Allen et al. Page 2087

Recombinant TRAIL and TRAIL-receptor agonist antibodies are being developed as antitumor therapies based on the tumor-selective cytotoxicity that result from ligation of the proapoptotic death receptors DR4 and DR5. To overcome limitations of available TRAIL receptor-targeting agents, Allen and colleagues engineered stable DR4 agonist proteins, DR4 Atrimer complexes, which mimic the trimeric geometry of natural ligand binding using tetranectin as a platform. DR4 Atrimer complexes are highly specific to DR4 and possess superior safety and affinity. This approach uses protein engineering to overcome limitations of available therapies and may be extended to other attractive therapeutic targets to improve therapeutic responses.

Liu and Korc Page 2138

Cyclin D-Cdk4/6 is an attractive therapeutic target in pancreatic ductal adenocarcinoma (PDAC). Liu and Korc determined that the Cdk4/Cdk6 inhibitor PD-0332991 promoted invasion, epithelial-mesenchymal transition, and Smad transcriptional activity in human pancreatic cancer cell lines expressing wild-type Smad4. Moreover, the type I TGF-β receptor kinase inhibitor SB-505124 blocked EMT induction by PD-0332991 and enhanced its growth inhibitory actions. Thus, by activating Smad-dependent TGF-β signaling in pancreatic cancer cells, targeting Cdk4/Cdk6 may be deleterious in the 45% of PDACs that express wild-type Smad4. Conversely, combining PD-0332991 and SB-505124 may represent a novel therapeutic strategy in this subgroup of PDAC patients.

Weisbart et al. Page 2169

The therapeutic use of antibodies is restricted by limited access of antibodies to intracellular compartments. To overcome this limitation, Weisbart and colleagues developed a cell-penetrating monoclonal antibody, mAb 3E10, as an intracellular delivery vehicle for the intracellular and intranuclear delivery of antibodies constructed as bispecific single-chain Fv fragments. In a proof-of-principle study, MDM2, an important target in cancer therapy, was successfully targeted in melanoma cells in vitro and in animal studies. The use of cell-penetrating bispecific antibodies in targeted molecular therapy will significantly broaden the spectrum of accessible intracellular targets and may have a profound impact in cancer therapy

Agnes et al. Page 2202

Epidermal growth factor receptors are overexpressed in glioblastoma. Agnes and colleagues modified a phage display peptide against EGFR with a discrete PEG linker and NIRF dye for optical imaging of brain tumors. In an orthotopic brain tumor model in mice, the imaging probe selectively accumulated in glioblastoma tumors overexpressing EGFR. Fluorescence molecular tomograpghy (FMT) was used to measure probe accumulation and showed that this novel EGFR probe had little association with normal brain tissue and was able to discriminate the levels of EGFR expressed on different tumor models. The probe may be used in screening and longitudinal studies of tumors overexpressing EGFR and may be potentially used during image-guided tumor resections.