Abstract C185: Targeting PARP and DNA as a novel unimolecular combination model for the enhancement of chemosensitivity
Bibliographic record
Abstract
Abstract The concept of synthetic lethality arises when the alteration of a single gene A or B alone does not affect cell survival but that of both genes lead to cell death. More importantly, if A is mutated, inhibition of the functions of the gene B product should also lead to cell death. This is achievable in some tumours, predominantly in breast and ovarian cancers, where the mutation of the DNA repair proteins BRCA1/2 depletes the DNA repair capacity of the cells. The compensatory DNA repair mechanism in the cells is supported by a DNA repair enzyme poly(ADP-ribose) polymerase (PARP), which when inhibited, leaves the cells with no compensatory DNA repair mechanisms. Hence DNA lesions accumulate in the cells and ultimately cause their death. The ability of PARP inhibitors to induce cell death in BRCA1/2 mutated tumours has been demonstrated in both preclinical models and in the clinic. While the PARP inhibitor olaparib met the requirements for recent FDA approval for the treatment of ovarian cancer, the overall survival obtained with many PARP inhibitors as single agents in patients with BRCA1,2 mutated tumours has been disappointing,. Also, acquired resistance caused by the reactivation of wild type BRCA1/2 is an emerging drawback in BRCA1/2 related therapies. Our hypothesis is that molecules termed “combi-molecules” capable of not only inhibiting PARP but also inducing DNA damage, could significantly enhance cell-killing in BRCA1/2 deficient tumours and perhaps be indicated at the earlier stages of the diseases. Here, we designed and studied the potency and mechanism of action of our first prototype EG22. The results showed that: (a) it inflicted higher levels of DNA damage than temozolomide (a clinical DNA damaging agent) and >100-fold stronger growth inhibitory potency than the latter in our cell panel, regardless of the BRCA1/2 status of the cells, (b) it showed more than 5-fold stronger growth inhibitory potency than 4-ANI, a known PARP inhibitor, in BRCA1/2 deficient cells and more than 8-fold in wild type expressing cells (c) a PARP assay showed that it induced a dose-dependent inhibition of PARP with an IC50 value almost equal to that of 4-ANI and (d) in cell-based selectivity assay involving a pair of isogenic Chinese hamster cell line (engineered to express BRCA2 wild type), it induced 20-fold selectivity for the mutant form. The results in toto suggest that EG22 is a new molecular entity with a novel and dual mechanism of action. Furthermore, reactivation of BRCA1/2 being one of the mechanisms of resistance to DNA damage-based therapy of patients with mutant BRCA1/2, the combi-molecular approach has the potential to be developed as an alternative treatment, when the tumours heterogeneously express BRCA1/2. Citation Format: Zhor Senhaji Mouhri, Elliot Goodfellow, Bertrand Jean-Claude. Targeting PARP and DNA as a novel unimolecular combination model for the enhancement of chemosensitivity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C185.
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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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 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".