siRNA-based Therapeutics for Oncology

siRNA Technology and Delivery System

Small interfering RNA (siRNA) has been investigated as an effective treatment for various diseases to block multiple disease-causing genes. To increase efficacy and potency in RNA interference (RNAi) for in vivo use, numerous chemical modifications have been proposed. Rational chemical designs make it more likely that the siRNA passenger strands will be modified than the siRNA guide strands. Besides, other strategies have been developed to deliver siRNAs safely in the cytoplasm. To date, significant progress has been made in recent years for the delivery of siRNA to tumors, and several promising siRNA delivery platforms have begun to emerge. The currently developed siRNA delivery systems for cancer therapy mainly include:

1. Chemical modifications of siRNA
2. Lipid-based siRNA delivery system
3. Polymer-based siRNA delivery system
4. Conjugate siRNA delivery systems
5. Co-delivery of siRNA and anticancer drugs
6. Inorganic nanoparticles (quantum dots, carbon nanotubes, gold nanoparticles)

Figure 1. Various types of siRNA cancer therapeutics. (Singh, 2018)

Among various kinds of delivery systems, lipid-based formulations and other lipid-like materials such as liposomes, niosomes, and stable nucleic acid lipid particles (SNALPs) have proved to be effective drug delivery systems as promising strategies for in vivo siRNA delivery.

siRNA Therapeutics for Oncology

Cancer is one of the major targets of RNAi-based therapy. Oncogenes, mutated tumor suppressor genes and several other genes contributing to tumor progression are potentially important targets. Besides surgery, classical chemotherapeutic and radiation methods, there is a need for novel and less aggressive treatments. RNAi can be considered as a promising alternative for cancer therapy. Such personalized medicine is likely to be more effective. The major advantage of RNAi therapeutics in cancer would be the simultaneous targeting of multiple genes, belonging to different cellular pathways that are involved in tumor progression. Another advantage of RNAi-based therapeutics involves the development of personalized anti-cancer drugs suitable for a particular patient.

Several popular siRNA targets in cancer have been reported. Here are some examples.

• Kinesin spindle protein (KSP) is a mitotic spindle motor protein that is involved in chromosome segregation during mitosis. Inhibition of KSP prevents the formation of bipolar mitotic spindles resulting in cell-cycle arrest and induction of apoptosis.
• Polo-like kinase 1 (PLK1) is a serine/threonine kinase that regulates multiple critical aspects of cell cycle progression and mitosis. Overexpression of PLK1 is observed in several human types of cancer and inhibition of PLK1 activity induces tumor cell apoptosis.
• Protein kinase N3 (PKN3) has been validated as a therapeutic target in cancer, as inhibition of this kinase resulted in the reduction of lymph node metastases in orthotopic prostate cancer models.
• M2 subunit of ribonucleotide reductase (RRM2), a gene involved in DNA replication.
• Vascular endothelial growth factor (VEGF) is believed to play a central role in the process of neovascularization, both in cancers as well as other inflammatory diseases.

siRNA in Clinical Trials for Cancer Therapy

After validation in the in vivo models, siRNA-based therapies will be introduced into clinical trials and it has been studied for treating diverse cancers. Some examples are shown in the following table.

To date, 20 clinically tested siRNA-based therapeutics have been administered by the intravenous (i.v.) route. Most of these siRNAs are carried by SNALPs. Although there are not a large number of siRNAs in advanced clinical trials, RNAi is a noteworthy mechanism for advanced novel therapeutics.

ALN-VSP02

Alnylam Pharmaceuticals developed ALN-VSP02, with two distinct siRNAs targeting KSP and VEGF, in a partnership with Tekmira for the use of SNALP as a carrier. In phase I, ALN-VSP02 was well tolerated and an anti-VEGF effect was observed in patients with advanced solid tumors with liver involvement. For clinical trial information, please refer to NCT00882180.

TKM-080301

TKM-080301 is a lipid nanoparticle formulation of a siRNA directed against PLK1. Anti-tumor activity and pharmacodynamic effects of PLK1 inhibition have been conclusively demonstrated in preclinical models. For clinical trial information, please refer to NCT01262235.

Please contact us for more information about siRNA-based therapeutics for oncology.

Reference

1. Singh, A.; et al. (2018). Advances in siRNA delivery in cancer therapy. Artificial cells, nanomedicine, and biotechnology. 46(2): 274-283.