654. Targeting Adenoviral Vectors for Use in Breast Cancer Gene Therapy
Bibliographic record
Abstract
The results of many cancer gene therapy clinical trials to date suggest that improvements must be made to increase gene delivery, expression levels, and/or potency of the genes in order to induce tumour regression. However, increasing any of these parameters will require additional safeguards to protect surrounding normal cells. Our goal is to develop adenoviral vector systems that target tumour cells transcriptionally (using various tumour- and tissue- specific promoters) as well as transductionally (by modifying the viral fiber protein to enhance binding to receptors on the tumour cell surface). We have isolated a novel promoter from the mammaglobin (MGB) gene that displays over ten-fold increase in expression levels in breast cancer cells relative to normal non-tumour cells (Shi, et al., 2004, Mol. Ther., 10:758–767; Shi, et al., 2006, J. Gene Med, in press). We have since developed a breast cancer targeted adenoviral (Ad) vector encoding the “suicide gene” herpes simplex virus (HSV)-1 thymidine kinase (TK) under the control of the MGB promoter (AdMGBTK). HSV-TK was chosen for this study because, in combination with nucleoside analogs, it has potential not only as a therapeutic, but also as an agent for non-invasive imaging of gene transfer in vivo. AdMGBTK, in combination with the prodrug ganciclovir (GCV), induces breast cancer-specific killing at levels comparable to a universal cytomegalovirus (CMV) TK vector. Combination with a radiolabeled TK substrate allows Positron Emission Tomography (PET) imaging in vivo, which has never been performed on breast cancer targeted vectors. In addition, we have engineered a modified-fiber virus to contain the ligand-binding domain of heregulin-α (HRG-α) within the fiber protein of Ad. HRG-α is a ligand for ErbB3 and ErbB4 receptors, both of which are over-expressed in many cancer types, including breast cancer. This modified-fiber virus demonstrated enhanced infection of tumour cells bearing ErbB3 and ErbB4. Generation of a vector expressing TK under the control of the MGB promoter and encapsidated within an HRG-modified fiber virus is in progress. This combination of transcriptional and translational targeting is expected to produce a highly specific breast cancer-targeted adenoviral vector which has potential as a clinical therapeutic.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.005 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".