Project Description
Detecting HBV-HCC with RNA logic sensors

The Challenge of Current Cancer Treatments

Chemotherapy, immune checkpoint blockade, and even many targeted therapies circulate throughout the body. They destroy cancer cells, but at the cost of harming healthy ones, producing toxic side effects and narrow therapeutic windows (Chhabra N. et al, 2021).

While cancer therapies have grown increasingly sophisticated, they remain constrained by a fundamental problem: most cancers lack a single biomarker that is both concentrated and specific enough to cancer cells to serve as a reliable therapeutic trigger (Batis N. et al, 2021). A biomarker might be overexpressed in tumor cells, but if it is also present in healthy tissues, activating therapy through it risks damaging the very body we are trying to heal.

The Need for Selective Approaches

This limitation explains why today's standard of care in oncology is largely systemic. In practice, patients often endure treatment as much as they benefit from it, highlighting the urgent need for safer and more selective approaches.

HBV-HCC as Target and Proof of Concept

We chose HBV-related Hepatocellular Carcinoma (HCC) as a target and proof of concept. More than 300 million people worldwide live with chronic hepatitis B, and up to half of HCC cases are linked to HBV infection (Yeh S.H. et al, 2023). For these patients, the burden of risk is immense: over 50% of HBV-HCC cases are diagnosed too late for curative treatment, when systemic approaches would be too harsh on the patient.

HCC biomarkers such as GPC3, AKR1B10, and RP11 are elevated in HCC tumors, yet they are also detectable in surrounding non-cancerous tissue. Relying on any one of them alone would cause devastating off-target effects (Zheng X. et al, 2022; Xiyong L. et al, 2015).

LiRA: A Logic-Gated Solution

If one signal is not enough, could combining multiple signals offer the precision we need? Inspired by the logic of AND-gates in computing, our team developed a programmable intracellular RNA "logic gate" system that activates only when two independent intracellular RNAs are detected.

Venn diagram showing logic gate approach

This design reduces off target effects in healthy tissue and creates a modular intracellular RNA-based logic gate system to target cancer cells.

The HBV-HCC Opportunity

HBV-HCC presents a unique opportunity. More than 90% of hepatocytes in HBV-HCC carry integrated HBV DNA (Lin S. et al, 2021), whose RNA transcripts can serve as highly specific triggers.

Paired with other HCC biomarkers, these viral integrations form the basis for an AND-gate therapeutic system that is both selective and broadly applicable.

To Smarter Therapies

This project reimagines cancer as a programmable decision-making process, opening a path toward safer, smarter treatments.

References

  1. Chhabra N, Kennedy J. A Review of Cancer Immunotherapy Toxicity: Immune Checkpoint Inhibitors. J Med Toxicol. 2021 Oct;17(4):411-424. doi: 10.1007/s13181-021-00833-8. Epub 2021 Apr 7. PMID: 33826117; PMCID: PMC8455777.
  2. Nikolaos Batis, Jill M. Brooks, Karl Payne, Neil Sharma, Paul Nankivell, Hisham Mehanna, Lack of predictive tools for conventional and targeted cancer therapy: Barriers to biomarker development and clinical translation. Advanced Drug Delivery Reviews. Volume 176,2021,113854,ISSN 0169-409X, https://doi.org/10.1016/j.addr.2021.113854.
  3. Yeh SH, Li CL, Lin YY, Ho MC, Wang YC, Tseng ST, Chen PJ. Hepatitis B Virus DNA Integration Drives Carcinogenesis and Provides a New Biomarker for HBV-related HCC. Cell Mol Gastroenterol Hepatol. 2023;15(4):921-929. doi: 10.1016/j.jcmgh.2023.01.001. Epub 2023 Jan 20. PMID: 36690297; PMCID: PMC9972564.
  4. Zheng, X., Liu, X., Lei, Y., Wang, G., & Liu, M. (2022). Glypican-3: a novel and promising target for the treatment of hepatocellular carcinoma. Frontiers in Oncology, 12. https://doi.org/10.3389/fonc.2022.824208
  5. Xiyong Liu, Sean K. Wang, Keqiang Zhang, Hang Zhang, Qin Pan, Zhiwei Liu, Hongming Pan, Lijun Xue, Yun Yen, Peiguo G. Chu, Expression of glypican 3 enriches hepatocellular carcinoma development-related genes and associates with carcinogenesis in cirrhotic livers, Carcinogenesis, Volume 36, Issue 2, February 2015, Pages 232–242, https://doi.org/10.1093/carcin/bgu245
  6. Lin, S. Y., Zhang, A., Lian, J., Wang, J., Chang, T.-T., Lin, Y.-J., Song, W., & Su, Y.-H. (2021). Recurrent HBV Integration Targets as Potential Drivers in Hepatocellular Carcinoma. Cells, 10(6), 1294. https://doi.org/10.3390/cells10061294