Abstract 1970: Liposomal nanoparticle siRNA delivery systems for <i>in vivo</i> silencing of the androgen receptor in human prostate cancer
Bibliographic record
Abstract
Abstract Prostate cancer is the most commonly diagnosed non-skin cancer in men and one of the leading causes of cancer-death. While frequently curable by surgical or radiation ablation, recurrent or metastatic disease is usually managed with androgen withdrawal therapies (medical castration), which block the growth promoting effects of androgens on the androgen receptor (AR). Unfortunately, the cancers eventually progress to the lethal castration-resistant state. Previously, we reported that knocking down the AR by RNA interference using small hairpin RNA (shRNA) inhibits this progression and, in about 50% of tumours, causes complete regression. In this study, we investigated the ability of small interfering RNA (siRNA) encapsulated in lipid nanoparticle (LNP) to silence AR in human prostate cancer cell lines and xenograft tumours following intravenous injections. In vitro screening studies with prostate cancer cell lines using a panel of cationic lipids demonstrated that siRNA formulated in LNPs containing the ionizable cationic lipid 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA) exhibited the most potent AR silencing effects. This is attributed to an optimized ability of DLin-KC2-DMA-containing LNP to enter into cells and to release the siRNA into the cell cytoplasm following endocytotic uptake. DLin-KC2-DMA LNPs were also effective in silencing the AR in a wild-type AR expressing cell line, LAPC-4, and a variant AR expressing cell line, CWR22Rv1. Importantly, we found that LNP AR-siRNA systems containing DLin-KC2-DMA could silence AR gene expression in distal LNCaP xenograft tumors and decrease serum PSA levels following intravenous injection. The 5′RACE experiments further confirmed that siRNA-induced specific cleavage of AR mRNA was the primary mechanism of action. In conclusion, these results indicate that in vivo delivery of siRNA to knockdown AR using our LNP formulations causes a decrease in serum PSA and provides proof in principle that this approach may offer a therapeutic strategy for treating advanced prostate cancer. (Funded by Canadian Institutes for Health Research and a PCF-STAR Project from Prostate Cancer Canada with the support of Safeway Canada) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1970. doi:1538-7445.AM2012-1970
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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) | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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".