Targeted therapy of DNA tumor virus-associated cancers using virus-activated transcription factors

Area of Science:

• Oncology
• Gene Therapy
• Virology

Background:

• DNA tumor viruses subvert cellular processes by inactivating tumor suppressors like pRB and p53, activating oncogenic transcription factors (e.g., E2Fs).
• This viral oncogene activity presents a therapeutic vulnerability for DNA tumor virus-associated cancers.

Purpose of the Study:

• To develop and evaluate a novel gene therapy strategy for DNA tumor virus-associated cancers.
• To engineer a synthetic gene expression system (pESM6) that is specifically regulated by viral oncogenes.

Main Methods:

• Constructed a synthetic E2F-regulated gene expression system (pESM6) incorporating E2F-responsive elements and binding sites for Sp1 and CTF/NF1.
• Assessed pESM6's transgene expression levels and regulatory activity in cancer cells versus normal cells.
• Evaluated the therapeutic efficacy of pESM6-driven cytosine deaminase expression in killing HPV-transformed cells and reducing tumor growth in vivo.

Main Results:

• pESM6 demonstrated high-level transgene expression, comparable to the CMV IE promoter, in cells with DNA tumor viral oncogenes.
• pESM6 exhibited minimal activity in non-transformed cells due to pRB-mediated repression.
• Gene therapy using pESM6 resulted in efficient killing of HPV-transformed fibroblasts and significant tumor mass reduction in a mouse model.
• pESM6 outperformed a previously reported E2F-regulated gene vector.

Conclusions:

• The pESM6 system offers a potent and specific gene expression platform for targeting DNA tumor virus-associated cancers.
• pESM6 holds significant potential for the development of novel gene therapies against these malignancies.