Downregulation of XIAP expression induces apoptosis and sensitizes a panel of pediatric tumor cells to cytotoxic agents
Bibliographic record
Abstract
B25 Cancer is one of the most common causes of death in children. Traditionally pediatric cancers have been treated, with reasonable success, by a range of cytotoxic agents. However, several tumor types fail to respond to conventional therapy and remain resistant to cytotoxic agents. One explanation for this is the inability of the cells to successfully execute the apoptotic pathway in response to cytotoxic drug exposure. The endogenous inhibitor of apoptosis proteins (IAP’s) function by inhibiting effector (-9) and initiator (-3 and -7) caspases. Interestingly, the X-linked inhibitor of apoptosis (XIAP) is observed to be overexpressed in several tumor types. Furthermore, down regulation of XIAP sensitises adult tumor cells to chemotherapeutic agents and radiotherapy. In adult cells, a novel XIAP antisense oligonucleotide (ASO), AEG 35156 (Aegera Therapeutics Inc.), had been shown to induce cell death, sensitise cells to cytotoxics and delay growth of tumor xenografts. AEG 35156 is currently in adult Phase I clinical trials in North America and the UK. A role for XIAP in pediatric tumors has not been elucidated but high expression levels correlate with poor survival in childhood AML. We have screened a panel of pediatric cancer cell lines and shown that XIAP is widely expressed. In order to study the role of XIAP in pediatric cancer cell lines, we have used the novel XIAP ASO, AEG 35156, and demonstrated that XIAP can be down regulated in osteosarcoma, neuroblastoma, rhabdomyosarcoma and Ewing’s sarcoma cells. We have observed that in response to AEG 35156 there is an increase in cell death. Subsequent analysis demonstrated increased levels of cleaved caspase 3 and PARP suggesting the cell death observed was due to apoptosis. In long term clonogenic assays, AEG 35156 sensitized 791T (osteosarcoma), SH-SY5Y (neuroblastoma) and A673 (Ewing’s sarcoma) to clinically relevant cytotoxic agents. We are currently extending our in vitro panel of cell lines and evaluating the XIAP ASO in pediatric xenografts models as a single agent and in combination with cytotoxics.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".