Priority Research Papers:
Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma
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Guillaume Carita1,*, Estelle Frisch-Dit-Leitz2,*, Ahmed Dahmani1, Chloé Raymondie1, Nathalie Cassoux3, Sophie Piperno-Neumann4, Fariba Némati1, Cécile Laurent5, Leanne De Koning6, Ensar Halilovic7, Sebastien Jeay7, Andrew Wylie7, Caroline Emery7, Sergio Roman-Roman2 , Marie Schoumacher2,*and Didier Decaudin1,4,*
1 Laboratory of preclinical investigation, Department of Translational Research, PSL University, Institut Curie, Paris, France
2 Department of Translational Research, Institut Curie, PSL University, Paris, France
3 Department of Ophthalmological Oncology, Institut Curie, Paris, France
4 Department of Medical Oncology, Institut Curie, Paris, France
5 Residual Tumor & Response to Treatment Lab, Department of Translational Research, Institut Curie, PSL University, Paris, Paris, France
6 RPPA Platform, Department of Translational Research, Institut Curie, PSL University, Paris, France
7 Novartis Institutes for Biomedical Research, Cambridge, MA USA
* These authors have contributed equally to this work
Didier Decaudin, email:
Keywords: xenograft models, cellular response to anticancer drugs, uveal melanoma, AEB071 combinations, synergy
Received: April 04, 2016 Accepted: May 10, 2016 Published: May 22, 2016
Uveal melanoma (UM) is the most common cancer of the eye in adults. Many UM patients develop metastases for which no curative treatment has been identified. Novel therapeutic approaches are therefore urgently needed. UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway, leading to the use of PKC inhibitors as a rational strategy to treat UM tumors. Encouraging clinical activity has been noted in UM patients treated with PKC inhibitors. However, it is likely that curative treatment regimens will require a combination of targeted therapeutic agents. Employing a large panel of UM patient-derived xenograft models (PDXs), several PKC inhibitor-based combinations were tested in vivo using the PKC inhibitor AEB071. The most promising approaches were further investigated in vitro using our unique panel of UM cell lines. When combined with AEB071, the two agents CGM097 (p53-MDM2 inhibitor) and RAD001 (mTORC1 inhibitor) demonstrated greater activity than single agents, with tumor regression observed in several UM PDXs. Follow-up studies in UM cell lines on these two drug associations confirmed their combination activity and ability to induce cell death. While no effective treatment currently exists for metastatic uveal melanoma, we have discovered using our unique panel of preclinical models that combinations between PKC/mTOR inhibitors and PKC/p53-MDM2 inhibitors are two novel and very effective therapeutic approaches for this disease. Together, our study reveals that combining PKC and p53-MDM2 or mTORC1 inhibitors may provide significant clinical benefit for UM patients.
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