Highlights of This Issue

Abstract

Numerous biologics have been developed to treat tumors by means of TRAIL apoptosis signaling. However, all efforts have thus far failed in early clinical stages due to poor antitumor efficacy. Here, Gieffers and colleagues introduced a novel compound class by fusing an in silico–designed TRAIL mimic to human Fc and created a hexavalent TRAIL receptor agonist with an overall antibody-like shape and volume. In contrast to anti-TRAIL receptor antibodies, these molecules induce spatially-defined clusters of TRAIL receptors and efficiently triggered tumor regression in vivo without the need of secondary cross-linking by Fc-receptors on the surface of immune cells.A novel targeted delivery system was developed by conjugating a urokinase plasminogen activator (uPA) antibody (ATN-291) with liposomal nanobins in order to specifically deliver a therapeutic cargo inside ovarian cancer cells. These targeted nanobins loaded with arsenic trioxide were efficiently internalized by cancer cells while normal mesothelial cells were not affected. The uPA-targeted nanobin also reduced tumor burden in an ovarian cancer xenograft model through the efficient induction of apoptosis and selective inhibition of tumor growth. These uPA-targeted nanobins could serve as a new platform for the treatment of malignancies overexpressing urokinase, including ovarian and breast cancers.Approved VEGFR inhibitors cannot bring out adequate potency in cancer therapy due to their severe toxicities. In this study, Fujita and colleagues developed TAS-115, a small molecular inhibitor of VEGFR/MET with minimized toxicity. TAS-115 offers potency that is comparable to existing VEGFR and MET inhibitors but with less damage to various normal cells than other VEGFR inhibitors. The high selectivity of TAS-115 for kinases and cells minimized toxicity and allowed improved potency without dose reduction or a washout period. These findings suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved efficacy and tolerability.PARP inhibitors have been used in therapy of hormonally regulated solid tumors; however, the effects of the endogenous hormonal milieu on their therapeutic efficacy are unknown. Here, Janzen and Paik et al. show that PTEN-null endometrial tumors were resistant to PARP inhibitors when estrogen levels were high, but remarkably became sensitized to this therapy with a decrease in estrogen. Estrogen deprivation caused an increase in serum concentration of PARP inhibitor resulting in sustained PARP inhibition in the tumor and decreased expression and function of Rad51, a key protein in homologous recombination. These findings suggest that estrogen depletion enhances response to PARP inhibitors.