Nucleic Acid Therapies for Cancer Treatment

Abstract

A better understanding of the biochemical pathways mediating tumor growth and progression has provided a new set of targets for therapeutic intervention. The ability to target highly specific segments of genetic material using oligonucleotide probes has been the subject of nucleic acid based therapy and is being applied to a variety of human diseases, including cancer. This chapter will discuss the various strategies utilizing nucleic acids for inhibiting gene transcription and translation with a major focus on RNAi and antisense oligodeoxynucleotides. Specific targets will be described and results of preliminary clinical trials reported. Future challenges in the clinical translation of nucleic acid treatments will also be described.

Clinical applications of aptamers and nucleic acid therapeutics in haematological malignancies

“…One of these, Genasense (oblimersen) (Genta Inc., Berkeley Heights, NJ, USA), targets the anti‐apoptotic gene BCL2 , which is over‐expressed in a wide variety of tumour types and is associated with increased resistance to radiation and chemotherapy (Klasa et al , 2002). In cell lines and animal models, this ASO has been shown to decrease tumour BCL2 expression and promote apoptosis (Vogl & Gewirtz, 2008). Phase II/III clinical trials have been conducted with oblimersen (through intravenous and subcutaneous routes of administration) in patients with chronic lymphocytic leukaemia (CLL), acute myeloid leukaemia (AML), multiple myeloma, non‐Hodgkin lymphoma and melanoma (Klasa et al , 2002; Bhindi et al , 2007; Rayburn & Zhang, 2008).…”

“…This ASO has been combined with chemotherapy and bone marrow transplantation in chronic myeloid leukaemia (CML) patients (phase II: NCT00002592), and also in patients with advanced haematological malignancies (phase I: NCT00780052) to purge the ex vivo bone marrow stem cells. It has been shown to suppress MYB mRNA levels in approximately half of the patients studied and to lead to complete cytogenetic remission post‐transplantation (Vogl & Gewirtz, 2008). A second gene associated with apoptosis inhibition is the X‐linked inhibitor of apoptosis ( XIAP ).…”

“…The overexpression of XIAP inhibits apoptosis caused by chemotherapy, radiation and growth‐factor deprivation through inhibition of caspase activity and its overexpression in AML is associated with a poor clinical outcome. In xenograft models, the ASO inhibited XIAP protein expression and enhanced chemotherapeutic activity (Vogl & Gewirtz, 2008). In addition, a phase I/II study testing the effectiveness of this ASO combined with chemotherapy for refractory or relapsed AML patients has recently been completed (NCT00363974), with a positive clinical response reported and limited side effects (peripheral neuropathy in <4% patients) (Aegera Therapeutics, Quebec, Canada) (Schimmer et al , 2009).…”

Delivery of Intracellular-Acting Biologics in Pro-Apoptotic Therapies

“…2). Single-stranded antisense ODN are thought to function by multiple mechanisms including translational arrest due to steric blockage of ribosomes by ODN-mRNA Watson-Crick base pairing and also through RNase-H-mediated cleavage of both the ODN and mRNA strands [65]. Endogenous RNAi molecules in the form of microRNA (miRNA) enter the cytoplasm after transcription, or alternatively, functionally-similar dsRNA can be exogenously delivered.…”

“…Initial RNAi applications in cancer therapy were primarily ODN approaches, and 21 example gene targets that have been pursued with antisense directed at inducing apoptosis in breast cancer were reviewed in a 2002 report [247]. However, due to the subsequent elucidation of the enzymatic mechanism and higher potency of double-stranded siRNA, the field has predominantly shifted from ODN toward siRNA approaches for cancer therapies [65]. The more recent approaches have utilized siRNA to manipulate targets in the Bcl-2 family and IAPs, in addition to other targets related to cell signaling, viral oncogenes, cell cycle, metabolism, and nutrient transport [248].…”