Targeted cancer ablation via programmable sensing of amplified oncogenic RNA
Selectively eliminating cancer cells based on their oncogenic drivers holds great promise but remains challenging for targeted cancer therapy. Here, we present ORCA (Oncogenic RNA-triggered Cancer Ablation), a programmable and modular platform that couples RADAR-based detection of oncogenic RNA with conditional expression of therapeutic payloads in cancer cells. We identify RADAR sensors…
A groundbreaking platform called ORCA (Oncogenic RNA-triggered Cancer Ablation) has been introduced, offering a promising solution for selectively eliminating cancer cells based on their unique oncogenic drivers. This modular system combines RADAR-based detection of oncogenic RNA with the conditional expression of therapeutic payloads, specifically targeting cancer cells harboring amplified oncogenes.
The researchers focused on colorectal cancer (CRC) cells driven by extrachromosomal DNA-amplified MYC. They developed two orthogonal strategies to achieve targeted ablation of high-MYC cancer cells. The first strategy involves the use of anti-CD19 CAR-T therapy, while the second strategy utilizes enzyme-prodrug therapy. By delivering ORCA using adeno-associated virus (AAV), the team managed to suppress tumor growth in a subcutaneous xenograft model and prolong survival in a CRC liver metastasis model.
One of the key advantages of ORCA is its ability to establish oncogenic RNAs as actionable inputs for targeted cancer therapy. By leveraging programmable RNA sensing, ORCA provides a strategy to target tumors through the transcripts of otherwise difficult-to-drug oncogenes, such as MYC. This innovative approach holds great promise for the future of targeted cancer therapy, offering a new avenue for selectively eliminating cancer cells based on their unique genetic profiles.
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