Trametinib (GSK1120212) combined with Pazopanib(Votrient)?

Elodie_Espesset · March 30, 2017, 2:05pm

Here is a new study from Japan suggesting Trametinib could help overcome Pazopanib resistance in synovial sarcoma:

ncbi.nlm.nih.gov

Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells.

N Yokoyama, T Matsunobu, Y Matsumoto, JI Fukushi, M Endo, M Hatano, A Nabeshima, S Fukushima, S Okada and Y Iwamoto, Scientific reports, 28 2017 03

Synovial sarcoma (SS) is a rare high-grade malignant mesenchymal tumour with a relatively poor prognosis despite intensive multimodal therapy. Although pazopanib, a multi-kinase inhibitor, is often used for advanced SS, most cases eventually become resistant to pazopanib. In the present study, we investigated the mechanisms of acquired pazopanib resistance in SS. To examine acquired pazopanib resistance, two SS cell lines, SYO-1 and HS-SY-II, were isolated after multiple selection steps with increasing concentrations of pazopanib. SYO-1 was also used in vivo. Then, pazopanib-resistant clones were investigated to assess potential mechanisms of acquired pazopanib resistance. Stable pazopanib-resistant clones were established and exhibited enhanced cell cycle progression, cell growth with increased ERK1/2 phosphorylation, and higher sensitivity than parental cells to a MEK-inhibitor, trametinib, both in vitro and in vivo. Furthermore, addition of low-dose trametinib partially reversed the pazopanib resistance. In the pazopanib-resistant clones, dual specificity phosphatase 6 (DUSP6) was downregulated. Inhibition of DUSP6 expression in parental HS-SY-II cells partially recapitulated acquired pazopanib resistance. Acquired pazopanib resistance in SS was associated with activation of ERK1/2 through downregulation of DUSP6 expression. Simultaneous treatment with pazopanib and a MEK inhibitor could be a promising strategy to overcome pazopanib resistance in SS.

Interestingly, a clinical trial with this combination started in 2011 and is still active but not recruiting anymore:

Does anybody have experience with this trial?

Elodie_Espesset · April 6, 2017, 1:46am

The results of this trial were presented at AACR and they look rather disappointing:
http://clincancerres.aacrjournals.org/content/early/2017/04/04/1078-0432.CCR-17-0272
It’s not clear whether any synovial sarcoma patient participated in this trial.

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Trametinib (GSK1120212) combined with Pazopanib(Votrient)?

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