SIK2 Sensitizes Ovarian Cancers to Paclitaxel
See article by Zhou et al., p. 1945
Salt-inducible kinase 2 (SIK2) is overexpressed in 30% of ovarian cancers and regulates centrosome splitting, mitotic progression, and activation of PI3K. A small-molecule inhibitor of SIK2 (ARN-3236) blocks the activity of SIK2 kinase, inhibits growth of ovarian cancer cell lines, and enhances sensitivity to paclitaxel in cell culture and in xenografts. ARN-3236 produces nuclear-centrosome dissociation, inhibits centrosome splitting, blocks mitotic progression, induces polyploidy, reduces AKT/survivin signaling, and triggers apoptotic cell death. Thus, ARN-3236 appears to be a drug with promise for enhancing primary treatment of ovarian cancers.
CDA Deficiency in Cancer
See article by Mameri et al., p. 2116
Mameri and colleagues report that cytidine deaminase (CDA) expression is downregulated in about 60% of tumors, mostly due to DNA methylation. Immunohistochemistry assessments of CDA expression status defined two new subgroups of tumors: CDA-deficient tumors and CDA-proficient tumors. CDA-deficient tumor cells, but not CDA-proficient tumor cells, present a marked susceptibility to aminoflavone, indicating that CDA expression status could be used to guide anticancer therapy. These results constitute a proof-of-concept that CDA deficiency may turn out to be a new predictive marker of susceptibility to antitumor drugs, thus opening up new possibilities for treating cancer.
Glioblastoma Survival Following Cytomegalovirus Vaccines and Dose-Intensified Temozolomide
See article by Batich et al., p. 1898
Patients with glioblastoma (GBM) have a median survival of <15 months despite surgical resection, high-dose radiation and chemotherapy with temozolomide (TMZ). Cytomegalovirus (CMV) proteins are expressed in over 90% of sampled GBM and expression is restricted to glioma cells not surrounding normal brain tissue. Batich and colleagues targeted the CMV antigen pp65 using dendritic cells (DCs) in combination with dose-intensified temozolomide (TMZ) and evaluated patient antitumor immune responses and survival. Despite increases in regulatory T cells after TMZ, patients treated with pp65-DCs showed increased pp65 immunity and long-term survival extending beyond predicted rates. Randomized studies on the prevention of generated regulatory T cells in the context of TMZ treatment and CMV targeting are under way.
PVT1-FOXM1 Loop Promotes Gastric Cancer Progression
See article by Xu et al., p. 2071
The lncRNA PVT1 is an important oncogene in human tumors; however, the mechanisms underlying the PVT1 functions remain elusive. Xu and colleagues demonstrate a reciprocal link between PVT1 and FOXM1 in gastric cancer (GC). PVT1 binds to the FOXM1 protein and enhances its stability, fulfills its functions in a FOXM1-mediated manner. Moreover, FOXM1 binds directly to and constitutively transactivates the PVT1 promoter. The authors report a novel mechanism by which transcript-induced lncRNA facilitate mRNA function by stabilizing a transcript-coding protein posttranscriptionally. PVT1 expression may be a useful biomarker for GC prognosis, and the PVT1-FOXM1 loop could be a therapeutic target.