Abstract NT-117: INHIBITION OF PARG, SENSITIZES OVARIAN CANCER CELLS TO PARP INHIBITORS AND DNA DAMAGING AGENTS
Bibliographic record
Abstract
Abstract BACKGROUND: Poly(ADP-ribose) glycohydrolase (PARG) is responsible poly(ADP-ribose) (PAR) catabolism, which is synthesized by poly(ADP-ribose) polymerases (PARPs) at the site of DNA single-strand breaks (SSB). Faulty PAR formation or disintegration inhibits SSB repair. PARP inhibitors (PARPi) exploit the synthetic lethality between SSB repair and homologous recombination (HR) double strand break (DSB) repair. The most effective PARPi traps PARP at the SSB site, causing a double strand break during DNA synthesis that the cell cannot repair. The trapping of PARP can also be achieved through PARG inhibition. Due to the high rate of HR defects in epithelial ovarian cancer, the aim of this study is to evaluate the effect of a PARG inhibitor (PARGi) on epithelial ovarian cancer cell lines, alone and in combination with PARPi or cisplatin. METHODS: PARG protein levels were assessed in 74, unselected, snap-frozen, tumors kept in our bio-bank by western blotting and immuno-histochemistry (IHC), as well as in the TCGA database. PARG was knocked down in two cell lines resistant to PARP inhibition, OVCAR3 and SKOV3. The knockdowns were subjected to cell migration and cell proliferation assays, as well as single cell analysis. BRCA1 mutated and BRCA1 wild-type cell lines were exposed to clinically relevant doses of PARGi, PARPi, or cisplatin, separately or in various combination. Therapeutic efficacy was assessed using colony formation assay. Western Blotting was used to detect the levels of PARG and PARP proteins in the cell lines. RESULTS: PARG mRNA was expressed in 30% of tumors in TCGA. PARG protein was also detected in 30% of the biobank tumors analyzed. PARG knockdowns exhibited reduced rates of cellular proliferation and significant G2/M cell cycle arrest. In PARG over expressed ovarian cancer cell lines, PARG inhibitor similarly reduced cell migration (OVCAR3 and SKOV3: 75% reduction, SNU-251: 48% reduction). CONCLUSION: PARG inhibition appears to be a viable, complementary strategy to PARP inhibition in HR-deficient cancers. The effect of BRCA1 on the efficacy of PARG inhibition, as well as various treatment combinations, are currently under investigation. Citation Format: Emad Matanes, Tahira Baloch , David Octeau, Roy Kessous, Liron Kogan, Ido Laskov, Walter Gotlieb, Amber Yasmeen. INHIBITION OF PARG, SENSITIZES OVARIAN CANCER CELLS TO PARP INHIBITORS AND DNA DAMAGING AGENTS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-117.
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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) | 0.003 | 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".