Targeted cancer ablation via programmable sensing of amplified oncogenic RNA
- 1Stanford University
Abstract
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 targeting the transcripts of endogenously amplified oncogenes, including MYC, FGFR2 and wild-type KRAS in colorectal and gastric cancer cells. Focusing on colorectal cancer (CRC) driven by extrachromosomal DNA-amplified MYC, we demonstrate targeted ablation of high-MYC cancer cells using two orthogonal strategies: anti-CD19 CAR-T therapy and enzyme-prodrug therapy. In vivo delivery of ORCA using adeno-associated virus (AAV) suppresses tumor growth in a subcutaneous xenograft model and prolongs survival in a CRC liver metastasis model. ORCA establishes oncogenic RNAs as actionable inputs for targeted cancer therapy via programmable RNA sensing, thus offering a strategy to target tumors through the transcripts of otherwise difficult-to-drug oncogenes such as MYC.
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BibTeX
@misc{zhang2026targeted,
title = {{Targeted cancer ablation via programmable sensing of amplified oncogenic RNA}},
author = {M. Zhang and Y. Hu and S. A. Yamada-Hunter and E. Sotillo and H. Dai and C. C. Call and A. M. Tousley and S. J. Kim and W. Liu and M. M. Winslow and C. Mackall and X. J. Gao},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.02.763782},
url = {https://www.biorxiv.org/content/10.64898/2026.11.02.763782v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Targeted cancer ablation via programmable sensing of amplified oncogenic RNA
AU - M. Zhang
AU - Y. Hu
AU - S. A. Yamada-Hunter
AU - E. Sotillo
AU - H. Dai
AU - C. C. Call
AU - A. M. Tousley
AU - S. J. Kim
AU - W. Liu
AU - M. M. Winslow
AU - C. Mackall
AU - X. J. Gao
PY - 2026
DA - 2026/11/02
PB - bioRxiv
DO - 10.64898/2026.11.02.763782
UR - https://www.biorxiv.org/content/10.64898/2026.11.02.763782v1
AB - 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 targeting the transcripts of endogenously amplified oncogenes, including MYC, FGFR2 and wild-type KRAS in colorectal and gastric cancer cells. Focusing on colorectal cancer (CRC) driven by extrachromosomal DNA-amplified MYC, we demonstrate targeted ablation of high-MYC cancer cells using two orthogonal strategies: anti-CD19 CAR-T therapy and enzyme-prodrug therapy. In vivo delivery of ORCA using adeno-associated virus (AAV) suppresses tumor growth in a subcutaneous xenograft model and prolongs survival in a CRC liver metastasis model. ORCA establishes oncogenic RNAs as actionable inputs for targeted cancer therapy via programmable RNA sensing, thus offering a strategy to target tumors through the transcripts of otherwise difficult-to-drug oncogenes such as MYC.
ER -