Abstract A037: TT-00420, a novel kinase inhibitor potentially benefiting c-Myc amplified/overexpressed osteosarcoma
Bibliographic record
Abstract
Abstract Osteosarcoma (OS) is the most common bone tumor in pediatric patients, whose effective therapies are of great unmet medical needs, particularly for those of high-risk features. c-Myc, a well-known oncogene, is commonly amplified/overexpressed in OS patients, contributes to dismal prognosis and associates with lower 5-year overall survival rate, which is also confirmed by our retrospective analysis for the correlation between c-Myc gene amplification/overexpression and patient prognosis in our patient cohort. TT-00420, a clinical-stage small molecule targeting Aurora A/B, VEGFRs, FGFRs, JAKs and CSF1R, has demonstrated down-regulation on c-Myc expression in TNBC studies. Moreover, as reported, Aurora kinases and c-Myc regulate each other back and forth, triggering maintenance of the malignant state. In this study, we examined the efficacy of TT-00420 in c-Myc-amplified/overexpressed OS. In pre-clinical clonogenic assay, TT-00420 significantly inhibited the colony formation in c-Myc-overexpressed OS cell lines in a dose-dependent manner. In MNNG/HOS cell line, we demonstrated that TT-00420 dramatically suppressed Aurora kinase pathway and blunted c-Myc protein expression level, indicating TT-00420 might down-regulate c-Myc by Aurora kinases inhibition. In pre-clinical in-vivo efficacy studies, 143B cells were injected into the medullary cavity of the tibia to make the orthotopic OS xenograft model. With 15 mg/kg/day treatment of TT-00420, tumor growth was obviously inhibited as compared to vehicle group. Immunohistochemistry (IHC) analyses in tumors revealed that TT-00420-treated tumors exhibited increased apoptosis with upregulated expression of cleaved caspase 3 (CC3) and H2AX, and significantly decreased proliferations with raised expression of Ki67. Moreover, in a c-Myc-overexpressed OS patient-derived xenograft (PDX) model from a male pediatric patient, 15 mg/kg/day TT-00420 dramatically blunted the tumor growth with a TGI of 87.6%. In China, an investigator-initiated trial is currently ongoing to evaluate the safety and tolerability of TT-00420 in OS patients with c-Myc overexpression (ChiCTR2000036618). Taken together, TT-00420 depicted robust anti-tumor activity in c-Myc overexpressed OS both in vitro and in vivo with downregulation of c-Myc expression, indicating its potential as a novel monotherapy for OS patients with c-Myc overexpression. Future clinical trial result is of great expectation. Citation Format: Yingqi Hua, Xiaoyan Qiang, Kai Tian, Yafei Jiang, Frank Wu, Peng Peng. TT-00420, a novel kinase inhibitor potentially benefiting c-Myc amplified/overexpressed osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A037.
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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) | 0.003 | 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".