Trabectedin

IC50 Value: 0.1-3.7 nM(breast cancer cell lines) [1] Trabectedin (Ecteinascidin-743 or ET-743) is a novel antitumour agent of marine origin with potent antitumour activity both in vitro and in vivo. in vitro: Trabectedin induced cytotoxicity and apoptosis in both breast cancer cells in a time and concentration-dependent manner. The expression levels of the death receptor pathway molecules, TRAIL-R1/DR4, TRAIL-R2/DR5, FAS/TNFRSF6, TNF RI/TNFRSF1A, and FADD were significantly increased by 2.6-, 3.1-, 1.7-, 11.2- and 4.0-fold by trabectedin treatment in MCF-7 cells. However, in MDA-MB-453 cells, the mitochondrial pathway related pro-apoptotic proteins Bax, Bad, Cytochrome c, Smac/DIABLO, and Cleaved Caspase-3 expressions were induced by 4.2-, 3.6-, 4.8-, 4.5-, and 4.4-fold, and the expression levels of anti-apoptotic proteins Bcl-2 and Bcl-XL were reduced by 4.8- and 5.2-fold in MDA-MB-453 cells [2]. In vitro treatment with noncytotoxic concentrations of trabectedin selectively inhibited the production of CCL2, CXCL8, IL-6, VEGF, and PTX3 by MLS primary tumor cultures and/or cell lines [3]. in vivo: A xenograft mouse model of human MLS showed marked reduction of CCL2, CXCL8, CD68+ infiltrating macrophages, CD31+ tumor vessels, and partial decrease of PTX3 after trabectedin treatment [3]. The MTD of trabectedin was 700 microg/m(2) due to dose-limiting neutropaenia and the RDs in the previously treated/untreated patients were 500 and 600 microg/m(2), respectively. Most common toxicities were nausea/vomiting (67%), asthenia/fatigue (55%) and reversible ASAT/ALAT elevation (51%) [4]. Toxicity: Most common toxicities were nausea/vomiting (67%), asthenia/fatigue (55%) and reversible ASAT/ALAT elevation (51%) [4]. Clinical trial: A Study to Assess the Potential Effects of Rifampin on the Pharmacokinetics of Trabectedin in Patients With Advanced Malignancies. Phase 1/2

Mechanism of action of trabectedin in desmoplastic small round cell tumor cells.[Pubmed:28166781]

BMC Cancer. 2017 Feb 6;17(1):107.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive disease, that can be described as a member of the family of small round blue cell tumors. The molecular diagnostic marker is the t(11;22)(p13;q12) translocation, which creates an aberrant transcription factor, EWS-WT1, that underlies the oncogenesis of DSRCT. Current treatments are not very effective so new active drugs are needed. Trabectedin, now used as a single agent for the treatment of soft tissue sarcoma, was reported to be active in some pre-treated DSRCT patients. Using JN-DSRCT-1, a cell line derived from DSRCT expressing the EWS-WT1 fusion protein, we investigated the ability of Trabectedin to modify the function of the chimeric protein, as in other sarcomas expressing fusion proteins. After detailed characterization of the EWS-WT1 transcripts structure, we investigated the mode of action of Trabectedin, looking at the expression and function of the oncogenic chimera. METHODS: We characterized JN-DSRCT-1 cells using cellular approaches (FISH, Clonogenicity assay) and molecular approaches (Sanger sequencing, ChIP, GEP). RESULTS: JN-DSRCT-1 cells were sensitive to Trabectedin at nanomolar concentrations. The cell line expresses different variants of EWS-WT1, some already identified in patients. EWS-WT1 mRNA expression was affected by Trabectedin and chimeric protein binding on its target gene promoters was reduced. Expression profiling indicated that Trabectedin affects the expression of genes involved in cell proliferation and apoptosis. CONCLUSIONS: The JN-DSRCT-1 cell line, in vitro, is sensitive to Trabectedin: after drug exposure, EWS-WT1 chimera expression decreases as well as binding on its target promoters. Probably the heterogeneity of chimera transcripts is an obstacle to precisely defining the molecular mode of action of drugs, calling for further cellular models of DSRCT, possibly growing in vivo too, to mimic the biological complexity of this disease.

Patient-derived solitary fibrous tumour xenografts predict high sensitivity to doxorubicin/dacarbazine combination confirmed in the clinic and highlight the potential effectiveness of trabectedin or eribulin against this tumour.[Pubmed:28284173]

Eur J Cancer. 2017 May;76:84-92.

