Silencing Cancer: A Meta-Analysis of RNAi Therapeutics for the Treatment of Cancer in Phase I Clinical Trials

Abstract

Due to the poor prognosis and limited treatment options associated with advanced stage cancers, additional therapeutic approaches are urgently needed. Recently, RNA interference (RNAi) therapeutics have emerged as a promising new anticancer therapy by targeting genes involved in cancer formation and progression. Several Phase I clinical trials treating patients with advanced cancers have been completed. The clinical benefit has, however, varied widely across these trials; thus, selection of clinical factors for implementation in future clinical trials and the overall efficacy of RNAi-based therapeutics remain unclear. In this thesis, a meta- analysis of Phase I clinical trials was performed to better understand the efficacy of RNAi therapeutics and the clinical factors that affect this efficacy. Ten Phase I clinical trials were identified, which together included 219 advanced cancer patients eligible for response rate evaluation. The overall pooled response rate of patients treated by RNAi therapeutics was 49% (95% confidence interval [CI]: 25%-74%). Subgroup meta-analyses identified the use of short hairpin RNAs (shRNAs), targeting of oncogenes, and treatment of patients with only one type of cancer as factors associated with greater clinical response. On the other hand, usage of lipid-based delivery and targeting of multiple genes were not associated with clinical benefit. Associations of patient cancer type with response rate and the potential use of RNAi therapeutics in personalized cancer therapies were also evaluated. To my knowledge, this thesis presents the first meta-analysis of RNAi therapeutics for cancer treatment, confirming the efficacy of this novel therapy and establishing the effect of different clinical factors on clinical benefit. As this class of therapeutics continues to progress, the information presented may help improve the development of targeted RNAi-based cancer therapies and clinical trial designs.