Cathepsin K: A Versatile Potential Biomarker and Therapeutic Target for Various Cancers

Round 1

Reviewer 1 Report

The paper, entitled " Cathepsin K: a versatile potential biomarker and therapeutic target for various cancers” aims to investigates the relations between to systematically review the relevant roles of cathepsin K (CTSK) in various possible cancers in existing studies. It is an interesting and comprehensive review.

-        How can be translated to clinical setting?

-        What is the added value?

-        Is there a bridge to exosome composition?

-        A graphical summary will help to disseminate the message.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

In this article, the authors summarize the current understanding of the role of CTSK in cancer and evaluate its potential as biomarker and/or novel therapeutic target for cancers. The manuscript is straightforward, well written, and concise and has clear results within the scope of a review article. Definitely deserves to be published and is a valuable contribution to the “Current Oncology” journal. Some minor comments need to be addressed before publication.

[1] “3. CTSK in Prostate Cancer”, Page 3, Lines 89-92:

“Prostate cancer (PCa) occurs mostly in middle-aged and elderly men, which is occurred most common cancer in the world [34]. The early stage of prostate cancer is difficult to diagnose due to no symptoms, and the prostate specific antigen (PSA) is commonly currently used to diagnose early prostate cancer [35,36]”.

At that stage, the authors should mention that more recently, large-scale sequencing efforts have allowed a better understanding of the genomic landscape of prostate cancer. Germline or somatic aberrations in the DNA damage repair genes are found in 19% of primary prostate cancer and almost 23% of metastatic castration-resistant prostate cancer and compromise genomic integrity. Patients with BRCA2 pathogenic sequence variants have increased levels of PSA at diagnosis, an increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rates.

[2] “7. CTSK in Colorectal Cancer”, Page 7, Lines 245-247:

“CRC is characterized by diverse molecular features and different cancer stages, with two major mechanisms of genetic instability leading to such changes: chromosomal instability and microsatellite instability.”.

At that point, it should be reported the recommended colon cancer screening for defective DNA mismatch repair using immunohistochemistry and/or MSI test. There are challenges in distilling the biological and technical heterogeneity of MSI testing down to usable data. It has been reported in the literature that immunohistochemistry testing of the mismatch repair machinery may give different results for a given germline mutation and has been suggested that this may be due to somatic mutations.

Recommended reference: Adeleke S, et al. Microsatellite instability testing in colorectal patients with Lynch syndrome: lessons learned from a case report and how to avoid such pitfalls. Per Med. 2022;19(4):277-286.

[3] “8.1. Ovarian cancer”, Page 8, Line 271:

“Moreover, OCa has often metastasized to other sites [101].”.

Genomic alterations in the DNA damage repair pathway are emerging as novel targets for treatment of ovarian cancer. Platinum compounds and PARP inhibitors are the two main classes of drugs active against cancer cells harboring DNA damage repair alterations. On the other hand, as PD-L1 expression remains rare in ovarian cancer, it is necessary to further investigate potential predictive biomarkers for immune-checkpoint inhibitors.

[4] “8.3. Melanoma”, Page 8, Lines 39-43:

“It is a kind of tumor with high degree of malignancy and poor prognosis, and is prone to distant metastasis [110]”.

That should discuss that recently has been published that patients with melanoma of unknown primary site seem to present better outcomes compared to those with stage-matched melanoma of known primary site, probably due to higher immunogenicity as reflected in the immunologically mediated primary site regression. As such, melanoma of unknown primary site patients on immunotherapy probably display better outcomes when compared to the melanoma of known primary site subset.

Recommended reference: Boussios S, et al. Melanoma of unknown primary: New perspectives for an old story. Crit Rev Oncol Hematol. 2021;158:103208.

Author Response

Please see the attachment.

Author Response File: Author Response.docx