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Ref Type Journal Article
PMID (27507190)
Authors Carita G, Frisch-Dit-Leitz E, Dahmani A, Raymondie C, Cassoux N, Piperno-Neumann S, Némati F, Laurent C, De Koning L, Halilovic E, Jeay S, Wylie A, Emery C, Roman-Roman S, Schoumacher M, Decaudin D
Title Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma.
Journal Oncotarget
Vol 7
Issue 23
Date 2016 Jun 07
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
GNAQ mutant uveal melanoma predicted - sensitive Everolimus + Sotrastaurin Preclinical - Pdx & cell culture Actionable In a preclinical study, treatment with the combination of Sotrastaurin (AEB071) and Afinitor (everolimus) inhibited tumor growth in patient-derived xenograft (PDX) models of uveal melanoma harboring GNAQ mutations, including tumor regression or stasis, and inhibited growth of GNAQ-mutant uveal melanoma cell lines in culture (PMID: 27507190). 27507190
GNA11 mutant uveal melanoma predicted - sensitive CGM097 + Sotrastaurin Preclinical - Pdx & cell culture Actionable In a preclinical study, treatment with the combination of Sotrastaurin (AEB071) and CGM097 resulted in tumor regression or stasis in patient-derived xenograft (PDX) models of uveal melanoma harboring GNA11 mutations, and induced apoptosis and inhibited growth of GNA11-mutant uveal melanoma cell lines in culture (PMID: 27507190). 27507190
GNAQ mutant uveal melanoma predicted - sensitive Binimetinib + Sotrastaurin Preclinical - Pdx & cell culture Actionable In a preclinical study, the combination of Binimetinib (MEK162) and Sotrastaurin (AEB071) inhibited tumor growth in patient-derived xenograft (PDX) models of uveal melanoma harboring GNAQ mutations, and inhibited growth of GNAQ-mutant uveal melanoma cell lines in culture (PMID: 27507190). 27507190
GNAQ mutant uveal melanoma predicted - sensitive CGM097 + Sotrastaurin Preclinical - Pdx & cell culture Actionable In a preclinical study, treatment with the combination of Sotrastaurin (AEB071) and CGM097 resulted in tumor regression or stasis in patient-derived xenograft (PDX) models of uveal melanoma harboring GNAQ mutations, and induced apoptosis and inhibited growth of GNAQ-mutant uveal melanoma cell lines in culture (PMID: 27507190). 27507190
GNA11 mutant uveal melanoma predicted - sensitive Binimetinib + Sotrastaurin Preclinical - Pdx & cell culture Actionable In a preclinical study, the combination of Binimetinib (MEK162) and Sotrastaurin (AEB071) inhibited tumor growth in patient-derived xenograft (PDX) models of uveal melanoma harboring GNA11 mutations, and inhibited growth of GNA11-mutant uveal melanoma cell lines in culture (PMID: 27507190). 27507190
GNA11 mutant uveal melanoma predicted - sensitive Everolimus + Sotrastaurin Preclinical - Pdx & cell culture Actionable In a preclinical study, treatment with the combination of Sotrastaurin (AEB071) and Afinitor (everolimus) inhibited tumor growth in patient-derived xenograft (PDX) models of uveal melanoma harboring GNA11 mutations, including tumor regression, and inhibited growth of GNA11-mutant uveal melanoma cell lines in culture (PMID: 27507190). 27507190