Highlights of This Issue

Abstract

Therapeutics targeting Her2 have shown impressive clinical activity, although there are resistance mechanisms leading to treatment failure. Granzyme B (GrB) is an intensely cytotoxic protein used by NK and CTL to kill target cells. Cao and colleagues fused GrB to the anti-Her2 scFv 4D5. This construct showed specific apoptosis induction and cytotoxicity to Her2 cells in vitro through a defined, multimodal mechanism and was active against 1apatanib, Herceptin-resistant, and MDR-expressing cells. Tumor-targeted GrB localized in tumor xenografts and resulted in tumor suppression. These studies suggest that tumor-directed GrB constructs have excellent potential as novel therapeutic agents.Drug resistance is a major cause of treatment failure in ovarian cancer, emphasizing the need for drugs with novel mechanism of action. Xu and colleagues identified gp130 as an important drug target in ovarian cancer and have developed a first-in-class small-molecule gp130 inhibitor. SC144 can be used as a new tool to interrogate the gp130-implicated signaling pathways affecting several malignancies. More significantly, SC144 shows efficacy in in vivo models of human ovarian cancer and displays no significant off-target toxicity in normal tissues. Our study offers a new approach to treat diseases with altered gp130 signaling, including multiple types of cancers.ATM signals DNA double strand breaks (DSB) to cell cycle checkpoints and for repair. Defects in ATM confer radiosensitivity and chemosensitivity, making ATM an attractive target for anticancer chemotherapy. Batey and colleagues have identified a potent ATM inhibitor, KU59403, that sensitizes human tumor cells to radiation and topoisomerase poisons in a p53-independent manner. Importantly, KU59403 is the first ATM inhibitor to demonstrate good tissue distribution and chemosensitization of human tumor xenografts without major toxicity, providing the first advanced pre-clinical proof-of-principle data to justify developing ATM inhibitors for clinical use.Alternate angiogenic pathways and/or hypoxia-induced eptithelial-to-mesenchymal transition (EMT) may facilitate resistance to anti-VEGF therapy. Kutluk Cenik and colleagues investigated the efficacy and biological effects of BIBF 1120 (nintedanib), a balanced inhibitor of VEGF, PDGF, and FGF pathways in xenografts of lung and pancreatic cancer. BIBF 1120 potently reduced tumor vascular density and function and inhibited primary tumor growth and metastasis. Despite induction of hypoxia, chronic BIBF 1120 did not enhance EMT or tumor invasiveness, suggesting a balanced multitarget strategy may combat the development of resistance. Clinical studies of BIBF 1120 are underway.