Preclinical evidence that chemotherapy for prostate cancer should be given at the same time as androgen withdrawal
Bibliographic record
Abstract
4617 Background: Androgen ablation is the mainstay of systemic therapy for prostate cancer, with cytotoxic chemotherapy reserved for hormone refractory disease. Earlier use of chemotherapy at the time of androgen dependence when there are potentially fewer multi-resistant clones, may yield greater benefit. This study addresses the ideal timing of systemic treatments in the androgen-dependent Shionogi tumour model. The hypothesis that stress-induced changes in gene expression after chemotherapy can induce a hormone independent phenotype was further explored in the LNCaP setting. Methods: Three groups of ten mice bearing Shionogi xenografts were treated with: 1) initial castration and delayed paclitaxel, 2) initial paclitaxel and delayed castration, or 3) combined therapy. Endpoints were time to tumour progression and time to sacrifice. The additive effects of combined therapy were also assessed through in vitro proliferation studies on LNCaP cells. Spotted microarray and RT-PCR analyses were carried out on mRNA from LNCaP cells exposed to paclitaxel to identify gene expression changes over time. Results: Mice receiving combined therapy demonstrated a significant improvement in time to progression (median 65 vs. 38 days, p=0.004) and time to sacrifice (median 83 vs. 66 days, p<0.014) versus sequential therapy. A marked lack of response to castration in the mice treated with paclitaxel first was observed. Similar effects were seen in vitro. Microarray studies identified increases in several genes known to play a role in androgen independence in response to paclitaxel exposure. Quantitative RT-PCR demonstrated an increase of expression of clusterin, bcl-2, bcl-xL and Hsp27 of between 30% and 60% after 48 hours of paclitaxel exposure. Conclusions: In laboratory models of prostate cancer, the combination of androgen deprivation and paclitaxel is more effective than sequential treatment. Molecular studies confirm that chemotherapy can induce alterations in gene expression associated with androgen independent proliferation. These findings provide pre-clinical proof-of-principle for ongoing clinical trials addressing the role and timing of systemic therapies in prostate cancer. No significant financial relationships to disclose.
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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 | 0.005 | 0.009 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".