# Understanding and Exacerbating the Biological Response of Uveal Melanoma to Proton Beam Therapy

## TL;DR

This review explores how proton beam therapy affects uveal melanoma and identifies factors that influence treatment response to improve patient outcomes.

## Contribution

The paper provides a comprehensive review of biological factors and emerging strategies to enhance proton therapy for uveal melanoma.

## Key findings

- DNA repair mechanisms and hypoxia significantly influence the response of uveal melanoma to proton beam therapy.
- Combination therapies targeting DNA repair and autophagy may improve treatment effectiveness.
- Advancements in PBT planning and delivery could optimize outcomes for larger tumors and metastases.

## Abstract

Proton beam therapy is a well-established precision radiotherapy treatment for cancers of the eye (uveal melanoma) that minimises damage to the surrounding normal tissues and preserves vision. The treatment effectiveness stems from the induction of DNA damage in tumour cells, which can overwhelm the repair mechanisms, driving cellular death. Despite the success of proton therapy, a subset of patients exhibit suboptimal responses, with some experiencing local recurrence and/or development of metastasis. This review presents current evidence on the biological factors, such as DNA repair mechanisms and reduced oxygen (hypoxia), that drive the responses of uveal melanoma to proton therapy. We also discuss emerging strategies aimed at treatment effectiveness, including targets for combination therapies. Understanding these aspects is critical for optimising treatment outcomes for eye cancer patients.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, associated with a high tendency for metastasis to the liver. Proton beam therapy (PBT) is the preferred external radiotherapy treatment for primary UM of certain sizes and locations in the eye, due to its efficacy and good local tumour control, as well as its precision to spare surrounding ocular structures. PBT is an effective alternative to surgical enucleation and other non-precision-targeted radiotherapies. Despite this, the radiobiology of UM in response to PBT is still not fully understood. This enhanced knowledge would help to further optimise UM treatment and improve patient outcomes through reducing radiation dosage to ocular structures, treating larger tumours that would otherwise require enucleation, or even offering a treatment strategy for the otherwise fatal liver metastases. In this review, we explore current knowledge of the treatment of UM with PBT, evaluating the biological responses to the therapy. Molecular factors, such as tumour size, oxygen tension levels, DNA damage proficiency, and autophagy, are known to influence the cellular response to radiotherapy, and these will be discussed. Furthermore, we examine innovative strategies to enhance radiotherapy outcomes, such as combination therapies with DNA damage repair and autophagy modulators, as well as advancements in PBT planning and delivery. By integrating current research and emerging technologies, we aim to provide opportunities to improve the therapeutic effectiveness of PBT in UM management.