Abstract 3186: Characterizing the antitumor effects of inhibiting translation initiation in glioblastoma multiforme.
Bibliographic record
Abstract
Abstract Oncogene addiction is the process by which a tumor cell becomes increasingly dependent on the expression of a particular gene for the maintenance of its tumorigenicity. Alleviating this dependence via genetic or pharmacological means may profoundly inhibit tumor growth. However many cancers are not dependent on a single gene for survival. Glioblastoma Multiforme (GBM) presents itself with many genetic aberrations contributing to its aggressive phenotype. These include loss of PTEN, amplification of CDK4 and EGFR among others, making targeting a single genetic node ineffective where other oncogenic networks may buffer any therapeutic benefit. Over the last 10 years it has been shown that targeting protein translation initiation results in the simultaneous targeting of many oncogenic pathways. Translation initiation is highly implicated in tumorigenesis with over 10 initiation factors acting as either proto-oncogenes or tumor suppressors, the most well described being the eIF4E. The overexpression of eIF4E in many cancers results in messenger RNA discrimination giving rise to an increased translation of a subset of oncogenic mRNAs with highly structured 5’UTRs. However the precise role translation initiation plays in maintaining tumorigenicity in GBM and the subsequent anti-neoplastic properties of its inhibition are not known. Here, we characterize the anti-tumor effects of targeting protein translation in three glioblastoma cell lines U87MG, U251N and the highly aggressive U87ΔEGFR, using a small molecule inhibitor of eIF4E, 4EGI-1. We show that 4EGI-1 severely impairs cell survival over a 72 hour time interval, in a dose-dependent manner. This is marked by an arrest of cell proliferation starting at 24 hours, induction of apoptosis at 48 hours with increased annexin V staining and a decrease in cell motility. We found these effects coincide with a decrease in protein expression of several oncogenes with highly structured 5’UTRs after treatment with 4EGI-1 including cell proliferation proteins c-Myc and Cyclin D1 which are completely lost by 48 hours and regulators of apoptosis such as Bcl-xL, Mcl-1 and Survivin which decrease and are lost by 72 hours, while not affecting overall transcription of these genes. Our results demonstrate the sensitivity of gliomas towards inhibition of translation initiation. This further highlights translation regulation control as a strong force in cancer therapy, particularly in glioblastoma where options are limiting. Citation Format: Arjuna K. Rajakumar, Josephine Nalbantoglu. Characterizing the antitumor effects of inhibiting translation initiation in glioblastoma multiforme. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3186. doi:10.1158/1538-7445.AM2013-3186
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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 | 0.000 |
| 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".