Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma

Abstract

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.

Dysregulated GPCR Signaling and Therapeutic Options in Uveal Melanoma

“…Furthermore, the inhibitors caused a strong synergistic growth inhibitory effect on UM cell lines and marked tumor regression in UM xenograft models. Recently, screening of drug combinations involving AEB701 in a large panel of UM patient-derived xenografts (PDX) also determined two non MEK inhibitors that could potentially be used in combination with PKC inhibitors as therapeutic strategies for metastatic UM (47). These were the p53-MDM2 inhibitor, CGM097 and the mTORC1 inhibitor, RAD001.…”

“…These were the p53-MDM2 inhibitor, CGM097 and the mTORC1 inhibitor, RAD001. AEB701 and CGM097 or AEB701 and RAD001 markedly reduced tumor growth and induced tumor regression (47). These studies provide evidence for a number of targeted therapies that may be evaluated in combination with MEK inhibitors or PKC inhibitors in clinical studies to improve the survival of patients with metastatic UM.…”

Reviving the guardian of the genome: Small molecule activators of p53

“…Yu et al, 2014). Novartis laboratories have also developed a novel MDM2:p53 protein inhibitor, a dihydroisoquinolinone derivative called NVP-CGM097, which, in addition to in vitro efficacy studies for AML and uveal melanoma, is currently undergoing phase I clinical trials in patients with selected advanced solid tumors (Carita et al, 2016; Holzer et al, 2015; Weisberg et al, 2015) (NCT01760525). Analysis of patient tumors by intersecting high-throughput cell line sensitivity data with genomic data from the ongoing trial has identified distinct p53 target genes that predict sensitivity to NVP-CGM097, a genetic signature that can be used for selection of patients that would be most sensitive to treatment with NVP-CGM097 or other MDM2 antagonists (Jeay et al, 2015).…”

Therapeutic targeting of oncogenic transcription factors by natural products in eye cancer

“…Combined treatment of MAPK and PKC inhibitors demonstrated synergistic antitumor effects [70]. Dual inhibitions of PKC/p53-MDM2 and PKC/mTORC1 were also found to regress preclinical models of metastatic UM tumors in a synergistic manner [71]. …”