; liposarcoma; quality of life; trabectedin
Myxoid liposarcoma (MLS) is a soft tissue sarcoma with adipocytic differentiation characterized by a unique chromosome rearrangement, t(12;16)(q13;p11). The exact efficacy of chemotherapy in MLS has not been clearly established.
Patients and methods
We retrospectively analyzed the records of 37 histologically confirmed MLS patients who were treated at the University of Texas MD Anderson Cancer Center from January 2000 to December 2009 with doxorubicin 75-90 mg/m2 over 72 hours combined with ifosfamide 10 gm/m2 in the first-line setting. Response was assessed using RECIST and Choi criteria. The Kaplan-Meier method and log-rank test was used to estimate clinical outcomes.
The median follow-up period was 50.1 months. The overall response rates were 43.2% using RECIST and 86.5% using the Choi criteria. The 5-year disease-free survival rate was 90% for patients with resectable tumors. Median time to progression and overall survival time for the advanced-disease group were 23 and 31.1 months, respectively.
Our study demonstrates that doxorubicin-ifosfamide combination therapy has a role in the treatment of MLS. The Choi criteria may be more sensitive in evaluating response to chemotherapy in MLS.
Choi criteria; doxorubicin; ifosfamide; myxoid liposarcoma
Soft tissue sarcoma accounts for less than 1% of all malignant neoplasms and is comprised of a very heterogeneous group of tumors with over 50 different subtypes. Due to its diversity and rarity, developing new therapeutics has been difficult, at best. The standard of care in the treatment of advanced and metastatic disease over the last 30 years has been doxorubicin and ifosfamide, either alone or in combination. There has been significant focus on developing new therapeutics to treat primary and metastatic disease. Trabectedin (ecteinascidin-743) is a tetrahydroiso-quinoline alkaloid which has been evaluated in the treatment of metastatic soft tissue sarcoma.
To review the current evidence for the therapeutic use of trabectedin in patients with soft tissue sarcoma.
Five phase I studies in patients with solid tumors, all of which include sarcoma patients, evaluating the dosing and toxicity of trabectedin were performed with efficacy being evaluated as a secondary endpoint. Additionally, there are four phase I trials evaluating trabectedin in combination with frontline therapeutic drugs in soft tissue sarcoma. Four phase II studies were performed in soft-tissue sarcoma patients with objective response rates ranging from 3.7% to 17.1%. Additionally, in two compassionate use trials, objective response rates between 14% and 51% were seen, the largest response resulting from a study specifically focusing on liposarcoma.
Place in therapy:
Trabectedin is a potential therapeutic option for the management of soft-tissue sarcoma. It appears to have specific activity in a select group of histologies, most notably myxoid/round cell liposarcoma. Although it would be helpful to study the use of trabectedin in a randomized, controlled fashion, the relative rarity of soft-tissue sarcoma, and heterogeneity of the histologic subtypes, makes phase III trials a difficult prospect.
soft tissue sarcoma; metastatic; trabectedin; ET-743; Yondelis®
Ecteinascidin 743 (Et743; trabectedin, Yondelis) has recently been approved in Europe for the treatment of soft tissue sarcomas and is undergoing clinical trials for other solid tumors. Et743 selectively targets cells proficient for TC-NER, which sets it apart from other DNA alkylating agents. In the present study, we examined the effects of Et743 on RNA Pol II.
Experimental Design and Results
We report that Et743 induces the rapid and massive degradation of transcribing Pol II in various cancer cell lines and normal fibroblasts. Pol II degradation was abrogated by the proteasome inhibitor MG132 and was dependent on TC-NER. Cockayne syndrome (CS) cells and xeroderma pigmentosum (XP) cells (XPD, XPA, XPG, and XPF) were defective in Pol II degradation, whereas XPC cells whose defect is limited to global genome NER in nontranscribing regions were proficient for Pol II degradation. Complementation of the CSB and XPD cells restored Pol II degradation. We also show that cells defective for the VHL complex were defective in Pol II degradation and that complementation of those cells restores Pol II degradation. Moreover, VHL deficiency rendered cells resistant to Et743-induced cell death, a similar effect to that of TC-NER deficiency.
