Genomic Profiling of Metastatic Uveal Melanoma and Clinical Results of a Phase I Study of the Protein Kinase C Inhibitor AEB071

Abstract

Up to 50% of patients with uveal melanoma (UM) develop metastatic disease, for which there is no effective systemic treatment. This study aimed to evaluate the safety and efficacy of the orally available protein kinase C inhibitor, AEB071, in patients with metastatic UM, and to perform genomic profiling of metastatic tumor samples, with the aim to propose combination therapies. Patients with metastatic UM (n ¼ 153) were treated with AEB071 in a phase I, single-arm study. Patients received total daily doses of AEB071 ranging from 450 to 1,400 mg. First-cycle doselimiting toxicities were observed in 13 patients (13%). These were most commonly gastrointestinal system toxicities and were dose related, occurring at doses ≥700 mg/day. Preliminary clinical activity was observed, with 3% of patients achieving a partial response and 50% with stable disease (median duration 15 weeks).High-depth, targeted next-generation DNA sequencing was performed on 89 metastatic tumor biopsy samples. Mutations previously identified in UM were observed, including mutations in GNAQ, GNA11, BAP1, SF3B1, PLCB4, and amplification of chromosome arm 8q. GNAQ/GNA11 mutations were observed at a similar frequency (93%) as previously reported, confirming a therapeutic window for inhibition of the downstream effector PKC in metastatic UM.In conclusion, the protein kinase C inhibitor AEB071 was well tolerated, and modest clinical activity was observed in metastatic UM. The genomic findings were consistent with previous reports in primary UM. Together, our data allow envisaging combination therapies of protein kinase C inhibitors with other compounds in metastatic UM.

Uveal melanoma: progress in molecular biology and therapeutics

“…Tumor reduction by ⩾10% from baseline was observed in 34 patients (22%) [ClinicalTrials.gov identifier: NCT01430416]. 186 This effect was enhanced by the combination with MEK inhibitors, MEK162 and PD0325901, as shown in an in vivo animal study. 171 However, a phase Ib/II clinical trial that combined the MEK inhibitor binimetinib with AEB071 was terminated prior to initiation of the phase II trial [ClinicalTrials.gov identifier: NCT01801358].…”

MicroRNAs and Uveal Melanoma: Understanding the Diverse Role of These Small Molecular Regulators

“…This results in constitutive activation of the Gα downstream signalling cascade including activation of MAPK, PI3K-Akt-mTOR and Hippo (including YAP-TAZ) pathways [27][28][29][30][31][32]. A number of signalling cascade molecules, such as mitogen-activated protein kinase kinase (MEK) (selumetinib [33][34][35][36], trametinib [37]) and protein kinase C (PKC) (AEB071 [38,39]), have been targeted by therapeutics, with little or no change in patient overall survival [40][41][42]. Additionally, immunotherapy treatments targeting anti-CTLA-4 (ipilimumab [43]) and anti-PD-1 [44][45][46] have had low response rates; however, combination trials with immunotherapy agents, HDAC inhibitors (entinostat) and radioembolization are currently ongoing [40,[47][48][49].…”

Antitumor Drugs Based on Indolocarbazol Derivatives

“…Numerous studies have been carried out in mono-and 4 combined therapy of oncological diseases of various nosologies, for example, tumors of the nervous system [42][43][44], colon [45], lymphoma [46][47][48][49], Waldenstrom's myeloma and macroglobulinemia [50], non-small-cell lung cancer [51], prostate [52], ovaries [53], etc. Sotrastaurine (AEB071) (Novartis Pharmaceuticals, Switzerland) is a selective inhibitor of PKC β [57], which prevents the activation of T cells, has a piperazine ring; therefore, this compound can be attributed to the class of organic compounds known as n-arylpiperazines (Fig. 6) [55].…”

“…6) [55]. The use of sotrastaurine in the treatment of diffuse large B-cell lymphoma, stomach cancer [56], ulveal melanoma [57], psoriasis [58], as well as in kidney transplantation, has been investigated [59,60].…”