Abstract 3050: Inducing apoptosis in mantle cell lymphoma using inhibitors of cyclin-dependent kinases and the Bcl-2 inhibitor ABT-737
Bibliographic record
Abstract
Abstract Mantle cell lymphoma (MCL) is a cyclin D1 over-expressing B cell lymphoma which displays unregulated cell cycle progression driven by increased cyclin-dependent kinase (CDK) activity. We are investigating selective small molecule CDK inhibitors as potential therapeutics in MCL. AZD5438, flavopiridol, PD-0332991 and SNS-032 have distinct efficacies against different groups of CDKs. We hypothesize that inhibiting CDK-7 and -9 will be more effective in causing cell death in MCL than inhibiting CDK-1,-2,-4 and- 6. In Jeko-1 cells, AZD5438 and flavopiridol displayed time- and dose-dependent inhibition of cell proliferation, inhibition of the phosphorylation of CDK substrates, and G1 cell cycle arrest; while PD-0332991 showed a strong cytostatic effect by inhibiting cell proliferation and arresting cells at the G1 phase, but not inducing apoptosis to the same extent as flavopiridol and AZD5438. In addition, AZD5438, flavopiridol and SNS-032 induced caspase-3 activation and down regulation of Mcl-1, but no apoptotic effect was shown in PD-0332991 treated cells. These differential effects may be associated with essential survival functions conferred by genes regulated by CDK7/9 including the pro-survival protein Mcl-1. However, there were no apoptotic effects observed with any of these CDK inhibitors in Granta-519 cells, which may due to high Bcl-2 levels. We are now exploring combinations of CDK7/9 inhibitors with a small molecule inhibitor of Bcl-2 function. We expect CDK7/9 inhibition will reduce Mcl-1 expression at the transcriptional level and thereby sensitize both Jeko-1 and Granta-519 cells to Bcl-2 inhibition. We will also investigate Mcl-1 and Bcl-2 levels in clinical samples to see if there is a correlation with outcomes. Our expectation is that Mcl-1/Bcl-2 levels may ultimately become a useful prognostic and predictive biomarker in MCL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3050. doi:1538-7445.AM2012-3050
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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".