Abstract 1452: Examination of mechanisms involved in spontaneous melanoma metastasis to CNS
Bibliographic record
Abstract
Abstract Cerebral metastases occur in a majority of metastatic melanoma patients and are the major cause of mortality in those cases. Testing of novel therapeutic approaches has been slowed by the absence of appropriate preclinical models of spontaneous metastatic melanoma, particularly spontaneous CNS metastasis. To examine the efficacy of potentially promising treatment regimens, a highly visceral metastatic variant of the human melanoma WM239 cell line, named 6-4L, was developed and used to test the effectiveness of metronomic chemotherapy in the treatment of advanced metastatic disease. Concurrent low-dose cyclophosphomide/vinblastine led to significant disease control of mice with overt metastases in lungs, liver and lymph nodes. Among mice that survived the long-term treatment, 20% showed the presence of spontaneous brain metastases which likely emerged as a result of prolonged survival mediated by the therapy. From these, 2 cell lines (131/4-5B1 and 131/4-5B2) were generated which metastasize spontaneously to brain parenchyma. This constitutes the first model of heritable spontaneous melanoma brain metastasis by a human cell line from a subdermal transplant, without any therapeutic intervention. Characterization shows two salient functional alterations that may contribute to this phenotype 1) adhesion to brain-endothelial cells and 2) proliferation in the presence of brain-derived factors. When compared to poorly or highly metastatic cell lines (WM239A and 113/6-4L respectively), microarray analysis shows that 4-5B1/B2 cell lines have markedly different expression profiles. These cell lines show differential expression of 108 genes, thirteen of which share a common alteration for both brain-metastatic cell lines, including ednrb (endothelin receptor B) and bcl2a1 (BCL2-related protein A1), which stand out as potentially relevant. These molecules have been previously associated with increased proliferation in the presence of ENT-3; a peptide expressed in the brain, as well as resistance to TNF induced apoptosis and increased metastatic potential. Lentiviral vectors were used to induce stable upregulation of these genes in the otherwise non-brain metastatic parental 113/6-4L cell line. This upregulation mediated an increase in metastatic potential and, in the case of EDNRB, increased intracranial tumor growth. Future efforts will focus on characterizing the alterations in these cell lines, to confirm their clinical relevance and to test novel inhibitors for treating melanoma brain metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1452.
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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) | 0.002 | 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".