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

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I am grateful for the opportunity to review manuscript # 3828608, entitled “Understanding and exacerbating the biological response of uveal melanoma to proton beam therapy.”

This review article provides an overview of proton beam therapy for uveal melanoma, highlighting key biological processes that influence efficacy, with the aim of identifying strategies to improve outcomes further. The manuscript is well-written, interesting, and cites a wealth of significant research in the field. This is a useful addition to the literature. I have no specific comments.

Author Response

Reviewer 1 Comments

I am grateful for the opportunity to review manuscript # 3828608, entitled “Understanding and exacerbating the biological response of uveal melanoma to proton beam therapy.”

This review article provides an overview of proton beam therapy for uveal melanoma, highlighting key biological processes that influence efficacy, with the aim of identifying strategies to improve outcomes further. The manuscript is well-written, interesting, and cites a wealth of significant research in the field. This is a useful addition to the literature. I have no specific comments.

Response: We thank the Reviewer for their kind comments.

Reviewer 2 Report

Comments and Suggestions for Authors

1. Figure 1. Please adjust line colors to improve contrast between groups
2. Please add additional references for the pathways shown in Figures 2 and 4.
3. Section 4 lists several key molecular factors for ionizing radiation-related cell death, while a specific mechanism for uveal melanoma-related PBT was unknown and not stressed. Please discuss.
4. In section 5, strategies to exacerbate PBT were introduced, but not all works were directly related to PBT. They seem more like proposals rather than a summary for a review paper.
5. Adding a Roadmap shows how this PBT technique has evolved can be helpful.

Author Response

Reviewer 2

1. Figure 1. Please adjust line colours to improve contrast between groups

Response: We thank the Reviewer for their suggestion. The lines on the graph have now been changed to improve the contrast between the groups.

 

2. Please add additional references for the pathways shown in Figures 2 and 4.

Response: We appreciate the Reviewer’s suggestion. Additional references have now been added into the main text relating to Figure 2 (page 6 line 188; page 7 lines 218 and 232-233) and Figure 4 (page 11 lines 365 and 367).

 

3. Section 4 lists several key molecular factors for ionizing radiation-related cell death, while a specific mechanism for uveal melanoma-related PBT was unknown and not stressed. Please discuss.

Response: We thank the Reviewer for their comment. We have now highlighted the fact that the response to PBT-induced DNA damage in UM has been largely unexplored (page 7 lines 234-235), but also that this relates to inadequate accessibility or the required resources for PBT research (page 8 lines 254-260).

 

4. In section 5, strategies to exacerbate PBT were introduced, but not all works were directly related to PBT. They seem more like proposals rather than a summary for a review paper.

Response: We appreciate the Reviewer’s observation and agree that some of the strategies discussed in Section 5 extend beyond current clinical applications of PBT. However, we believe this section is essential to the overall scope of the review as it highlights emerging technological innovations and conceptual advances that have the potential to significantly enhance the therapeutic efficacy and accessibility of PBT in the near future. Indeed, some of these approaches are actively being explored in preclinical models and research. Additionally, these strategies provide a forward-looking perspective that is valuable for researchers and clinicians seeking to understand not only the current landscape, but also the trajectory of PBT development. Our review therefore not only presents existing knowledge but also identifies promising avenues for future investigation.

 

5. Adding a Roadmap shows how this PBT technique has evolved can be helpful.

Response: Whilst we thank the Reviewer for their comment, a roadmap on the historical evolution of PBT is not entirely relevant to the main topic discussed, which is centred on the need for further understanding of the radiobiology of PBT through research. This knowledge will then help to drive strategies in the clinic used to improve the outcome and survival of UM patients.

Reviewer 3 Report

Comments and Suggestions for Authors

I acknowledge the authors’ efforts to prepare an excellent review article on this topic. Only one comment is about the FLASH therapy as applied to the proton therapy of uveal melanoma. Considering that only a single energy can be used to treat such small, thin tumors and the critical structures are near the cancer, the proton FLASH therapy technique may be ideal. I would appreciate hearing the authors’ thoughts on this topic.

[Ref.] Hrbacek J, Kacperek A, Beenakker JM, Mortimer L, Denker A, Mazal A, et al. PTCOG Ocular Statement: Expert Summary of Current Practices and Future Developments in Ocular Proton Therapy. Int J Radiat Oncol Biol Phys. 2024;120(5):1307-25. DOI:10.1016/j.ijrobp.2024.06.017.

Author Response

Reviewer 3

I acknowledge the authors’ efforts to prepare an excellent review article on this topic. Only one comment is about the FLASH therapy as applied to the proton therapy of uveal melanoma. Considering that only a single energy can be used to treat such small, thin tumors and the critical structures are near the cancer, the proton FLASH therapy technique may be ideal. I would appreciate hearing the authors’ thoughts on this topic.

Response: We thank the Reviewer for highlighting this, and we have now included a new section (page 13, lines 441-464) discussing the potential merits and shortcomings of FLASH in relation to UM treatment.