A phase I trial of LXS196, a protein kinase C (PKC) inhibitor, for metastatic uveal melanoma.

BACKGROUND: Up to 50% of patients with uveal melanoma develop metastases (MUM) with a poor prognosis and median overall survival of approximately 1 year. METHODS: This phase I study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the oral protein kinase C inhibitor LXS196 in 68 patients with MUM (NCT02601378). Patients received LXS196 doses ranging from 100-1000 mg once daily (QD; n = 38) and 200-400 mg twice daily (BID; n = 30). RESULTS: First cycle dose-limiting toxicities (DLTs) were observed in 7/38 (18.4%) QD and 2/17 (11.8%) BID patients. Hypotension was the most common DLT, occurring at doses ≥500 mg/day, and manageable with LXS196 interruption and dose reduction. Median duration of exposure to LXS196 was 3.71 months (range: 1.81-15.28) for QD and 4.6 months (range: 0.33-58.32) for BID dosing. Clinical activity was observed in 6/66 (9.1%) evaluable patients achieving response (CR/PR), with a median duration of response of 10.15 months (range: 2.99-41.95); 45/66 had stable disease (SD) per RECIST v1.1. At 300 mg BID, the recommended dose for expansion, 2/18 (11.1%) evaluable patients achieved PR and 12/18 (66.7%) had SD. CONCLUSION: These results suggest manageable toxicity and encouraging clinical activity of single-agent LXS196 in patients with MUM.

Androgen-controlled specific gene expression in neuroblastoma cells.

In Kennedy's syndrome, a mutation in the androgen receptor (AR) gene leads to sensory and lower motor neurone degeneration, therefore genes that are regulated by androgens in neurones may be important in the process of motor neurone cell death. The aim of this study was to identify androgen-inducible genes in the human neuroblastoma cell line SH-SY5Y. We have shown that SH-SY5Y cells expressed the AR by Northern blot analysis using a 32P-labelled probe derived from a human AR cDNA. Differential display of mRNAs has been used to identify and clone putative genes that are regulated by androgens in SH-SY5Y cells. Nine cDNA fragments, ranging in size from 180 bp to 480 bp, corresponding to mRNA species which appear to be differentially expressed in response to 5 alpha dihydrotestosterone (DHT), have been successfully cloned. These are now being sequenced and used as hybridisation probes for Northern blot analysis in order to confirm their induction by DHT. Characterisation of these genes may provide clues to the mechanisms of motor neurone degeneration.