Abstract 1062: Antiproliferative activity of EC359, an inhibitor of leukemia inhibitory factor receptor (LIF-R), singly and in combination with chemotherapy drugs against pancreatic cancer cell lines
Bibliographic record
Abstract
Abstract Although combination chemotherapy treatments such as FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan), gem-abraxane (gemcitabine and nab-paclitaxel) and GTX (gemcitabine, docetaxel and capecitabine) have improved survival of pancreatic cancer patients incrementally, 5-year-survival for this disease remains dismal. New and more effective treatments are needed. Pancreatic stellate cells (PSCs), a form of fibroblasts that comprise much of the pancreatic tumor microenvironment, interact with the cancer cells via the cytokine leukemia inhibitory factor (LIF) and its receptor, LIF-R. This interaction contributes to tumor progression, survival, and resistance to various therapies, and is an important target for novel therapy. A small molecule inhibitor of LIF-R, EC359, inhibits growth of breast cancer cell line tumor explants in mice (Mol Cancer Ther 18: 1341-1354, 2019) and potentially modulates the activity of gemcitabine against such explants (Genes Cancer 10: 1-10, 2019). Given the involvement of the LIF axis in pancreatic cancer, EC359 was tested for its ability to inhibit proliferation of the human pancreatic cancer cell lines PANC-1, Capan-1, and Capan-2, and its possible influence on activity of chemotherapy drugs against these cell lines. Five-day drug exposures were conducted in 96-well plates. Relative cell density determined using vital stains (alamarBlue©, neutral red) was reported as a percent of the fluorescence/absorbance of control cultures. The 3 cell lines exhibited different sensitivities to EC359, with IC50 values ranging from 5 nM (Capan-1) to 150 nM (Capan-2). When combined with anti-pancreatic cancer standard-of-care drugs, EC359 yielded synergistic interactions in a concentration-dependent manner. Depending on the cell line, EC359 decreased the IC50 value for oxaliplatin by as much as 83%. Such enhancements of cytotoxicity for other drugs were up to 84% for docetaxel, 67% for paclitaxel, and 50% for irinotecan. EC359 was also synergistic with IBR120 (a novel small molecule inhibitor of RAD51) against PANC-1 cells. EC359 additively inhibited proliferation in combination with irinotecan or 5-FUdR. The nanomolar activity of EC359 against pancreatic cancer cell lines makes it a good candidate for potential treatment of this generally refractory disease. The synergistic interaction of EC359 with standard-of-care drugs provides an opportunity for increasing the therapeutic index for these agents, and ultimately improving clinical outcomes for pancreatic cancer and other cancers against which EC359 is currently in clinical trial. Citation Format: Peter J. Ferguson, Hareesh Nair, Mark D. Vincent, James Koropatnick. Antiproliferative activity of EC359, an inhibitor of leukemia inhibitory factor receptor (LIF-R), singly and in combination with chemotherapy drugs against pancreatic cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1062.
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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 | 0.001 |
| 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 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".