Selective targeting of MYC mRNA by stabilized antisense oligonucleotides

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• MYC is a proto-oncogene crucial for cancer development, but effective inhibitors are lacking.
• Targeting MYC translation presents a therapeutic strategy for MYC-driven cancers.
• Antisense oligonucleotides offer a potential approach for modulating MYC expression.

Purpose of the Study:

• To design and synthesize novel MYC-targeting antisense oligonucleotides (MYCASOs).
• To evaluate the efficacy of MYCASOs in reducing MYC mRNA and protein levels in cancer cells.
• To assess the therapeutic potential of MYCASOs in preclinical cancer models.

Main Methods:

• Synthesis of conformationally stabilized MYCASOs with locked nucleic acid (LNA) modifications.
• Treatment of MYC-expressing cancer cell lines with MYCASOs.
• Quantification of MYC mRNA and protein levels using RT-qPCR and Western blotting.
• Analysis of MYC mRNA cleavage via 5' Rapid Amplification of cDNA Ends (RACE).
• Assessment of cellular proliferation and gene expression changes.
• In vivo studies using a MYC-induced hepatocellular carcinoma mouse model.

Main Results:

• MYCASOs effectively decreased MYC mRNA and protein levels in cancer cells.
• MYCASO treatment led to significant inhibition of cancer cell proliferation.
• Specific perturbation of MYC-driven gene expression signatures was observed.
• In vivo, MYCASOs reduced tumor burden and improved survival in a hepatocellular carcinoma model.
• MYC protein levels were decreased within tumors following MYCASO treatment.

Conclusions:

• MYCASOs are effective chemical tools for modulating MYC activity in vitro and in vivo.
• These MYCASOs demonstrate promise as therapeutic agents for MYC-addicted cancers.
• The development of MYCASOs represents a significant advancement in targeting MYC for cancer therapy.