ESTRO 2025 - Abstract Book

S31

Invited Speaker

ESTRO 2025

Furthermore, we will present recent findings from our research group characterizing the molecular mechanisms underlying rhabdomyosarcoma (RMS) radioresistance, the most common pediatric soft tissue sarcoma. We have recently demonstrated that inhibition of class I histone deacetylases (HDACs)—key "epigenetic writers"— radiosensitizes the high-risk PAX3-FOXO1 fusion-positive subtype (FP-RMS), which is otherwise highly resistant to radiotherapy, both in vitro and in vivo. Moreover, by dissecting the role of class I HDACs in RMS radioresistance, we propose HDAC3 genetic or pharmacological inhibition as a promising strategy to overcome radioresistance in this tumor. For the first time, we will also present evidence of the critical role of bromodomain-containing proteins (BRDs), "epigenetic readers," in sustaining RMS stemness and radioresistance through enhanced DNA repair. Thus, this presentation will highlight recent insights into epigenetic modifications, DNA double-strand break repair, and cancer radiotherapy. Additionally, we will outline the latest findings on epigenetic-based radiosensitization strategies. We believe that combining epigenetic-targeted therapies with radiotherapy will play an increasingly significant role in future cancer treatments.

4692

Speaker Abstracts Clinical trials of radiotherapy-DDR inhibitor combinations: What have we learned and where are we heading? Anthony J Chalmers School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom

Abstract:

Ionizing radiation kills cells predominantly by inflicting DNA damage. Cells use a repertoire of sophisticated molecular pathways to recognise and repair this damage; these are integrated with cell cycle checkpoint mechanisms that contribute to minimising the impact of DNA damage, maintaining genomic integrity and promoting cell survival. Detailed understanding of cellular DNA damage response (DDR) pathways has enabled the developement of potent and specific inhibitors, several of which are known to enhance radiation sensitivity and increase the effects of radiation therapy in preclinical models. Clinical evaluation of DDR inhibitors in combination with radiation therapy has been underway for several years. While knowledge about effects on normal tissue toxicities is accruing, evidence of improved tumour control is still awaited. PARP inhibitors are the most advanced class of agents to be tested in this context, and this presentation will summarise the key observations made in early phase trials, focusing on tissue specific toxicities that have hampered further development. I will also consider how progress might have been accelerated if more efficient clinical trial designs had been adopted. Inhibitors of additional DDR proteins such as ATM and ATR have also entered the clinic, both as single agents and in combination with radiotherapy. Preclinical data indicate that some of these agents are more potent radiosensitizers than PARP inhibitors. After summarising pre-clinical findings, I will review the key clinical trials and consider how we might select patients and tumour types for particular radiation-DDRi combinations. 4693

Speaker Abstracts Artificial intelligence in treatment preparation and delivery: A game changer Marianne Aznar Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom