Abstract LB-38: Selective Smoothened antagonists for anti-tumor therapy
Bibliographic record
Abstract
Abstract The Hedgehog (Hh) pathway is an important signaling pathway during cellular proliferation, differentiation and embryonic morphogenesis. Aberrant pathway activation has been linked to tumorigenesis in several cancers, (including pancreatic, prostate, lung, colorectal, bladder and ovarian) and therefore the inhibition of the pathway could be an attractive approach for anticancer therapy. The pathway is either activated by the binding of one of the three Hh ligands (sonic, Indian and desert) to the Patched transmembrane protein or by the mutation of inhibitory pathway components (e.g. Pached, SUFU,…). Pathway activation by ligand binding to Patched releases patched repression of the smoothened (Smo) receptor. Activated Smo initiates a cascade of events leading to the activation of transcription factors of the Gli family. Pathway activation by mutation has been reported in diseases such as medulloblastoma or basal cell carcinoma in which the Patched co-receptor is mutated, thereby functionally inactivated and unable to repress the Smo receptor. We report the characterization of a novel Smoothened receptor antagonist (SEN450), showing Hedgehog pathway specific activity in hedgehog responsive cellular models. Finally, we show a synergistic effect of SEN450 with temozolomide in a subcutaneous CD-1 nude mice xenograft of DBTRG-05MG neurospheres. Our data indicate that growing conditions can affect hedgehog responsive cells and that a combined therapy with temozolomide and hedgehog inhibitors could be helpful in the prevention/delay of GBM recurrence. Moreover, we have obtained extremely promising in vivo data using two compounds structurally related to SEN450 in a xenograft tumour model that have been generated from irradiated heterozygous Patched mice. In the current study, the Ptc+/− mice were used to generate a tumor model by transplanting medulloblatoma fragments subcutaneously in nude mice. Upon tumor development two Smo antagonists administered orally were tested in this model. Both compounds showed a significant reduction in tumor volume that was maintained over the entire dosing period. Histological examination showed very low mitotic index in treated tumors versus controls. The expression of the target gene Gli1 revealed a significant decrease of the gene expression in treated samples. The results corroborated the specificity of action of both molecules in targeting the Hh pathway always activated in this tumor model. Further investigation is in progress in order to verify the antitumor capacity of the compounds in other tumor models. 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-38. doi:10.1158/1538-7445.AM2011-LB-38
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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) | 0.005 | 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".