Highlights of This Issue

Abstract

Expression profiling of mRNA and microRNA for the 60 cell lines of the NCI-DTP drug screen (NCI-60) is reported in two high-quality Agilent microarrays. Comparison of these expression patterns with activity data for 1429 drugs obtained from the NCI-DTP drug screen shows: 1) broad coherent patterns of correlation between hundreds of genes and drugs, and 2) similarly coherent patterns of correlation between microRNAs and drugs, which implies a robust three-way combinatorial relationship between microRNA expression, mRNA expression, and pharmacological response. The study also reveals new classes of drugs acting in an inverse fashion from most currently used anticancer agents.Harikumar and colleagues studies demonstrate for the first time that activated protein kinase D (PKD) family members are overexpressed in pancreatic cancer. They evaluated antitumor activities of a novel orally bioavailable PKD family inhibitor CRT0066101 both in vitro and in vivo. They demonstrated that CRT0066101 blocked neurotensin-induced PKD activation as well as reduced proliferation, inhibited Hsp27 phosphorylation, and suppressed PKD-dependent NF-κB activation in multiple pancreatic cancer cells. CRT0066101 also inhibited tumor growth in both heterotopic and orthotopic pancreatic cancer models in nu/nu mice. Collectively, their study identified CRT0066101 as a potent inhibitor of PKD family and validated the role of PKD in pancreatic tumorigenesis.Treatment with the methylating agent temozolomide during and after radiotherapy improves survival in adult glioblastomas. To investigate underlying mechanisms, Bobola and colleagues showed that minimally cytotoxic doses of temozolomide produced dose-dependent radiosensitization in O6-methylguanine-DNA methyltransferase (MGMT)-deficient, MGMT-proficient, and MGMT- and mismatch repair-deficient glioblastoma cells. Ten-fold higher doses were required for MGMT+ and MGMT-MMR- cells, suggesting that adducts in addition to O6-methylguanine and repair pathways other than MGMT are involved in radiosensitization. In accord, suppressing alkyladenine-DNA glycosylase reduced the temozolomide dose-dependence of radiation killing, implicating 3-methyladenine as a radiosensitizing lesion. These results suggest new strategies to combat resistance to concurrent temozolomide radiotherapy.Glioblastomas are invasive brain tumors with poor prognosis. HSP90 molecular chaperone inhibitors deplete multiple oncogenic HSP90 ‘client’ proteins that are important for the malignant behavior of glioblastomas. Gaspar and colleagues investigated the molecular and therapeutic effects of the geldanamycin-based HSP90 inhibitor 17-AAG (tanespimycin) and the new resorcinylic diaryl isoxazole HSP90 inhibitor NVP-AUY922 in adult and pediatric glioblastoma models. The results established mechanistic proof of the concept for the potential of novel synthetic HSP90 inhibitors in these tumors, either alone or incombination with PI3 kinase or MEK inhibitors.