SIK2 Sensitizes Ovarian Cancers to Paclitaxel
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
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
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
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.
- ©2017 American Association for Cancer Research.