Highlights of This Issue

To assess the utility of cell-based models in cancer pharmacogenomic biomarker discovery, Wheeler and colleagues compared genome-wide association study results of paclitaxel-induced cytotoxicity in lymphoblastoid cell lines (LCL) and paclitaxel-induced peripheral neuropathy in breast cancer patients. Significant overlap between the clinical and LCL studies was observed, confirming a role for the LCL model in the analysis of a subset of genes involved in patient paclitaxel-induced toxicity. One overlap gene, RFX2, was functionally validated in a nerve cell model of paclitaxel response. These results are consistent with an underlying polygenic architecture for paclitaxel-induced toxicity and inform future studies of related phenotypes.

Toll-like receptors (TLR) that recognize microbial components and trigger innate immune responses are expressed by chronic lymphocytic leukemia (CLL) cells. Fonte and colleagues asked if TLR stimulation might modulate the leukemic cell response to therapy. In vitro, different TLR ligands protected CLL cells from drug-induced cell death in a sizable proportion of cases. The molecular pathways involved include distinct molecules such as lymphotoxin and mir-155-3p. Hence, leukemic cell drug sensitivity may be modulated in vitro by TLR stimulation, likely mirroring the in vivo influence of microenvironmental signals. Lymphotoxin and mir-155-3p warrant further validation as markers of chemoresistance.

The achievement of complete tumor remission is the ultimate goal of cancer therapy. Kim and colleagues utilized engineered mesenchymal stem cells coexpressing dodecameric TRAIL (dTRAIL) and HSV-TK (MSC/dTRAIL-TK) and showed combinatory antitumor activities of dTRAIL and HSV-TK/ganciclovir (GCV) in an experimental metastasis model of renal cell carcinoma. In addition, MSC/dTRAIL-TK was preferentially located in the vicinity of tumor nodule sites within the lung tissue of metastatic tumor-bearing mice. Most importantly, triple administration of MSC/dTRAIL-TK with GCV could exhibit 100% survival. These findings provide a promising therapeutic strategy for complete cure of metastatic tumor by simple, repeated injection of MSC/dTRAIL-TK.

Defining appropriate dosing regimens for anticancer drugs in children represents a major challenge. Veal and colleagues show how an adaptive dosing approach can be successfully utilized to reduce interpatient variability in 13-cis-retinoic acid exposure in neuroblastoma patients. The study revealed that reduced body weight–based dosing should not be implemented for children <12 kg and that increased doses may be beneficial for children unable to swallow 13-cis-retinoic acid capsules, a group representing the majority of high-risk neuroblastoma patients. The findings highlight the importance of using drugs optimally in poor prognosis tumor types and the need for appropriate drug formulations for all patients.