Abstract LB-297: The EMT inhibitor AB-16B5 interacts with specific isoforms of secreted clusterin
Bibliographic record
Abstract
Abstract Secreted clusterin (sCLU) exhibits elevated expression in several cancer indications. sCLU plays a pro-survival role in tumors and, more recently, it was found to be a potent stimulator of the epithelial-to-mesenchymal transition (EMT). These findings led to the development of a monoclonal antibody, AB-16B5, that interacts with a specific EMT-inducing domain in sCLU resulting in abrogation of migration and invasion of many types of cancer cells. We previously showed that blocking tumor-associated sCLU with AB-16B5 reduced the expression of mesenchymal markers and restored the expression of epithelial markers in human tumor xenografts, observations that were in line with inhibition of EMT in vivo. Consequently, this resulted in reduced metastatic invasion and increased response to cytotoxic agents in animal models of human cancer. We now report new results that shed light on the biochemical differences between sCLU that is secreted by tumor cells or normal cells. Using two-dimensional gel electrophoresis, we found that there was a difference in the number and composition of sCLU isoforms present in the plasma of cancer patients compared with those expressed in healthy individuals. In particular, the post-translational modifications were more complex on sCLU secreted from tumor cells compared with those present in sCLU from healthy individuals. Moreover, AB-16B5 was found to specifically interact with several of the isoforms expressed from tumor cells but exhibited a reduced ability to interact with sCLU from plasma from healthy individuals. We also examined the interaction between AB-16B5 and tumor-associated sCLU in vivo. In these studies, injection of AB-16B5 conjugated to a fluorophore in mice harboring sub-cutaneously implanted human pancreatic tumor xenografts resulted in a rapid enrichment of fluorescence signal in the tumors. Interestingly, administration of high concentrations of human recombinant sCLU immediately prior to injection of the AB-16B5 fluorophore-conjugate still resulted in enrichment of fluorescence signal in the tumors, albeit at slightly lower intensity than was observed in the absence of recombinant sCLU. Our findings indicate that AB-16B5 can efficiently interact with tumor-associated sCLU despite the presence of excess concentrations of sCLU in the circulation. Taken together, our results suggest that AB-16B5 has increased affinity for sCLU isoforms that are specifically expressed from tumor cells that have undergone an EMT. 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 LB-297. doi:1538-7445.AM2012-LB-297
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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".