Abstract A51: Identification of compounds targeting human leukemia stem cells
Bibliographic record
Abstract
Abstract Over the past 15 years, research has conclusively shown the existence of a rare population of cancer cells, termed cancer stem cells, in leukemia, brain, colon, and breast cancers. These cells are biologically distinct from bulk cells and are the only cells able to initiate and sustain the disease. Recent experiments indicate that standard chemotherapy for leukemia is less effective against leukemia stem cells (LSC) than bulk leukemia cells and typically does not spare normal hematopoietic stem cells (HSC) and progenitor cells leading to myelosuppression. Therefore, a new paradigm is needed to develop cancer therapeutics that effectively eradicate the disease by targeting the LSC. Here, we sought to identify compounds that selectively target LSC but not normal HSC by using populations enriched for LSC and HSC, instead of traditional cancer cell lines, in high-throughput screening of three libraries of small chemicals comprising over 4000 known bioactive, off-patent, and natural compounds. Recently, we generated human leukemia cells by direct transformation of normal human primitive hematopoietic cells (Lin- CB) with leukemogenic fusion oncogenes. These cells exhibit features of LSC, such as hierarchical organization, engraftment of NOD/SCID mice, and a differentiation block. As a proof of principle, we screened two leukemia cell lines using a simple cell-growth inhibition assay. 76 compounds were scored as positive against both lines. Numerous anti-cancer therapeutics (paclitaxel, etoposide, and vincristine), general cytotoxic agents (brefeldin), and the digitalis family of ion pump inhibitors (digoxin, ouabain) were identified. Since LSC share some pathways with normal HSC, we counter-screened potential hits on normal HSC and progenitor cells and identified only 10 compounds. Three of the 10 compounds targeted LSC, ciclopirox olamine, etoposide, and kinetin riboside (KR). KR was effective on primary AML and CML at levels similar to the AML chemotherapeutics cytarabine and mitoxantrone. Kinetin riboside induced apoptosis in phenotypic CD34+CD38- LSC, but not CD34+CD38- HSC similar to the anti-LSC compound parthenolide. In contrast to parthenolide, treatment of primary AML cells with kinetin riboside inhibited engraftment in NOD/SCID mice for 2 of 4 samples. The second compound, ciclopirox olamine, targeted LSC and not HSC, by chelating intracellular iron and inhibited the ribonucleotide reductase enzyme. Ciclopirox olamine is a clinically used antifungal and could be rapidly repurposed for treating leukemia. The third compound, etoposide, was effective in vitro on 29% (15 of 51) of primary AML and 67% (8 of 12) of CML patient cells. Etoposide inhibited NOD/SCID engraftment of three responsive AML samples, but not three non-responsive samples, indicating etoposide targeted the LSC in a subset of patients. Together, these screens have identified multiple anti-LSC compounds and represent a new paradigm for drug screening against LSC. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A51.
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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".