Abstract 980: Preclinical evaluation of mps1 inhibition in uterine leiomyosarcoma
Bibliographic record
Abstract
Abstract Background: Uterine leiomyosarcoma (Ut-LMS) is the commonest malignant mesenchymal tumor arising from the uterus. It is aggressive and the prognosis is dismal. To-date, no specific oncogenic drivers have been identified. Conventional adjuvant therapy and immunotherapy are ineffective and treatment largely remains surgical. MPS1 kinase is vital in spindle assembly checkpoint which safeguards the faithful segregation of chromosomes. Its inactivation leads to mitotic defects and induces mitotic catastrophe. Compare with normal tissue, MPS1 has shown to be overexpressed in Ut-LMS. Method: The Ut-LMS cell lines SK-UT-1 and SKN were treated with a MPS1 inhibitor. RT-qPCR was performed to analyze mRNA expression levels of Spindle Assembly Checkpoint-related genes. Cells were seeded in 96-well plates and treated with MPS1 inhibitor for 4 days. Sulforhodamine B stain was used to labelled viable cells. IC50 of different cell lines was determined by SRB assay. Cell cycle analysis was done after 2 days treatment by propidium iodide staining. Apoptosis study was done after 3 days treatment by AnnexinV/PI apoptotic assay. Flow cytometry was used to analyze PI assay and AnnexinV/PI apoptotic assay. Immunofluorescence staining of centromere, α-tubulin and DAPI was used to label kinetochore, mitotic spindles and DNA. Cells with chromosome missegregation were counted in treated and non-treated samples. Ut-LMS cell lines SKN was injected subcutaneously in Balb/c nude mice and MPS1 inhibitor was administrated through oral gavage daily, tumor weight was record and tumor size was estimated by caliper. Results: The Spindle Assembly Checkpoint-related genes MPS1, CDC20, MAD2L1, BUB1, BUB1B, and KNL1 were found to be overexpressed. SRB assays had shown that there was growth inhibition of both cell lines in a concentration-dependent manner with IC50 values ranged between 40-65 nM. An increase in aneuploidy cells was demonstrated by PI assay, which suggested that MPS1 inhibitor disrupted cell cycle and induced aneuploidy. The inhibitor also induced apoptosis as demonstrated an increase in AnnexinV+/PI+ cells. Chromosome missegregation was demonstrated in double-thymidine block synchronized anaphase cells with immunofluorescence staining. Micronuclei were also identified in tetraploid cells. In a preliminary in vivo study, MPS1 inhibitor was shown to reduce tumor growth in xenograft models. Conclusion: Our preclinical results indicated that MPS1 inhibitor was an effective treatment in Ut-LMS as a single agent by causing chromosome missegregation, mitotic catastrophe, genomic instability and cell death. Further evaluation of its use in combination with other pharmacological agents is in progress. Citation Format: Ho Shing Wong, Hok Yeung H. Lee, Ka Yu Tse, Tak Wah Mak, Philip PC Ip. Preclinical evaluation of mps1 inhibition in uterine leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 980.
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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) | 0.001 | 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".