Abstract 2171: Amezalpat, a peroxisome proliferator-activated receptor alpha (PPARα) antagonist, inhibits suppressive macrophage development, activation and function
Bibliographic record
Abstract
Amezalpat (TPST-1120) is a first-in-class, small molecule competitive antagonist of peroxisome proliferator-activated receptor alpha (PPARα), the master transcriptional regulator of fatty acid oxidation (FAO). Analysis of biomarker data from a previous Phase I study demonstrated amezalpat dose-dependent changes in immune genes associated with myeloid populations. Suppressive M2 macrophages are a prominent myeloid population associated with poor prognosis in many cancers. As M2 macrophages are reliant on FAO, we sought to assess the effects of amezalpat on development, activation and function of these cells. Flow cytometry analysis of M2 macrophages polarized in the presence of amezalpat displayed concentration-dependent reductions in canonical M2 macrophage markers CD163, CD206, and Arg-1 (p<0.05 by Wilcoxon’s test). ELISA measurement of cytokine production by amezalpat-treated M2 macrophages demonstrated a statistically significant reduction in the suppressive cytokines IL-10 (n=8; p<0.05 by Wilcoxon’s test) and TGF-β (n=3 by One-way ANOVA), suggesting amezalpat-induced functional impairment of this population. Additionally, amezalpat treatment of M2 macrophages caused significant reductions in mitochondrial mass, measured with a mitochondria-specific dye by flow cytometry (p<0.01 by two-sample T test). Finally, in co-cultures of M2 macrophages with autologous activated CD8+ T cells and HCC tumor cells (SNU-449), amezalpat induced tumor cell cytotoxicity and M2 cell death commensurate with cell-type specific expression levels of its target PPARα. Together, these data suggest amezalpat modulates suppressive macrophage development and function and supports the contribution of an immune-mediated mechanism to anti-tumor activity reported in clinical studies. Citation Format: Mandy I. Cheng, Ademola Esomojumi, Dara Burdette, Valerie Chen, Jorg H. Fritz, Sam Whiting, Nathan Standifer. Amezalpat, a peroxisome proliferator-activated receptor alpha (PPARα) antagonist, inhibits suppressive macrophage development, activation and function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2171.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.006 | 0.002 |
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".