Abstract LB-205: Combination of DNA methyltransferase and PARP inhibitors as a novel therapy strategy for poor prognosis acute myeloid leukemia and triple-negative breast cancers
Notice bibliographique
Résumé
Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) have shown efficacy in treatment of breast and ovarian cancers with hereditary deletions of BRCA1/2, but the high promise of these drugs has not yet been realized in sporadic cancers. We present here strong preclinical data for a novel, mechanistically based, combinatorial approach to using DNA methyltransferase inhibitors (DNMTi’s), such as decitabine (DAC) and 5-Azacytidine (5-AZA), with PARP inhibitors (PARPi’s) as a treatment strategy for acute myelogenous leukemias (AML) and estogen-, progesterone- and HER2-receptor negative, or triple negative breast cancer (TNBC). We have previously demonstrated that low doses of 5-AZA and DAC alone show efficacy in AML and TNBC, and propose treatment with PARPi's to enhance sensitivity of cancer cells to DNMTis. The mechanistic rationale for our approach is based upon: 1) data from our group and others showing DNMT1 and PARP1 associate in a complex, and this association increases with DNA damage; 2) the fact that 5-AZA and DAC trap DNMT's led us to hypothesize that these drugs might also increase PARP trapping at DNA damage sites; and 3) the cytotoxicity of the most potent PARPi's (e.g. Talazoparib) appears to correlate with the degree of trapping of PARP1 in chromatin. We find that in cultured human AML and TNBC cells, the DNMTi's (5 to 20 nM DAC or 100 to 200nM 5-AZA) and PARPi's (1 to 10 nM Talazoparib) alone trap PARP into chromatin, and this effect is enhanced when the drugs are combined. In addition, the PARPi-DNMTi combination treatment in TNBC MDA-MB-231 and AML MOLM-14 cell lines resulted in significantly increased DNA double strand breaks (DSBs) and enhanced retention of PARP1 and DNMT1 at laser microirradiation DNA damage sites. Compared with non-tumorigenic MCF10A cells, in TNBC cell lines (N = 4), the combined doses resulted in significant (p<0.05) increases in colony survival, when compared to single drug treatments. Similarly, AML cell lines (N = 3) as well as primary cells (N = 8) showed dramatic decreases (p<0.05) in colonies in combination vs single agent drug treatments. In the most important translational implications, mouse xenograft experiments, using BRCA mutant TNBC cell line SUM149PT and MDA-MB-231 with intact BRCA1, both models demonstrated that the combination treatment has a significant (p<0.05) survival advantage, compared to control (vehicle), AZA (0.5mg/kg) or BMN (0.3 mg/kg) alone. Likewise in AML xenografts of MOLM14 and MV411 cell lines with poor prognosis marker, FMS-like 3 internal tandem duplication (FLT3/ITD), the drug combination show (p<0.05) significantly decreased leukemia burden, as measured by luciferase imaging. Our data suggest a novel use of both DNMTi's and PARPi's in a compelling therapeutic strategy for TNBCs independent of BRCA mutations and poor prognosis AML; the latter will be investigated in a clinical trial funded by Van Andel-SU2C. Citation Format: Feyruz V. Rassool, Nidal Muvarak, Khadiza Chowdury, Carine Robert, Limin Xia, Eun Yong Choi, Yi Cai, Marina Bellani, Ying Zou, Michael Seidman, Søren Bentzen, Maria Baer, Rena Lapidus, Stephen B. Baylin. Combination of DNA methyltransferase and PARP inhibitors as a novel therapy strategy for poor prognosis acute myeloid leukemia and triple-negative breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-205.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».