BACKGROUND: Preclinical models that mimic pathological and molecular features of solitary fibrous tumour (SFT) represent an important tool to select effective regimes and novel compounds to be tested in the clinic. This study was aimed at developing two preclinical models of SFT, assessing their predictive value in the clinic and selecting potential novel effective treatments. MATERIAL AND METHODS: Two dedifferentiated-SFT (D-SFT) models obtained from patients' biopsies were grown in immunodeficient mice. The antitumour activity on these models of doxorubicin, dacarbazine (DTIC), ifosfamide (monotherapy or combination), Trabectedin and eribulin was tested. Twelve SFT patients were treated with doxorubicin and DTIC. Response by RECIST, progression-free survival and overall survival were retrospectively evaluated, distinguishing malignant-SFT (M-SFT) and D-SFT. RESULTS: Two D-SFT patient-derived xenografts (PDXs) that represent the first available preclinical in vivo models of SFT were developed and characterised. Doxorubicin/DTIC, DTIC/ifosfamide, doxorubicin/ifosfamide combinations consistently induced better antitumour activity than the single-agents. Particularly, doxorubicin/DTIC combination caused a max tumour volume inhibition >80% in both models. Doxorubicin/DTIC combo showed activity also in the case-series. Best RECIST responses were: 6 responses (M-SFT = 2 of 7, D-SFT = 4 of 5), 1 stable disease, 5 progressions, with a 6-month median progression-free survival (M-SFT = 6, D-SFT = 10 months). The PDXs were very sensitive to Trabectedin and eribulin. CONCLUSION: Doxorubicin plus DTIC combination was effective in our two D-SFT mice models and appeared to be active also in the clinic, especially in high-grade D-SFT patients. Among additional drugs tested in the PDXs, Trabectedin and eribulin were highly effective, providing a rational to test these drugs in D-SFT patients.

Stable disease in a patient with metastatic leiomyosarcoma treated with trabectedin.[Pubmed:28181940]

Anticancer Drugs. 2017 Apr;28(4):465-468.

Leiomyosarcomas represent the most common variant of uterine sarcomas, and are also considered to be the least chemosensitive. To date, adriamycin and ifosfamide are believed to be the most effective drugs for its treatment, in addition to docetaxel and gemcitabine. Recently, the introduction of Trabectedin has provided clinicians with another treatment option, and the drug may have some benefits for patients as it may allow for long-term treatment. We present the case of a patient who previously failed multiple cycles of chemotherapy and who was subsequently treated with 30 cycles of Trabectedin as third-line therapy for multiple metastases of uterine leiomyosarcoma. During the treatment period, the dosage and dose interval of Trabectedin were optimized because of the appearance of grade 4 hematological and gastrointestinal toxicity. Dose adjustments led to acceptable tolerability. Trabectedin was associated with a very good partial response, especially at the pulmonary and pancreatic levels, and stable disease was achieved at all metastatic sites. The patient is currently continuing treatment with Trabectedin and has clinically stable disease after 2 years of therapy. This case report provides further evidence that Trabectedin is a valid and well-tolerated therapeutic option that can be used in the long term in uterine leiomyosarcoma.

Update on the role of trabectedin in the treatment of intractable soft tissue sarcomas.[Pubmed:28260930]

Onco Targets Ther. 2017 Feb 23;10:1155-1164.

Soft tissue sarcomas (STS) represent a variety of tumors of mesenchymal origin, accounting for about 1% of all adult cancers. This group of tumors comprises over 60 different histotypes with different biology showing different sensitivity to therapeutic agents. For decades, the standard first-line systemic treatment of metastatic STS has comprised anthracycline based-chemotherapy. Second-line therapy options include agents such as ifosfamide, gemcitabine, and pazopanib, but the optimal sequential therapy for the management of metastatic disease has yet to be defined. Trabectedin is one of the new molecules approved for patients in progression after first-line chemotherapy with anthracyclines or for those unfit for these agents. The compound is characterized by multiple potential mechanisms of action combining cytotoxic, targeted, and immunological effects. This article takes an in-depth look at the role of Trabectedin in the management of metastatic STS, including L-sarcoma and non-L-sarcoma.

Trabectedin (Ecteinascidin 743; ET-743) a tetrahydroisoquinoline alkaloid with potent antitumor activity isolated from Ecteinascidia turbinata. Trabectedin binds to the minor groove of DNA, blocks transcription of stress-induced proteins, induces DNA backbone cleavage and cancer cells apoptosis, and increases the generation of ROS in MCF-7 and MDA-MB-453 cells. Trabectedin has tje potential for soft tissue sarcoma and ovarian cancer treatment.

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