Abstract 863: Inhibition of breast cancer metastaticprogression by a novel uPAR targeted monoclonal antibody, ATN-658, correlateswith the uPAR expression.
Bibliographic record
Abstract
Abstract The urokinase plasminogen activator receptor (uPAR) has been implicated in the progression of metastatic disease in a number of different solid tumor types including breast cancer. We have developed a therapeutic monoclonal antibody, ATN-658, that targets uPAR in a novel manner. ATN-658 does not inhibit the binding of uPA to uPAR but appears to have pleiotropic effects on other uPAR interactions including those with various integrins. In the present study, we utilized 231LM2-4H2N, a novel highly metastatic variant of the triple negative breast cancer cell line cell line, MDA-MB-231, to evaluate the effect of ATN-658 on metastasis. This variant has been transfected to also express HER2 and metastases in this model are resistant to targeted treatments such as trastuzumab and sunitinib. Orthotopic 231LM2-4H2N xenograft tumor spontaneously metastasizes to lung and liver and forms large macroscopic metastases that lead to death. We transfected 231LM2-4H2N cells with dTomato and Luc2 to allow for real time assessment of metastatic progression using IVIS imaging. Primary orthotopic tumors were staged to 500 mm3, at which time they were resected and the mice followed using bioluminescence to detect metastases, which typically appear in the lungs within 2-3 weeks post-resection. Mice were randomized once lung metastases were visible and treatment was initiated using vehicle control, lapatanib (30 mg/kg QD), ATN-658 (10 mg/kg Q3D) or the combination of lapatanib and ATN-658. Growth of metastases was estimated using average radiance measurements. ATN-658 inhibited metastatic progression by ∼90% and doubled median survival compared to the vehicle control in this study. Lapatanib had no effect on the size of the metastases or survival and the combination of ATN-658+lapatanib inhibited metastatic progression and survival to the same extent as ATN-658 monotherapy. The activation of ERK was significantly inhibited by ATN-658 in vivo although this alone was insufficient to inhibit tumor growth since lapatanib also inhibited ERK to the same extent suggesting the other effects were being mediated by ATN-658. The effect of ATN-658 monotherapy on metastatic tumor growth was much greater in the 231LM2-4H2N model than in the parental MDA-MB-231 model. In order to probe the reason for this difference in effect, we analyzed the expression of uPAR in the various MDA-MB-231 variants. uPAR expression was significantly upregulated in HER2-transfected MDA-MB-231 breast cancer cells suggesting that the level of uPAR expression may dictate the degree of response to ATN-658. If this hypothesis can be validated, this would provide a patient enrichment strategy for the humanized version of ATN-658, huATN-658, which is getting ready to go into the clinic. Citation Format: Irawati Kandela, Andrey Ugolkov, Giulio Francia, Shafaat Rabbani, Robert S. Kerbel, Andrew P. Mazar. Inhibition of breast cancer metastaticprogression by a novel uPAR targeted monoclonal antibody, ATN-658, correlateswith the uPAR expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 863. doi:10.1158/1538-7445.AM2013-863
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".