Abstract SY37-01: Augmenting the therapeutic ratio by combining radiation therapy with inhibitors of the DNA damage response

Abstract Radiation therapy is an effective curative treatment modality across a broad spectrum of cancer types. A favorable therapeutic ratio is achieved through a combination of precise anatomical targeting and innate sensitivity of many tumors to ionizing radiation which exceeds that of the relevant normal tissues. Several types of cancer, however, cannot currently be cured by radiation therapy. Amongst localized (non-metastatic) cancers, two key reasons for treatment failure are: (i) intrinsic radioresistance of tumor cells and (ii) infiltration of adjacent normal tissues which restricts the dose of radiation that can be safely delivered. In this setting, escalation of radiation dose is not feasible, so biologically driven approaches are required to augment the therapeutic ratio in order to achieve tumor cure without unacceptable toxicity. Ionizing radiation kills cells predominantly by inflicting DNA damage. Cells use a repertoire of sophisticated repair pathways to recognize and repair this damage; these pathways are closely connected with cell cycle checkpoint mechanisms that contribute to minimizing the impact of DNA damage, maintaining genomic integrity and promoting cell survival. Detailed understanding of cellular DNA damage response (DDR) pathways has enabled the developed 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 and, while knowledge about effects on normal tissue toxicities is accruing, evidence of improved tumor control is still awaited. PARP inhibitors are the most advanced class of agents to be tested in this context, and this presentation will summarize 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 are more potent radiosensitizers than PARP inhibitors. After summarizing pre-clinical findings, I will review the key clinical trials and consider how we might select patients and tumor types for particular radiation-DDRi combinations. Although the addition of DDRi to radiation has been shown to exacerbate normal tissue toxicity in some anatomical locations, emerging preclinical data indicate that ATM and PARP inhibitors may exert radioprotective effects in the brain. I will present a summary of these exciting data and consider potential mechanisms and clinical implications. Finally I will present a novel clinical trial design that should enable us to make more rapid progress in this area. Citation Format: Anthony Chalmers. Augmenting the therapeutic ratio by combining radiation therapy with inhibitors of the DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY37-01.