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Targeted suppression of tumor growth by CREPT promoter-driven diphtheria toxin fragment A
Jingya Li1,2, Mengdi Li1, Wenchen Wang3,4
1State Key Laboratory of Membrane Biology, School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing, China.
Abstract:
Despite significant advancements in diagnosis and treatment, cancer remains a leading cause of mortality globally. Cancer gene therapy has emerged as a promising strategy, with numerous clinical trials demonstrating its efficacy in targeting tumor cells, vasculature, and immune components. However, precise and selective gene expression regulation remains a challenge. In this study, we demonstrated that the CREPT (cell-cycle related and expression-elevated protein in tumor) promoter holds great potential for targeted cancer gene therapy. CREPT, a tumor-promoting protein as a positive regulator of gene transcription, is highly expressed across various cancer types while exhibiting minimal expression in normal tissues. The CREPT promoter mediated robust and tumor-selective transgene expression in vivo following both local and systemic administration, with only minimal off-target expression detected in blood and none in normal organs. Leveraging this specificity, we engineered an adenovirus encoding diphtheria toxin fragment A under CREPT promoter regulation. This construct was selectively expressed and inhibited protein synthesis, leading cancer cell death in vitro and in vivo. These findings demonstrate that the CREPT promoter may serve as a useful regulatory element for the development of targeted cancer gene therapy.
Insights
The CREPT promoter shows promise for targeted cancer gene therapy by driving gene expression specifically in tumors, not normal tissues. This allows for effective cancer cell killing with minimal side effects.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Cancer remains a major global health challenge despite treatment advances.
- Gene therapy offers a promising approach for cancer treatment, but precise gene regulation is difficult.
- Tumor-specific promoters are crucial for selective gene delivery in cancer therapy.
Purpose of the Study:
- To evaluate the potential of the CREPT promoter for targeted cancer gene therapy.
- To assess the tumor-specific expression driven by the CREPT promoter in vivo.
- To develop and test a gene therapy construct utilizing the CREPT promoter for cancer cell ablation.
Main Methods:
- Investigated the CREPT promoter's activity in various cancer types and normal tissues.
- Engineered an adenovirus carrying the diphtheria toxin fragment A gene under CREPT promoter control.
- Assessed transgene expression and therapeutic efficacy in vitro and in vivo models.
Main Results:
- The CREPT promoter demonstrated high expression in diverse cancer types with minimal activity in normal tissues.
- Robust and tumor-selective transgene expression was observed following both local and systemic administration.
- The CREPT-driven diphtheria toxin construct effectively induced cancer cell death in vitro and in vivo.
Conclusions:
- The CREPT promoter is a highly specific regulatory element for targeted cancer gene therapy.
- This promoter enables selective transgene expression in tumors, minimizing off-target effects.
- The CREPT promoter holds significant potential for developing novel, targeted cancer therapeutics.
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