Kinases Inhibitors as New Therapeutic Opportunities in Cutaneous T-Cell Lymphoma

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a straightforward review of CTCL and the kinase pathways involved in this multifactorial disease.  This review is complete with need for minor modifications.  Table 1 is especially good.

 

Figure 1 should be larger.

Why is it better to inhibit NIK more than IKKalpha (line 246)?

Line 299 needs a reference.

Line 372 miR-122  is first introduced but not explained well its role in signal transduction pathways.

In each section where description of kinase and phosphorylation is included, are there any additional phenotypical consequences (for example line 393).

 

 

Author Response

Comments 1: Figure 1 should be larger.

Response 1: Thank you for your comment, we did Figure 1 larger. Done. 

 

Comments 2: Why is it better to inhibit NIK more than IKKalpha (line 246)?

Response 2:  Done.  IKK activation represents the key step of NF-kB activation, thus this kinase could be pharmacologically targeted. IKKβ selective inhibitors have been the main focus of modulating abnormal NF-kB signalling, however, problems of toxicity and the lack of clinically positive results led to a reduced interest in the pharmaceutical industry.

 

Comments 3: Line 299 needs a reference.

Response 3: Thanks for your suggestion we added a reference. Done.

 

Comments 4: Line 372 miR-122  is first introduced but not explained well its role in signal transduction pathways.

Response 4: Thanks for your comment, but miR-122 is not a main component of the signalling pathway and it is written what is known until now in CTCL. Done.

 

Comments 5: In each section where description of kinase and phosphorylation is included, are there any additional phenotypical consequences (for example line 393).

Response 5:  We appreciate your comment, we checked and completed it. Done.

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for your comprehensive review on therapeutic opportunities in cutaneous T-cell lymphoma (CTCL). The manuscript provides valuable insights into various kinase inhibitors and their roles in treating CTCL. However, I have identified a few critical areas that need to be addressed to enhance the depth and relevance of the discussion:

1. Inclusion of Recent Studies on PI3K Inhibitors:

   • The manuscript discusses the role of Duvelisib in targeting the PI3K/Akt/mTOR pathway but fails to reference a recent significant study.
   • Please include the study by Bazewicz et al., which highlights the utility of low-dose Duvelisib for advanced Mycosis Fungoides. This study suggests that the effects of PI3K inhibitors may not be dose-dependent and provides a broader perspective on the therapeutic use of these inhibitors.
     • Reference: Bazewicz C, Verardi N, Akilov O. Utility of Low-Dose Duvelisib for Advanced Mycosis Fungoides: A Single-Institution Study. Oncologist. 2024 Mar 4;29(3):272-274. doi: 10.1093/oncolo/oyad345. PMID: 38243388; PMCID: PMC10911911.

2. Discussion on JAK Inhibitors in Dermatology:

   • While the manuscript addresses the use of JAK inhibitors, it does not sufficiently cover their broad applications in dermatology. JAK inhibitors like upadacitinib and abrocitinib have shown significant efficacy in treating conditions such as atopic dermatitis, psoriasis, and alopecia areata.
   • Expanding the discussion to include these newer treatments will provide a more comprehensive overview of the therapeutic potential of JAK inhibitors.

3. Strengthening the Conclusion:

   • The conclusion should be more robust, defining future directions and potential combination therapies. Emphasize the need for further clinical trials to explore combinations of kinase inhibitors with other treatment modalities, such as HDAC inhibitors, to enhance therapeutic efficacy and overcome drug resistance.
   • Outline specific perspectives on how these combinations could be integrated into current treatment protocols and the expected outcomes based on existing data.

Author Response

Comments 1: Inclusion of Recent Studies on PI3K Inhibitors:

• • The manuscript discusses the role of Duvelisib in targeting the PI3K/Akt/mTOR pathway but fails to reference a recent significant study.
  • Please include the study by Bazewicz et al., which highlights the utility of low-dose Duvelisib for advanced Mycosis Fungoides. This study suggests that the effects of PI3K inhibitors may not be dose-dependent and provides a broader perspective on the therapeutic use of these inhibitors.
    • Reference: Bazewicz C, Verardi N, Akilov O. Utility of Low-Dose Duvelisib for Advanced Mycosis Fungoides: A Single-Institution Study. Oncologist. 2024 Mar 4;29(3):272-274. doi: 10.1093/oncolo/oyad345. PMID: 38243388; PMCID: PMC10911911.

Response 1:  We appreciate your comment. We included recent studies on PI3K inhibitors. Done.

 

Comments 2: Discussion on JAK Inhibitors in Dermatology:

• • While the manuscript addresses the use of JAK inhibitors, it does not sufficiently cover their broad applications in dermatology. JAK inhibitors like upadacitinib and abrocitinib have shown significant efficacy in treating conditions such as atopic dermatitis, psoriasis, and alopecia areata.
  • Expanding the discussion to include these newer treatments will provide a more comprehensive overview of the therapeutic potential of JAK inhibitors.

Response 2: Thank you for your suggestion. We added data and expanded the discussion about JAK inhibitor's broad applications in dermatology.

 

Comments 3: Strengthening the Conclusion:

• • The conclusion should be more robust, defining future directions and potential combination therapies. Emphasize the need for further clinical trials to explore combinations of kinase inhibitors with other treatment modalities, such as HDAC inhibitors, to enhance therapeutic efficacy and overcome drug resistance.
  • Outline specific perspectives on how these combinations could be integrated into current treatment protocols and the expected outcomes based on existing data.

Response 3: Thanks for your comments. Done.

Reviewer 3 Report

Comments and Suggestions for Authors

The review "Therapeutic opportunities in cutaneous T-cell lymphoma " summarises different role of kinases in CTCL and kinase inhibitors as promising therapeutic avenue. Review is well compiled and structured, however, there are several points that authors should address. 

 

1.The title needs to include 'kinase inhibitors' as that is the focus of authors. 

2.Authors elaborated only role of jak in CTCL with diagram, authors should provide a figure depicting different kinases and specific aspects of CTCL progress and biology influenced. 

3. Authors should also compile effects of different categories of kinase inhibitors that affects CTCL. 

4. Table 1, authors should include citation for each kinases inhibitor and experimental or clinical results that they have depicted in the table. 

 

Comments on the Quality of English Language

Minor editing for spell check needed. 

Author Response

Comments 1: The title needs to include 'kinase inhibitors' as that is the focus of authors. 

Response 1: Thank you for your comment. We totally agree. We included a new tittle: “Kinases inhibitors as new therapeutic opportunities in cutaneous T-cell lymphoma”. Done.

 

Comments 2: Authors elaborated only role of jak in CTCL with diagram, authors should provide a figure depicting different kinases and specific aspects of CTCL progress and biology influenced. 

Response 2: Thank you for your comment. It is already added: all different JAK and MAPK kinases related with CTCL and the specific aspects are described just underneath.

 

Comments 3: Authors should also compile effects of different categories of kinase inhibitors that affects CTCL. 

Response 3: Thank you for your suggestion. We added effects of different categories of kinase inhibitors during CTCL tumour progression. Checked and completed. 

 

Comments 4: Table 1, authors should include citation for each kinases inhibitor and experimental or clinical results that they have depicted in the table. 

Response 4: We appreciate your comment. We added it on Table 1. Done.

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Authors have addressed concerns of this reviewer adequately.