These results suggest that both TC-NER ^ induced and VHL-mediated Pol II degradation play a role in cell killing by Et743.
Yondelis® (trabectedin, ET-743) is a novel marine-derived anticancer compound found in the ascidian Ecteinascidia turbinata. It is currently under phase II/III development in breast cancer, hormone refractory prostate cancer, sarcomas and ovarian cancer. Activity in breast cancer experimental models has been reported, and preliminary evidence of activity in this setting during the phase I programme has also been observed. The present study assessed the activity and feasibility of trabectedin in women with advanced breast cancer previously treated with conventional therapies. Patients with advanced disease previously treated with at least one but not more than two regimens that included taxanes or anthracyclines as palliative therapy were eligible. Trabectedin 1.5 mg m−2 was administered as a 24-h continuous infusion every 3 weeks. Patients were kept on therapy until disease progression, unacceptable toxicity or patient refusal. Twenty-seven patients were included between April 1999 and September 2000. Their median age was 54 years (range: 36–67) and 63% of them had two metastatic sites. Twenty-two patients were performance status 1. All patients had previously received anthracyclines, and 23 out of 27 patients had received taxanes. Of 21 patients with measurable disease, three confirmed partial responses, one unconfirmed partial response and two minor responses (49 and 32% tumour shrinkage) were observed; six patients had stable disease. Median survival was 10 months (95% confidence interval: 4.88–15.18). Transient and noncumulative transaminitis was observed in most of the patients. The pharmacokinetic profile of trabectedin in this patient's population is in line with the overall data available with this schedule. The policy of dose adjustments based on the intercycle peaks of bilirubin and alkaline phosphatase appears to have a positive impact in the therapeutic index of trabectedin. Trabectedin can induce response and tumour control in previously treated advanced breast cancer, with manageable toxicity, thus warranting further development as a single agent or in combination regimens.
Yondelis; trabectedin; breast cancer
The objective of this study was to determine the objective response rate in patients with platinum-sensitive and platinum-resistant recurrent ovarian cancer to treatment with trabectedin (Yondelis®) administered as a 3-h infusion weekly for 3 weeks of a 4-week cycle. We carried out a multicentre Phase II trial of trabectedin in patients with advanced recurrent ovarian cancer. Trabectedin (0.58 mg m−2) was administered via a central line, after premedication with dexamethasone, to 147 patients as a 3-h infusion weekly for 3 weeks followed by 1-week rest. Major eligibility criteria included measurable relapsed advanced ovarian cancer and not more than two prior platinum-containing regimens. Patients were stratified according to the treatment-free interval (TFI) between having either platinum-sensitive (⩾6 months TFI) or platinum-resistant disease (<6 months TFI)/platinum-refractory disease (progression during first line therapy). In the platinum-sensitive cohort, 62 evaluable patients with measurable disease had an overall response rate (ORR) of 29.0% (95% CI: 18.2–41.9%) and median progression-free survival (PFS) was 5.1 months (95% CI: 2.8–6.2). Four patients with measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) criteria had no follow-up scans at the end of treatment. In the platinum-resistant/refractory cohort, 79 patients were evaluable with an ORR of 6.3% (95% CI: 2.1–14.2%). Median PFS was 2.0 months (95% CI: 1.7–3.5 months). Two patients with measurable disease per RECIST criteria had no follow-up scans at the end of treatment. The most frequent (⩾2% of patients) drug-related treatment-emergent grade 3/4 adverse events were reversible liver alanine transferase elevation (10%), neutropaenia (8%), nausea, vomiting, and fatigue (5% each). Trabectedin is an active treatment, with documented responses in patients with platinum sensitive advanced relapsed ovarian cancer, and has a manageable toxicity profile.
trabectedin; ovarian cancer; overall response rate; platinum-sensitive; platinum-resistant; progression-free survival
We used 2-deoxy-2-[18F] fluoro-D-glucose (FDG) positron emission tomography (PET) to evaluate the FDG uptake in patients with advanced and/or metastatic soft tissue sarcoma (STS) undergoing therapy with Ecteinascidin-743 (ET-743, Trabectedin, Yondelis™).
