Abstract NTOC-084: THE PROMISE OF COMBINATIONAL TREATMENT OF HISTONE DEACETYLASE 6 INHIBITOR ACY-1215 AND PROTEASOME INHIBITOR BORTEZOMIB IN SCCOHT
Bibliographic record
Abstract
Abstract PURPOSE: Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a rare ovarian cancer that predominantly affects young women with a median age of 24 years. Although half of the tumors are diagnosed at an early stage, the prognosis is dismal due to lack of effective treatment options. In response to drastic increase of protein translation and cellular stress during malignant transformation, cancer cells have evolved to highly depend on protein surveillance pathways to correct or degrade unfolded and misfolded proteins to ensure protein homeostasis. Inhibition of these protein surveillance pathways has been proven to selectively target cancer cells. Particularly, inhibition of proteasome, which degrades more than 80% of cellular proteins, by selective inhibitors leads to accumulation of its substrates and consequently results in activation of apoptotic pathways in highly proliferative cancer cells. However, resistance occurs frequently. As a result several combinational treatments have been investigated in clinical trials with various drugs, such as HDAC6 inhibitor, which shuts down the aggresome-mediated proteolysis. Therefore, we aimed to determine the promise of inhibiting both protein degradation pathways as a novel therapeutic strategy for SCCOHT. EXPERIMENTAL PROCEDURE: Concentration-effect relationships were determined for both proteasome and HDAC6 inhibitors, alone or in combination, in SCCOHT cell lines and other ovarian carcinoma cell lines using a 3-day cell viability assay measured by crystal violet staining. Cell apoptosis was measured by live cell imaging with activated caspase-3/7. Drug action mechanism was interrogated by Western blotting. RESULT: SCCOHT cells are hypersensitive to both proteasome inhibitor (Bortezomib) and HDAC6 inhibitor (ACY-1215) with IC50 around low nM and μM, respectively. In addition, both Bortezomib and ACY-1215 inhibited cell proliferation and induced apoptosis in SCCOHT cells. Treatment with ACY-1215 led to inhibition of the aggresome as evidenced by an increased level of acetyl-tubulin, accumulation of polyubiquitinated proteins and upregulation of the unfolded protein response. Combination of Bortezomib and ACY-1215 led to an increased level of poly-ubiquitinated proteins, stronger suppression of cell proliferation and more apoptosis compared to either drug alone in SCCOHT cells, with some dosing having synergistic effect. CONCLUSION: Our data suggest that ACY-1215 or Bortezomib alone significantly suppressed the growth and induced apoptosis of SCCOHT cells. Combination of ACY-1215 and Bortezomib synergistically increased growth suppression and cell apoptosis and thereby may be a potential rational therapeutic strategy for SCCOHT. Citation Format: Yuting Shary Chen, Yemin Wang, Anthony Karnezis, Pilar Ramos, Holly Yine, Bernard Weissman, Jeffrey Trent, David Huntsman. THE PROMISE OF COMBINATIONAL TREATMENT OF HISTONE DEACETYLASE 6 INHIBITOR ACY-1215 AND PROTEASOME INHIBITOR BORTEZOMIB IN SCCOHT [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-084.
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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) | 0.001 | 0.001 |
| 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) | 0.002 | 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 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".