Targeting Susceptible Signaling Pathways in Chronic Lymphocytic Leukemia
Bibliographic record
Abstract
Chronic lymphocytic leukemia (CLL) is a cancer of B cells and is the most common leukemia in North America. Current therapies are fraught with challenges, and drug resistance and disease relapse remain common occurrences. Therefore, novel therapies and novel therapeutic strategies are needed to improve CLL therapy. Better yet, therapies targeted at specific weaknesses of CLL cells will ensure maximum efficacy and minimum adverse toxicity. To this end, this thesis focuses on targeting the susceptible BCR pathway and lysosome-mediated cell death pathway using gefitinib and lysosomotropic agents, respectively. Firstly, the novel use of the tyrosine kinase inhibitor gefitinib was explored. This drug was most effective in aggressive ZAP-70+ CLL cells and cell lines. A similar inhibitor, erlotinib, had no effect in CLL. Gefitinib inhibited phosphorylation of Syk and ZAP-70, prevented downstream kinase activation, and supressed the pro-survival BCR response. ZAP-70 is implicated in the mechanism of action of gefitinib as introduction of ZAP-70 into a B cell line increased their sensitivity to gefitinib. Secondly, the novel strategy of targeting lysosomes was explored. The lysosomotropic drugs siramesine, nortriptyline, desipramine, mefloquine, and tafenoquine were all found to induce cytotoxicity and lysosome permeabilization. Lysosome permeabilization was accompanied with lipid peroxidation and followed by loss of mitochondrial membrane potential. Compared with healthy B cells, CLL cells were more sensitive to this cell death pathway. This was potentially due to the overexpression of SPP1 and overproduction of sphingosine, which destabilized lysosomes. Lastly, this thesis explored the clinical utility of these targeted therapies. Both gefitinib and siramesine were more effective in CLL cells than patient T cells. Furthermore, they retained efficacy amid protective stromal cells. Clinical correlations revealed that gefitinib and siramesine were effective in CLL cells with poor prognostic features. Siramesine was more effective in male cells and in previously-treated cells. Gefitinib was most effective in young patients. Overall, work presented herein demonstrates the efficacy of the tyrosine kinase inhibitor gefitinib and lysosomotropic agents in primary CLL cells. This work investigates the altered biology of the BCR pathway and lysosomes in CLL cells, and takes advantage of these weaknesses using targeted therapies.
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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".