Gene silencing in the development of personalized cancer treatment: the targets, the agents and the delivery systems.
The advent of sophisticated experimental tools that can probe the molecular pathology of cancer has revealed a number of genes and gene families that could prove attractive targets for cancer therapy. Thus, gene silencing strategies have been envisioned to treat cancer by targeting the cancer cell's capacity to: (I) resist conventional treatment methods (chemotherapy and radiotherapy), (II) promote angiogenesis, and (III) metastasize and/or to survive microenvironments that normally would promote cell apoptosis/necrosis. The realization of such strategies is limited by the lack of pharmaceutically-viable technologies that enable the safe and effective delivery of gene-targeting agents to neoplastic cells following systemic administration. There are many reasons for this, including an incomplete understanding of how cancer cells respond when genes are silenced. Further the pharmacokinetic and pharmacodynamic attributes of gene therapy products are not well understood. This review will discuss gene therapy strategies that have been developed based on gene inhibition by the use of antisense oligonucleotides, ribozymes and RNA interference (RNAi). In this context, several particularly promising targets will be described, with a focus on strategies that have progressed to the stage where clinical trials have been initiated. The review highlights product development strategies that emphasize non-viral systemic formulations and the potential for delivery systems to become an enabling technology for development of effective gene therapy products.
Verreault
Maite
M
Advanced Therapeutics, British Columbia Cancer Agency, 675 West 10 Avenue, Vancouver, BC V5Z 1L3, Canada. mverreau@bccrc.ca
Webb
Murray S
MS
Ramsay
Euan C
EC
Bally
Marcel B
MB
D000818:Animals; D016503:Drug Delivery Systems; D020868:Gene Silencing / Q000502:physiology*; D015316:Genetic Therapy; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D034622:RNA Interference; D016372:RNA, Antisense; D016337:RNA, Catalytic
D016372:RNA, Antisense; D016337:RNA, Catalytic