ATPS-65AN ONCOLYTIC MYXOMA VIRUS CONSTRUCT (M011L KNOCK-OUT) INDUCES APOPTOSIS AND IS A POTENT PRO-APOPTOTIC THERAPY IN BOTH HUMAN AND IMMUNOCOMPETENT MURINE GLIOBLASTOMA CANCER STEM CELLS MODELS
Bibliographic record
Abstract
BACKGROUND: GBM is a deadly brain cancer with an average survival of 12 months. In the past, a treatment-resistant Brain Tumor Initiating Cell (BTIC) compartment has been identified and is thought to drive tumor recurrence. One experimental strategy to target BTICs is the use of oncolytic viruses (OVs). A number of studies have found that OVs may be used to target BTICs in vivo and that some require the innate or acquired immune response for their efficacy. Myxoma Virus (MyxV-WT) is a promising oncolytic virus that is highly effective against glioma cell lines but less effective for BTICs. We hypothesized that MyxV virally encoded anti-apoptotic proteins is a limiting factor for oncolytic efficacy in BTICs. By manipulating MyxV-WT and genetic deletion of the anti-apoptotic gene M11L we will have better therapeutic efficacy and enhanced cell death in BTICs that might be synergistic with conventional Temozolomide therapy. RESULTS: We utilized a panel of patient-derived BTICs and developed syngeneic mBTIC line arising in Trp53+/-/Nf1+/- mice. We compared the efficacy of the MyxV-WT with the MyxV, in which the anti-apoptotic protein M011L has been deleted. We found that MyxV-M011L-KO induced significant amount of intrinsic apoptosis as compared to MyxV-WT, resulting in robust BTICs cell death. Silencing the Bax significantly blocked the induction of apoptosis and cell death induced by MyxV-M011L-KO. Using immunocompetent orthotopic syngeneic glioma model, we found that M011L-KO treatment statistically prolonged survival (38 days) as compared to WT or inactivated virus (30 and 27 days respectively) whereas addition of clinical relevant dose of TMZ resulted in 50% long-term survival rate (>90 days). In contrast, MYXV-M011L-KO treatment in SCID models, failed to provide significant survival advantage in both human and murine BTICs. These results suggest that intact immune response is critical factor regulating oncolytic efficacy of MYXV-M011L-KO in vivo.
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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 | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".