Abstract A01: Distinct mechanism of action of DNA-damaging agent dianhydrogalactitol (VAL-083) suggests combination therapy with PARP inhibitors
Notice bibliographique
Résumé
Abstract DNA damage response (DDR) is a network of intracellular pathways designed to minimize the impact of DNA damage. Multiple DNA repair pathways are known, including mismatch repair (MMR), O6-methylguanine DNA methyltransferase (MGMT), non-homologous end joining (NHEJ), and homologous recombination (HR), which act either by repairing the damage, arresting cell growth or, if necessary, promoting cell death. DDR defects are a hallmark of cancer development, rendering the cancer cells highly sensitive to targeted DNA-damaging agents. Ovarian cancer is normally treated with platinum (Pt)-based chemotherapy, which forms predominantly intrastrand DNA crosslinks; however, most advanced ovarian cancer patients develop episodes of recurrent disease with progressively shorter disease-free intervals. Dysfunctional p53 diminishes the therapeutic cytotoxicity of many DNA-targeting drugs, including Pt-based agents, comprising a therapeutic challenge in high-grade serous ovarian cancer (HGSOC), where p53 is almost universally mutated (~96%). Attempts to overcome Pt-resistance in HGSOC include PARP inhibitors (PARPi), which target tumors with deficiencies in the HR pathway (50% of HGSOC), responsible for the repair of DNA double-strand breaks (DSBs). Unfortunately, PARPi resistance frequently arises, leading to a 5-year survival rate of only 40% in this cancer. VAL-083 is a first-in-class DNA-damaging agent that has demonstrated clinical activity against a range of tumor types, including ovarian cancer, in historical NCI-sponsored clinical studies. VAL-083 rapidly induces interstrand crosslinks at guanine-N7, causing DNA DSBs that, if left unrepaired, are lethal to the cancer cell. We have shown that VAL-083 treatment leads to DNA damage that activates HR and is independent of common DNA repair pathways, including MGMT, MMR, and NHEJ. Notably, VAL-083 induces persistent S/G2 phase cell cycle arrest through two parallel pathways--one p53-independent and one p53-dependent. Taken together, these data propose the potential for targeting HR-impaired tumors and for combination treatment with S-phase specific DNA-targeting agents, including PARPi. We have previously seen VAL-083 cytotoxicity against a panel of ovarian cancer cells with differing p53 status and superadditivity between VAL-083 and PARPi olaparib, in vitro. The purpose of this study was to expand on these studies by examining the cytotoxicity of VAL-083 against HR-impaired ovarian cancer cells, the impact of p53 status, and the potential for VAL-083 combination with PARPi as part of a treatment strategy for HR-impaired, p53 dysfunctional HGSOC. VAL-083 cytotoxicity was investigated using the 5-day MTT assay in A2780 ovarian cancer cells. HR-impaired A2780 were examined using BRCA1 siRNA oligos prior to VAL-083 exposure. Combinations with PARPi veliparib (catalytic) and talazoparib (trapping) were examined in HR-proficient and HR–impaired A2780. The impact of p53 status was investigated by CRISPR/cas 9 knockout of p53 in the wildtype (wt) A2780 cells and in p53-mutated OVCAR3 cancer cells. We report increased VAL-083 cytotoxicity against HR-impaired A2780 cancer cells, further supporting HR as the main repair pathway for VAL-083-induced DNA damage, and suggesting HR-impaired HGSOC as a target for VAL-083 treatment. We further report superadditivity between VAL-083 and PARPi veliparib and talazoparib. Significantly, VAL-083 cytotoxicity against wt and knockout p53 A2780 cells and against p53-mutated OVCAR3 cells differed only by a factor of ~2, supporting a p53-independent mechanism of action for VAL-083. In conclusion, our results demonstrate a distinct DNA-damaging mechanism for VAL-083, resulting in the ability to target HR-impaired tumors and overcome MGMT- , MMR- , and NHEJ-related chemoresistance. VAL-083 activity was independent of p53 status, and superadditivity with PARPi was identified in HR-proficient A2780. Studies in HR-impaired A2780 are ongoing and will also be presented. Citation Format: Jeffrey A. Bacha, Guangan He, Xiaolei Xie, Anne Steino, Dennis M. Brown, Zahid H. Siddik. Distinct mechanism of action of DNA-damaging agent dianhydrogalactitol (VAL-083) suggests combination therapy with PARP inhibitors. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A01.
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) | 0,003 | 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 ».