The roots of resistance

Development of Therapeutic-Grade Small Interfering RNAs by Chemical Engineering

“…As a scientific tool in mammalian cell cultures, the potency and specificity of unmodified synthetic siRNA may be considered sufficient, yet chemical engineering of siRNAs is a prerequisite to transform them into a novel class of safe therapeutics, a natural progression similar to the development of second generation ASO (Potera, 2007). Recent concerns regarding siRNA delivery and safety have dampened initial excitement and Big Pharma have recently down sized their investments in RNAi R&D (Ledford, 2010; Krieg, 2011; Schmidt, 2011). In particular, the size, lability, and negative charge of siRNAs severely complicate efficient intracellular delivery in vivo (Meade and Dowdy, 2009) and siRNA may trigger innate immune-response and lead to unintended deregulation of endogenous gene expression in several ways, as described in the following sections.…”

PLX4032 and melanoma: resistance, expectations and uncertainty

“…Pharmaceutical firms have already started clinical trials to test PLX4032 in combination with experimental drugs that inhibit MEK; it may be necessary to combine four or more drugs in these studies to create a potent cancer-fighting cocktail. PLX4032 is a good place to start, because it's highly selective targeting of BRAF means it is likely to have fewer unwanted side effects [15].…”