Highlights of This Issue

Insulin-like growth factor (IGF) signaling proteins are frequently overexpressed in pancreatic ductal adenocarcinoma (PDAC) and therapeutic targeting of the IGF pathway carries significant potential. Awasthi and colleagues evaluated BMS-754807, an IGF-1R and insulin receptor inhibitor, in experimental PDAC. BMS-754807 displayed strong inhibitory effects on phospho-IGF-1R and phospho-AKT signaling and led to antitumor effects in vitro and in vivo. BMS-754807 was particularly well combined with traditional gemcitabine cytotoxic therapy, as the BMS-754807+gemcitabine combination led to significant survival benefits over monotherapy groups. These findings lend specific support to the potential of BMS-754807 as a targeting agent for clinical PDAC therapy.

Chronic myelogenous leukemia (CML) was rapidly transformed, with median survival changing from 4 to nearly 20 years, by inhibition of a critical molecular aberration with a specific inhibitor. Equally important was the therapeutic timing, specifically administration of the targeted therapy to patients with newly diagnosed disease. Targeted therapies are often used in relapsed, metastatic malignancies in a setting similar to blast-crisis CML where response rates are less than 15%, all patients relapse, and median survival is approximately one year. The authors hypothesize that the imatinib-led revolution in CML, including the critically important factor of timing, may be applicable to other cancers.

Mutations in KRAS are prevalent oncogenic drivers in non-small cell lung cancer (NSCLC) and currently there are no effective therapies for KRAS-driven NSCLC patients. Acquaviva and colleagues examined the activity of ganetespib, an Hsp90 inhibitor, in lung cancer cell lines harboring a spectrum of KRAS mutations. As a single agent, ganetespib was potently cytotoxic. Interestingly, ganetespib sensitized mutant KRAS NSCLC cells to standard of care chemotherapeutics and its antitumor activity was potentiated by cotreatment with targeted MEK or PI3K/mTOR inhibitors both in vitro and in vivo. This study underscores the promise of ganetespib for the treatment of KRAS-driven NSCLC.

An important objective to assay drug efficacy in cancer is the identification of biomarkers predictive for the drug sensitivity of tumor cells. Moreaux and colleagues report the building of a gene-based DNA methylation score (DM score), which predicts for patients' overall survival as well as for the sensitivity of primary myeloma cells or human myeloma cell lines to DNA methyltransferase (DMNT) inhibitor. DM score could be useful to identify patients who could mostly benefit from DMNT inhibitor treatment. In addition, this study highlights epigenetically regulated prognostic genes, which could be involved in multiple myeloma disease development.