Abstract A38: Targeting Microenvironment Damage Responses via PARP inhibition to Enhance Prostate Cancer Therapy
Notice bibliographique
Résumé
Abstract Introduction: Radiation and chemotherapeutic drugs have significantly improved the long-term outlook for patients diagnosed with prostate cancer. However, in men with metastatic prostate cancer, the development of radio and chemo resistance is almost universal. As a result, understanding and circumventing chemo/radiotherapy resistance has become a research priority. In addition to damaging neoplastic cells, radiation and chemotherapy also exert potent “bystander” effects on the tumor microenvironment (TME) by induction of a DNA Damage Secretory Program (DDSP). In this study we sought to identify and modulate master regulators of the DDSP in order to augment the effectiveness of conventional cancer therapeutics. The Nelson group and others have shown that NFkB is a master regulator of the DDSP, but pharmacological inhibition of NFkB has been challenging. As PARP can activate NFkB and PARP inhibitors (PARPi) have received clinical approval for cancer therapy, we evaluated the effects of PARPi to modulate the DDSP. Results: We used prostate (PF) and bone fibroblasts (BF) as our experimental model as this cell type comprises a substantial component of the TME in bone. We determined that ionizing radiation (IR) induced DDSP in PFs and BFs that was suppressed by PARPi, and observed significant reductions in transcripts encoding several key tumor promoting DDSP factors such as IL8, Wnt16b. Fractionated IR was more effective in increasing the transcript levels of various DDSP factors compared to single dose of IR. PARPi also suppressed DDSP-induced nuclear translocation of NFkB in fibroblasts and modulated the DDSP via the function/modification of NEMO. Conditioned media from irradiated PFs and BFs or co-culture with them induced growth and therapy resistance in prostate cancer (PCa) cells, indicative of the tumor promoting role of DDSP, which was suppressed after PARPi addition either later or in the cells treated with both IR and PARPi. Another PARP family member, PARP5 inhibition in irradiated BFs showed significant reduction in DDSP marker's transcript level, which was also reflected by inhibited growth of PCa cells when radiated BF's condition media was added along with PARP5 inhibitor. Conclusions: PARP inhibitors, developed primarily to target vulnerabilities in tumor cells directly, may provide additional anti-tumor effects via DDSP and repurposing PARPi to suppress the DDSP could augment responses to radiation and chemotherapy via microenvironment modulation. In addition to PARP1, our ongoing studies are designed to evaluate other PARP family members including PARP5 and PARP10 that may influence damage responses. Citation Format: Payel Chatterjee, Peter Nelson. Targeting Microenvironment Damage Responses via PARP inhibition to Enhance Prostate Cancer Therapy [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A38.
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) | 0,007 | 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 ».