Docetaxel-loaded nanoparticles shrink human tumors

Abstract

Engineering a patient's own T cells to express tumor-targeting het-erodimeric T-cell receptors (TCRs) is a promising therapeutic strat-egy. Even so, development of this method has been undermined by unintended dimerization of endogenous and exogenous TCR chains, resulting in hybrid receptors that lead to off-target effects and autoim-munity, and by suboptimal expression of the introduced tumor-spe-cific TCR. Provasi et al. overcome these obstacles by first disrupting the endogenous TCR a and b chains using zinc-finger nucleases. Subsequent expression of tumor-targeting TCR chains delivered by lentiviral vectors produced high levels of expression of the expected antigen-specific TCRs. Tested in a series of experimental mouse mod-els, the engineered cells did not set off an auto-immune response and protected the mice against leukemia. (Nat. Med. advance online publication, doi:10.1038/nm.2700, 1 April 2012) JK Drug lead for osteoarthritis Osteoarthritis occurs when synovial joints fail. Drugs that alter the course of this disease, rather than simply alleviate symp-toms, are in clinical trials, but none have been approved yet in the United States or the European Union. Johnson et al. describe the discovery and characterization of a small molecule, kartogenin, that improves joint function and promotes the regeneration of cartilage in vivo in two rodent models of chronic and acute joint injury. In vitro experiments indicated that kartogenin induces the differentiation of mesenchymal stem cells into cartilage cells (chondrocytes) and protects existing chondrocytes under patho-physiological conditions. The authors found that kartogenin binds filamin A, a protein that crosslinks actin filaments, through which it regulates the nuclear localization of a transcription factor com-plex of CBFb and RUNX2. Knockdown of either CBFb or RUNX2 with short-hairpin RNAs blocked the effect of kartogenin on cel-lular differentiation. Kartogenin is the first drug reported to tar-get filamin A and as such may complement other osteoarthritis drugs under development.