Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript reviews currently emerging therapeutic strategies for squamous cell carcinomas of the head and neck (SCCHN). Overall, the review is well written and covers sufficient preclinical and clinical trials data from recent years. The authors successfully depict the rapidly evolving landscape of novel therapeutic strategies to improve outcomes for patients with SCCHN, although several challenges remain, warranting future efforts.

I have a few comments as outlined in attached file.

Comments for author File: Comments.docx

Author Response

Dear reviewer,

Thank you for your comments. We have taken note of them and have made an effort to revise the manuscript as such:

1) Supplemented references where deemed insufficient

2) Improved on our figures and cited them accordingly to make them more relevant to the script

3) Expanded on section 5.4 

4) Added in a section on use of Metformin

 

Please take the time to look through our revised manuscript and we hope that it meets your expectations. 

Reviewer 2 Report

Comments and Suggestions for Authors

see attached

Comments for author File: Comments.pdf

Author Response

Dear Reviewer,

Thank you for your comments. 

 

General remarks

1) The overall accepted and used name and abbreviation of the entity is head and neck squamous cell carcinoma and HNSCC, not SCCHN! Authors should adapt that in the whole manuscript

- We agree with this comment and have changed all abbreviations to HNSCC

2) A comprehensive review article needs some more high-quality figures, for example depicting HNSCC tumorigenesis, localization, treatment options, prognosis, signaling pathways or else…

- We agree with this comment and have made an effort to improve on this with new figures that succinctly summarise the mechanisms of actions of some of these new therapeutic approaches 

3) Manuscript lacks references on other relevant studies

- We agree and have made an effort to improve on our references; to supplement more where it is lacking

4) For some potential new approaches it remains sometimes unclear if this has been already tested (pre-clinical/clinical) for HNSCC, e.g. for PROTACs (section 6.2). Authors should always clarify if this is their own suggestion or if this has been already tested before.

- We agree and have clarified this in the sections where it might seem vague on whether or not the treatment is in its clinical or preclinical phase

 

 

Specific Comments

1) The introduction is very short, authors should include more details about state-of-the art treatment of HNSCC

- While we recognise this as a valid point, we feel that the focus of this already lengthy review should still be on the newer approaches rather than to reiterate the current standards of care, which are already well established

2) Section 2.1: list formatting should be changed to normal text to increase clarity

- We agree and have sought to correct this 

3) General formatting should be revised, e.g. sometimes subheadings with : , sometimes without

- We agree and have sought to correct this 

4) Sections 3.1- 3.6: “Targeting” is always repeated in the subheadings and can be deleted

- We agree and have removed this 

5) Many sections lack convincing references, e.g. sections 3.6, 4.1, 4.2 just a single source, 5.4 no ref at all?! Is this relevant then?

- We agree and have improved on supplementing more references 

6)  Figures lack detailed legend/description

- We have put in new figures with a more detailed legend

7) 7.1: the description of chemoresistance acquisition to cisplatin seems very “specific”, and is surely not the general mechanism in all tumors! General resistance pathways should be mentioned, such as efflux/channel-, and DNA repair-associated, as reported before (e.g. (4))

- We have tried to expand on this to include broader mechanisms of resistance

8) 7.3: here, many important facts are provided. However, the authors might also discuss here the options of de-escalation therapies for HPV-positive OSCC, since also promising studies exist showing hypoxia as biomarker for de-escalating radiotherapy (30 ROC trial, (5))

- We agree and have included a portion on de-escalation of therapies in HPV positive OSCC

Please take your time to read through the revised manuscript and we hope that it meets your standards. 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors provided a revised version in which all comments were addressed and appropriately revised. I suggest publication after formal revision by the editor.