Abstract 3804: CPA-7, an inhibitor of STAT3, is a potent tumoricidal agent in peripheral tumor models and is impermeable to the CNS
Bibliographic record
Abstract
Abstract Analogues of the prototypical cancer drug cisplatin number by the hundreds with variable effects on DNA and signal transduction. Of these compounds, CPA-7 has been shown to elicit potent tumoricidal activity by preferentially targeting STAT3 in transformed cells. In this study, we characterized the response of rodent and human glioma cells to STAT3 inhibition by CPA-7. In addition, we determined if CPA-7 administration is sufficient for the induction of tumor regression in intracranial and peripheral mouse tumor models. Cultured glioma cells treated with CPA-7 ceased to proliferate and underwent apoptosis. Induction of apoptosis was associated with reduction of phosphorylated STAT3 and downstream transcriptional products such as cyclin D, survivin, and Bcl-xl. Although CPA-7 inhibits STAT3 preferentially, we observed an inhibition of STAT1 at doses higher than 30uM. Furthermore, mice bearing GL26 flank tumors underwent complete tumor regression in response to CPA-7 administration. This potent therapeutic effect of CPA-7 could not be duplicated in mice bearing intracranial GL26 brain tumors as that group became moribund at the same time as vehicle treated mice. Western blot and immunohistochemistry analysis of tumors isolated from CPA-7 treated mice demonstrated a reduction of phosphorylated STAT3 in peripheral but not intracranial tumors. This data suggests that CPA-7 is impermeable to the brain as a consequence of its molecular structure. Permeability measurements of CPA-7 using the PAMPA assay support this notion. These observations were corroborated in the B16-f0 and B16-f10 mouse melanoma models. Inhibition of STAT3 has been shown to be an effective strategy at inducing tumor regression in multiple cancer types. Although the discovery of effective and specific inhibitors has been limited, we believe that CPA-7 is a compound with potential therapeutic activity for peripheral solid tumors and warrants further evaluation and pharmacological characterization. Supported by NIH/NINDS Citation Format: Hikmat Assi, Chris Paran, Jon Savakus, James Hoeschle, Leda Raptis, Pedro R. Lowenstein, Maria G. Castro. CPA-7, an inhibitor of STAT3, is a potent tumoricidal agent in peripheral tumor models and is impermeable to the CNS. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3804. doi:10.1158/1538-7445.AM2014-3804
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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 | 0.002 | 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".