Patients and Methods
The pilot study included nine patients with metastatic STS receiving a minimum of one cycle of treatment with trabectedin. Patients were examined using PET prior to onset of therapy and after completion of one or three cycles of trabectedin. Restaging according to Response Evaluation Criteria in Solid Tumours (RECIST) was performed in parallel using computed tomography (CT) and/or magnetic resonance imaging (MRI) and served for reference.
Clinical outcome of nine evaluable patients was as follows: one patient with partial remission (PR), three patients with stable disease (SD), and five patients with progressive disease (PD). A more than 40% decrease of the standardized uptake value (SUV) of sequential PET examination could be demonstrated for the responding patient (PR), whereas patients with SD or PD showed a stable SUV, but no increase in SUV.
To our knowledge, this is the first small series of patients being treated with trabectedin and monitored using sequential PET imaging demonstrating SUV stabilization in nearly all monitored patients.
fluorodeoxyglucose; positron emission tomography; RECIST; soft tissue sarcoma; trabectedin
Brostallicin is a DNA minor groove binder in Phase II clinical trials. Here we show that brostallicin induces γ-H2AX nuclear foci that co-localize with 53BP1 and are dependent on glutathione, as demonstrated by inhibition of those γ-H2AX foci by L-buthionine sulfoximine (BSO). To differentiate brostallicin from the clinically approved minor groove binder trabectedin (ecteinascidin 743), we tested whether the brostallicin-induced γ-H2AX and antiproliferative responses were dependent on nucleotide excision repair (NER) and found that, unlike trabectedin, they are not. Additionally, brostallicin retained activity in the trabectedin-resistant HCT116-ER5 cell line. Induction of γ-H2AX foci by brostallicin was partially dependent on the repair nuclease Mre11. Pretreatment with aphidicolin partially reduced brostallicin-induced γ-H2AX foci, suggesting that brostallicin induces both replication-associated and replication-independent DNA damage. Replication-associated DNA damage was further demonstrated by the co-localization of γ-H2AX foci with replication foci and by the rapid inhibition of DNA synthesis and accumulation of cells in S-phase in response to brostallicin. In addition, brostallicin was able to induce lower intensity γ-H2AX foci in human circulating lymphocytes. Together our results indicate that brostallicin induces DNA double-strand breaks and suggest ©-H2AX as a pharmacodynamic biomarker for brostallicin.
Brostallicin; Glutathione; Mre11; Nucleotide excision repair; DNA double-strand breaks; Histone γ-H2AX; DNA minor groove binder
Solitary fibrous tumor is a rare tumor type and has an unpredictable course. Local recurrence rate varies between 9 and 19%, and rate of metastatic involvement between 0 and 36 %. It is characterized by a typical architecture and immuno-histochemistry tests. The most important prognostic factor is the complete resection of primary tumor. Treatment of recurrences is not clearly established. If a solitary fibrous tumor is too advanced to allow surgical resection, radiotherapy and chemotherapy may be used. The most often used drugs are doxorubicine and\or ifosfamide. We report the case of man with metastatic solitary fibrous tumor treated with trabectedin, administered at a dose of 1.5 mg/m² every 3 weeks. After 3 cycles, metastases had significantly decreased. Recurrence of the disease was demonstrated 8 months after the start of trabectedin. This case shows that trabectedin is a possible treatment option.
metastatic solitary fibrous tumor; trabectedin.
