Abstract 3673: Targeting the epigenome of small cell hypercalcemic carcinoma of the ovary, hypercalcemic type (SCCOHT)
Bibliographic record
Abstract
Abstract Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare and poorly differentiated cancer that impacts young women with an average 2-year survival of less than 35%. We and others have discovered the inactivating mutations of SMARCA4 as the only consistent genetic alternation in SCCOHT genomes. SMARCA4 is the ATPase of the SWI/SNF chromatin-remodeling complex, which modulates chromatin accessibility to regulate transcription and plays critical roles in many biologic processes such as cell cycle control, apoptosis, and differentiation. SCCOHT also lacks the expression of SMARCA2, the alternative ATPase in the complex, contrasting the requirement of SMARCA2 for survival of most SMARCA4-deficient cancer cells. This suggest that the complete loss of chromatin-remodeling activity may rewire the epigenome and create opportunities for synthetic lethal targeting. A rational epigenetic drug screen identified EZH2 inhibitors and HDAC inhibitors as promising therapeutic agents in SCCOHT cells. We confirm that catalytic inhibition of EZH2 selectively suppressed the growth of SCCOHT cells in vitro and in xenograft models through activation of apoptosis and differentiation. Pan-HDAC inhibitors also displayed a more robust anticancer effect in SCCOHT cells than other in other ovarian cancer cell lines. Furthermore, combined treatment of EZH2 inhibitors and pan-HDAC inhibitors increased the global acetylation level at histone H3K27 site and synergistically suppressed the growth of SCCOHT cell lines and xenografts through robust induction of apoptosis. Although EZH2 or HDAC inhibitor treatment led to re-expression of SMARCA2, depletion of SMARCA2 had only minimal effect on drug response. Proteomic analysis identified key signaling pathways underlying the efficacy of epigenetic therapy that are under investigation. Therefore, inactivation of SWI/SNF chromatin remodeling complex may drive SCCOHT development through PRC2-dependent rewiring of the epigenome. Targeting these oncogenic events can be the feasible strategies for treatment of SCCOHT that warrant clinical investigation. Citation Format: Yemin Wang, Shary Yu-ting Chen, Shane Colborne, Krystal Orlando, Jessica Lang, Anthony Karnezis, William Hendricks, Gregg Morin, Bernard Weissman, Jeffrey Trent, David Huntsman. Targeting the epigenome of small cell hypercalcemic carcinoma of the ovary, hypercalcemic type (SCCOHT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3673.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".