Abstract 2069: Targeting the DNA damage response in combination with high Z metal nanoparticle radiosensitizers in glioblastoma

• Published in: Cancer research (Chicago, Ill.) Vol. 81; no. 13_Supplement; p. 2069
• Main Author: Kerr, Brianna
• Format: Journal Article
• Language: English
• Published: 01-07-2021
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2021-2069

Abstract
Introduction: Glioblastoma (GBM) is a devastating disease with an extremely poor prognosis of approximately 11-15 months following standard-of-care treatments. There is a critical need for the development of clinical unmet need and a need for novel therapies in GBM. Combining novel drugs with radiotherapy has clear potential to considerably improve patient outcomes. Metal nanoparticles (NPs) and inhibitors of the DNA damage response (DDRIs) have been successfully translated to the clinical setting to benefit patients. In this study, we aimed to evaluate a novel multi-modal treatment in GBM by combining radiotherapy with metal NPs and DDRIs.
Materials and methods: GBM cell models (U87 & U251) were screened with different NP formulations and sizes, including gadolinium-, iron- and gold-based NPs, to determine the most effective NP. Cells were transiently exposed to NPs for 1 or 24 hr prior to irradiation by x-rays and cell survival determined. IC50 values were determined for various DDRIs which specifically target PARP, ATR, ATM and DNA-PKcs. Clonogenic cell survival assays were conducted and cells treated with NP and DDRI combinations either 1 or 24 hr prior to irradiation to define the optimum schedule for drugging.
Results and conclusions: We have demonstrated the radiosensitizing potential of Activation and Guidance of Irradiation by X-ray (AGuIX), a gadolinium-based NP, at low-moderate concentrations with the highest concentration tested (2mM) showing the greatest efficacy. A promising lack of cytotoxicity on both GBM cell models was observed. In contrast to AGuIX, U87 and U251 cell survival responses indicated a lack of dose dependency when exposed to varying concentrations of Superparamagnetic Iron Oxide Nanoparticles (SPIONs). Both cell models exhibited differential radiotherapy responses when exposed to ID10 and ID11, gold-based NPs with varying PEG chain lengths. Combination treatment with AGuIX and Olaparib resulted in differential efficacy between cell lines. A non-significant difference in cell survival was observed between differing treatment scheduling. Future work will explore several variations of NP and DDRI treatments in combination with irradiation by x-rays on GBM cell models. The future implications of this research are GBM patients would receive combination therapies tailored to the specific DNA mutations in their tumor.
Citation Format: Brianna Kerr. Targeting the DNA damage response in combination with high Z metal nanoparticle radiosensitizers in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2069.