Trabectedin is a promising anticancer agent, but dose-limiting hepatotoxicity was observed during phase I/II clinical trials. Dexamethasone (DEX) has been shown to significantly reduce trabectedin-mediated hepatotoxicity. The current study was designed to assess the capability of sandwich-cultured primary rat hepatocytes (SCRH) to predict the hepato-protective effect of DEX against trabectedin-mediated cytotoxicity. The role of multidrug resistance-associated protein 2 (Mrp2; Abcc2) in trabectedin hepatic disposition also was examined. In SCRH from wild-type Wistar rats, cytotoxicity was observed after 24-hr continuous exposure to trabectedin. SCRH pretreated with additional DEX (1 µM) exhibited a 2–3-fold decrease in toxicity at 100 nM and 1000 nM trabectedin. Unexpectedly, toxicity in SCRH from Mrp2-deficient (TR−) compared to wild-type Wistar rats was markedly reduced. Depletion of glutathione from SCRH using buthionine sulfoximine (BSO) mitigated trabectedin toxicity associated with 100 nM and 1000 nM trabectedin. Western blot analysis demonstrated increased levels of CYP3A1/2 and Mrp2 in SCRH pretreated with DEX; interestingly, Mrp4 expression was increased in SCRH after BSO exposure. Trabectedin biliary recovery in isolated perfused livers from TR− rats was decreased by ~75% compared to wild-type livers. In conclusion, SCRH represent a useful in vitro model to predict the hepatotoxicity of trabectedin observed in vivo. The protection by DEX against trabectedin-mediated cytotoxicity may be attributed, in part, to enhanced Mrp2 biliary excretion and increased metabolism by CYP3A1/2. Decreased trabectedin toxicity in SCRH from TR− rats, and in SCRH pretreated with BSO, may be due to increased basolateral excretion of trabectedin by Mrp3 and/or Mrp4.
Trabectedin; Dexamethasone; Sandwich-cultured primary rat hepatocytes; Multidrug resistance-associated proteins
Liposarcomas are malignant tumors of the soft tissue, with myxoid liposarcoma being the second most common subtype, tending to occur in the limbs, particularly in the thighs. Myxoid liposarcomas have an intermediate prognosis between well-differentiated and pleomorphic tumors. Spinal metastasis is usual but intradural involvement is extremely rare. We present an unusual case of a multicentric myxoid liposarcoma with intradural involvement. A 41-year-old woman complained of tingling sensation on her left arm. Radiological evaluation revealed multiple masses in her cervical spine, abdominal wall, liver, heart and right thigh, all of which were resected. She was histologically diagnosed with small round cell myxoid sarcoma and underwent adjuvant chemotherapy. However, magnetic resonance imaging analysis after 1 year revealed a large metastatic mass with bony invasion at the C6-T1 level. This mass consisted of extradural and intradural components causing severe compression of the spinal cord. She underwent resection via a posterior facetectomy of C6-7 and an anterior C7 corpectomy. However, the patient died of multiple metastases 18 months after the first diagnosis.
Cervical spine; lntradural; Multicentric; Myxoid liposarcoma; Metastasis
Soft tissue sarcomas are heterogeneous tumors that are difficult to treat. Up to 50 percent of patients develop metastatic disease and require systemic chemotherapy. Ifosfamide and doxorubicin are the two most active agents.
A 33-year-old Caucasian woman presented to our facility with a metastatic myxoid liposarcoma. Our patient was initially treated with surgery and radiation therapy, but experienced three recurrences during a six-year period, the first and the last occurring while our patient was pregnant. The first recurrence, which occurred two years after diagnosis and was localized in the left cervical and right axillary region, was treated with surgery followed by chemotherapy. Molecular analysis of this tumor showed a t(12,16) + translocation resulting in a FUS-DDIT3 or EWSR1-DDIT3 fusion. Three years later our patient experienced a second recurrence in the left supraclavicular fossa, upper thoracic and anterior mediastinum, which was treated with surgery alone. Eight months later, during the second pregnancy, our patient experienced a third recurrence as a large cervical mass that was treated, upon pregnancy, with trabectedin (1.5mg/m2/24-hour continuous infusion) for a total of 12 cycles. At that time a computed tomography scan showed long-term partial response with excellent treatment tolerability.
This case report illustrates the potential therapeutic activity of trabectedin in patients with myxoid liposarcoma.