Abstract 4378: Poly(ADP-ribose)glycohydrolase (PARG) is a novel therapeutic target in breast cancer.
Bibliographic record
Abstract
Abstract Poly(ADP-ribose)polymerase (PARP) is an enzyme responsible for catalyzing the addition of poly(ADP-ribose) chains onto target proteins in a process known as PARylation. This post-translational modification has been implicated in numerous cellular processes including gene expression, chromatin remodeling, apoptosis and DNA damage repair. In particular, the role of PARP activation in response to DNA damage has been intensely studied. BRCA mutated tumors are highly sensitive to DNA breaks and are therefore critically dependent on alternative repair mechanisms involving PARP. This forms the basis for a synthetic lethal therapeutic approach that has been met with much success in the clinic. BRCA mutated breast and ovarian tumors, in particular, are acutely sensitive to PARP inhibitors. Currently, it is unclear from in vitro and clinical studies to what extent PARP inhibitors can be used as chemotherapeutics to treat tumors beyond those harboring BRCA mutations. Due to the insensitivity of most solid tumors to PARP inhibitors, we have begun to study the role of the dePARylating enzyme poly(ADP-ribose)glycohydrolase (PARG), as a possible target in cancer therapy. PARG, like PARP, maintains a critical role in DNA repair and can therefore be a target in cells with defective repair mechanisms (e.g. BRCA mutant cells). We further hypothesize that targeting this factor may activate the expression of tumor suppressor genes, thus limiting cell proliferation. Thus far, we have novel data indicating that targeting PARG may indeed have therapeutic benefit. We show that PARG knockdowns of the T47D and MDA-MB-468 breast cancer cell lines have dramatically reduced rates of cellular proliferation. Gene expression analyses of the knockdown cells indicated that cell cycle related pathways may be affected. As such, we examined cell cycle profiles by BrdU and PI staining and found that PARG knockdown cells were arrested in S phase. These results are particularly striking given that these cells show resistance to PARP inhibition. Subsequent studies using the PARG inhibitor gallotannin successfully reconstituted the results obtained with the PARG knockdowns. Overall, our data illustrates that PARG has great potential as a new anti-cancer target. Citation Format: Amanda Lovato, Tiejun Zhao, Qiang Sun, Michael Witcher. Poly(ADP-ribose)glycohydrolase (PARG) is a novel therapeutic target in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4378. doi:10.1158/1538-7445.AM2013-4378
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.003 |
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".