Bcl-2 Antisense in the Treatment of Human Malignancies: A Delusion in Targeted Therapy

Abstract

Regulation of cell death (apoptosis) is frequently affected in the development of malignant diseases, and all molecular steps from extracellular signalling receptors through intracellular pathways, cell death rheostats and cell death executioners may be involved. Bcl-2 is an anti-apoptotic member of a family of anti- and pro-apoptotic proteins that is upregulated in a variety of cancers and specifically overexpressed through chromosomal translocation in some non-Hodgkin lymphomas. Experimental attenuation of Bcl-2 lowers the threshold for undergoing chemotherapy-induced apoptosis. Therefore, therapeutic targeting of Bcl-2 appears as an attractive approach currently intensely explored using mRNA degradation strategies and small inhibitory molecules. One phosphorothioate oligodeoxynucleotide antisense against Bcl-2 mRNA, oblimersen (Genasense, G3139), has been used in a substantial number of clinical trials. In this review we will discuss the current developments of G3139, and scrutinize its proposed mechanism of action. Several studies indicate that G3139 involves various intracellular mechanisms and modulation of the immune system. To this date G3139 has not been justified in cancer therapy due to modest or absent effects. But, surprisingly, some of its off-target effects may represent useful therapeutic principles. Therefore, antisense uptake improvements and new design of the oligonucleotide may provide us with useful therapeutics, including both the targeted gene and new anticancer mechanisms. This may be another example of how targeted therapy molecules evolve into multimodality drugs when moved from laboratory bench to bedside use, and illustrate our limited ability for target prediction and scant understanding of biological systems when designing therapeutic strategies.

Co-Inhibition of BCL-W and BCL2 Restores Antiestrogen Sensitivity through BECN1 and Promotes an Autophagy-Associated Necrosis

“…From a therapeutic perspective, these data also suggest that broad rather than specific BCL2 family member inhibitors will have greater clinical value and may explain the apparent lack of activity of targeted BCL2 antisense monotherapy in clinical trials [43]. Combination therapy with endocrine agents and broadly active small molecule inhibitors of BCL2 family members may delay, prevent, or reverse the acquisition of antiestrogen resistance in breast cancer patients and lead to significant improvements in survival.…”

Oligonucleotides designed to inhibit TLR9 block Herpes simplex virus type 1 infection at multiple steps

“…We postulate that when oligonucleotides are added 2 hours prior to infection, the majority are internalized and not available on the cell surface to interfere with viral attachment or entry, thus allowing for robust infection during these assays. Phosphorothioation of nucleci acids can lead to off-target effects, which in the case of oblimersen, a phosphorothioate antisense oligonucleotide directed against bcl-2 , results in useful therapeutic properties (Anderson et al, 2006; Gjertsen et al, 2007; Winkler et al, 2010). This may be the case for TLR9 oligonucleotides, which are potent antivirals even in TLR9 negative cells.…”

Non-coding RNAs as drug targets

“…During the years of Genasense' development and sometimes promising clinical trial results, the question was raised regarding whether understanding mechanism mattered 139,140 . A patient may not care about the mechanism of a successful drug, but knowing the mechanism of a drug development candidate will make it much more likely that the drug will be successful and applied in a manner most likely to be beneficial.…”