Abstract A087: Enzalutamide-induced hypoxia attenuates response and promotes resistance to enzalutamide in preclinical models of prostate cancer
Bibliographic record
Abstract
Abstract Inhibition of androgen signaling remains the therapeutic mainstay in castrate-resistant prostate cancer. The expression of androgen receptor (AR) splice variants and the retention of active AR signaling have been reported as mechanisms of resistance to the anti-androgen enzalutamide. Other non-AR dependent mechanisms of resistance have also been proposed, including acquisition of a hypoxic tumor microenvironment. We propose that treatment-induced hypoxia and the subsequent induction of angiogenesis may define a novel mechanism of relapse to enzalutamide. Preclinical experiments were conducted in LNCaP tumors, endothelial cells, and established human prostate cancer cell lines. The effects of enzalutamide on endothelial cells were examined in vivo and in vitro. Tumor growth, intratumoral hypoxia, and blood vessel density were measured in vivo. AR expression, activation, and target gene expression were measured in vitro. The effect of enzalutamide on hypoxia-driven, disease-progressing pathways and genes of interest, and the role of these genes in resistance to enzalutamide, was investigated. Administration of enzalutamide rapidly induced hypoxia in LNCaP tumors in vivo, followed by angiogenesis-promoted restoration of oxygen tension, increased vessel density, and accelerated tumor growth. In vitro, enzalutamide directly targeted AR-expressing endothelial cells, resulting in decreased growth and tubule formation. Exposure to hypoxia in vitro increased AR expression and transcriptional activity in LNCaP prostate cancer cells and sustained, but did not further potentiate, high basal AR and ARv7 expression and activity in 22Rv1 cells. Enzalutamide failed to attenuate the concurrent hypoxia-induced HIF-1 and NF-κB signaling, resulting in upregulation of disease-progressing genes and pathways. Administration of neutralizing antibodies to two hypoxia-regulated genes, interleukin-8 (IL-8) and VEGF, prolonged enzalutamide-mediated hypoxia over 14 days and LNCaP tumor growth control over 28 days in vivo (p<0.001). Elevated expression of IL-8 and VEGF-A was also detected in MDV3100-resistant models, where neutralization of IL-8 and VEGF-A inhibited tumor angiogenesis and partially reversed resistance to enzalutamide. We conclude that enzalutamide-induced hypoxia upregulates the expression of VEGF and IL-8, whose multimodel signaling effects, in turn, contribute to microenvironment-promoted resistance in prostate tumors. Citation Format: Pamela J. Maxwell, Melanie McKechnie, Oisin Duddy, Christopher W. Armstrong, Judith M. Manley, Chee Wee Ong, Jenny Worthington, Elena Deryugina, James P. Quigley, Amina Zoubeidi, David J.J. Waugh, Melissa J. LaBonte. Enzalutamide-induced hypoxia attenuates response and promotes resistance to enzalutamide in preclinical models of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A087.
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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) | 0.003 | 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".