Abstract LB-33: Pre-clinical evaluation of AB-16B5, a monoclonal antibody specific for tumor-associated sCLU, demonstrates therapeutic potential as an inhibitor of EMT in prostate, pancreatic and lung cancer
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. In previous studies, AB-16B5 reduced the invasion of tumors in models of metastatic breast cancer suggesting that the antibody blocked EMT in vivo. Here we present pre-clinical findings in models of prostate cancer, pancreatic cancer, and NSCLC. DU145 and PC-3 prostate cancer cells implanted in SCID mice grew slower in the groups treated with AB-16B5 as a monotherapy or in combination with docetaxel. This observation suggested that blocking sCLU with AB-16B5 enhanced the chemo-responsiveness to cytotoxic drugs, a finding that was consistent with the proposed role of sCLU as an inhibitor of apoptosis in cancer cells. Immunohistochemical examination of sections prepared from the prostate tumors exposed to AB-16B5 showed an increase in E-cadherin, a marker of epithelial cells, and a reduction of vimentin, a marker of mesenchymal cells, which indicated that EMT was blocked or even reversed in vivo. Additional analyses of tumors derived from human pancreatic cancer showed that sCLU was expressed in this indication as well, especially in tumors that were resistant to gemcitabine. In agreement with the role of sCLU as an inducer of EMT, AB-16B5 inhibited the invasion of PANC-1 pancreatic cancer cells in vitro. Importantly, treatment of SCID mice harboring BxPC-3 pancreatic tumors with AB-16B5 resulted in a significant enhancement of the response to gemcitabine. Similarly, the growth of tumors grown from the NSCLC cell line, A549, was also inhibited by AB-16B5. To explore the behavior of AB-16B5 in cynomolgus monkeys, the antibody was administered by i.v. infusion every 14 days at two doses of 10 and 50 mg/kg. Results indicated that AB-16B5 was well tolerated and no signs of toxicity were observed. Finally, to address the mechanism of action of sCLU, cell biology experiments indicated that sCLU is internalized in cancer cells, which leads to the activation of critical signaling pathways that favor cell proliferation and survival, including those pathways leading to a stimulation of NF-kappaB. Our studies imply that the combination of increased epithelial character of tumor cells exposed to AB-16B5 coupled with a reduction in the activation of survival pathways contribute to an increase in the sensitivity to chemotherapy and a significant reduction of tumor growth, in particular in cancer types such as pancreatic cancer, where EMT likely contributes to increased chemo-resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-33. doi:10.1158/1538-7445.AM2011-LB-33
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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 | 0.004 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| 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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".