Lemur tail kinase 3 serves as a predictor of patient outcomes and a target for the treatment of ovarian cancer.

Lemur tail kinase 3 (LMTK3) belongs to a family of tyrosine kinases that are known to correlate with tumor grade and patient survival in some cancers. Here, we validated LMTK3 as a specific target and a prognostic biomarker in ovarian cancer (OC). In samples from 204 stage I-II OC patients, immunohistochemical studies revealed a higher cytoplasmic-to-nuclear staining intensity of LMTK3, which correlated with worse overall survival (p < 0.001). Efficacy studies utilizing novel LMTK3 binding peptides (LMTK3BPs) showed that all chemosensitive and chemoresistant OC cells were killed without affecting normal cells (p < 0.005), with synergistic effects shown following cisplatin and docetaxel treatment. In an orthotopic xenograft mouse model of OC, we saw a 35% tumor reduction in response to intravenous injections of 2 mg/kg LMTK3BP given three times a week for 3 weeks. Furthermore, in vivo safety studies showed no signs of toxicity after LMTK3BP treatment, even at doses as high as 40 mg/kg. This study highlights LMTK3 as a predictor of patient clinical outcomes. More importantly, novel LMTK3BPs represent potential safe treatment options, either alone or in combination with therapies, for OC.

Low levels of WRAP53 predict decreased efficacy of radiotherapy and are prognostic for local recurrence and death from breast cancer: a long-term follow-up of the SweBCG91RT randomized trial.

Downregulation of the DNA repair protein WD40-encoding RNA antisense to p53 (WRAP53) has been associated with radiotherapy resistance and reduced cancer survival. The aim of this study was to evaluate WRAP53 protein and RNA levels as prognostic and predictive markers in the SweBCG91RT trial, in which breast cancer patients were randomized for postoperative radiotherapy. Using tissue microarray and microarray-based gene expression, 965 and 759 tumors were assessed for WRAP53 protein and RNA levels, respectively. Correlation with local recurrence and breast cancer-related death was assessed for prognosis, and the interaction between WRAP53 and radiotherapy in relation to local recurrence was assessed for radioresistance prediction. Tumors with low WRAP53 protein levels had a higher subhazard ratio (SHR) for local recurrence [1.76 (95% CI 1.10-2.79)] and breast cancer-related death [1.55 (1.02-2.38)]. Low WRAP53 RNA levels were associated with almost a three-fold decreased effect of radiotherapy in relation to ipsilateral breast tumor recurrence [IBTR; SHR 0.87 (95% CI 0.44-1.72)] compared with high RNA levels [0.33 (0.19-0.55)], with a significant interaction (P = 0.024). In conclusion, low WRAP53 protein is prognostic for local recurrence and breast cancer-related death. Low WRAP53 RNA is a potential marker for radioresistance.