The natural killer (NK) type of aggressive large granular lymphocytic (LGL) leukemia is a fatal illness that pursues a rapid clinical course. There are no effective therapies for this illness, and pathogenetic mechanisms remain undefined. Here we report that the survivin was highly expressed in both aggressive and chronic leukemic NK cells but not in normal NK cells. In vitro treatment of human and rat NK-LGL leukemia cells with cell-permeable, short-chain C₆-ceramide (C₆) in nanoliposomal formulation led to caspase-dependent apoptosis and diminished survivin protein expression, in a time- and dose-dependent manner. Importantly, systemic intravenous delivery of nanoliposomal ceramide induced complete remission in the syngeneic Fischer F344 rat model of aggressive NK-LGL leukemia. Therapeutic efficacy was associated with decreased expression of survivin in vivo. These data suggest that in vivo targeting of survivin through delivery of nanoliposomal C₆-ceramide may be a promising therapeutic approach for a fatal leukemia.

The potential use of K-RAS mutation as a cancer screening biomarker has been investigated for many years. Numerous associations between K-RAS mutation and various cancers have been established, but these associations have not been translated into effective, cost-efficient cancer screening strategies. This lack of progress may be due to the existence of K-RAS mutation in nontumor tissues and/or using detection, rather than quantitation, of K-RAS mutation as the endpoint for cancer risk categorization. K-RAS mutation appears to be a useful prognostic biomarker for colon cancer. Recent progress toward sensitive and quantitative mutation characterization and the successful use of K-RAS mutation in a personalized medicine approach to targeted biological therapy selection are likely to re-direct and expand the use of K-RAS mutation as a cancer biomarker in the near future.

Aim This study quantified low-frequency KRAS mutations in normal lung and lung adenocarcinomas, to understand their potential significance in the development of acquired resistance to EGFR-targeted therapies. Materials & Methods Allele-specific Competitive Blocker-PCR was used to quantify KRAS codon 12 GAT (G12D) and GTT (G12V) mutation in 19 normal lung and 21 lung adenocarcinoma samples. Results Lung adenocarcinomas had KRAS codon 12 GAT and GTT geometric mean mutant fractions of 1.94 × 10−4 and 1.16 × 10−3, respectively. For 76.2% of lung adenocarcinomas, the level of KRAS mutation was greater than the upper 95% confidence interval of that in normal lung. Conclusion KRAS mutant tumor subpopulations, not detectable by DNA sequencing, may drive resistance to EGFR blockade in lung adenocarcinoma patients.