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Published on: November 24, 2014
Transcriptional blocks limit adenoviral replication in primary ovarian tumor
Meredith A Preuss1, John T Lam, Minghui Wang
1Division of Human Gene Therapy and The Gene Therapy Center, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Purpose:
Despite the success of conditionally replicating adenoviruses in tumor models, clinical success has been limited when they are used as a single modality agent. Overcoming the disparity in efficacy between in vivo animal models and human use is a key hurdle for better conditionally replicating adenovirus therapy in humans. We endeavored to identify biological blocks to adenoviral infection and replication in tumor cells.
Experimental Design:
We hypothesized that the differences in adenoviral replication between ovarian cancer cell lines and patient tumor samples are the result of a block in viral RNA transcription. To test this hypothesis, established ovarian cancer cell lines and purified patient ovarian cancer cells were infected with wild-type adenovirus. RNA for early adenoviral genes E1A and E1B as well as the late transcripts for fiber and hexon were measured using real-time PCR.
Results:
Established ovarian cancer cell lines treated with wild-type virus had a lower E1A:E1B ratio than the patient samples. Additionally, the levels of fiber and hexon relative to E1A were also decreased in the patient samples compared with the established cell lines. These findings were consistent with an early- to late-phase block in the adenovirus replication cycle.
Conclusions:
These data suggest that the biology of abortive infection in the patient samples may be linked to a defect in the production of early and late viral transcripts. Identification of factors leading to abortive infection will be crucial to understanding the low viral replication in patient samples.
Insights
Tumor cells show limited adenovirus replication due to a block in viral RNA transcription. This hinders effective conditionally replicating adenovirus therapy in patients.
Area of Science:
- Oncolytic virotherapy
- Molecular virology
Background:
- Conditionally replicating adenoviruses show promise in preclinical tumor models.
- Clinical efficacy of these agents as single modalities is limited in humans.
Purpose of the Study:
- To identify biological barriers limiting adenovirus replication in human tumor cells.
- To explain the discrepancy between in vivo animal model success and human clinical outcomes.
Main Methods:
- Infection of ovarian cancer cell lines and primary patient tumor cells with wild-type adenovirus.
- Quantification of early (E1A, E1B) and late (fiber, hexon) viral gene RNA using real-time PCR.
Main Results:
- Patient tumor cells exhibited a higher E1A:E1B ratio compared to established cell lines.
- Decreased levels of late viral transcripts (fiber, hexon) relative to E1A were observed in patient samples.
- Findings indicate an early- to late-phase replication block in patient tumor cells.
Conclusions:
- Abortive adenovirus infection in patient samples may stem from defects in viral transcript production.
- Understanding factors causing abortive infection is critical for improving oncolytic adenovirus therapy.
