Precision Targeting in Metastatic Prostate Cancer: Molecular Insights to Therapeutic Frontiers

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript is quite interesting, however the authors need to address several issues to further ameliorate it:

1. it could be useful to include a comparative table summarizing the key therapeutic strategies (e.g., PARP inhibitors, PSMA therapy, immunotherapy) with their respective advantages, disadvantages, and associated biomarkers.
2. Some references are outdated, particularly those concerning emerging biomarkers and the use of liquid biopsy for monitoring AR-V7. Update citations by including more recent studies
3. Add a table containing data on the sensitivity, specificity, and positive/negative predictive value of molecular biomarkers

 

Comments on the Quality of English Language

1. Some sentences are lengthy and complex and there are some grammatical and punctuation errors. Consider submitting the manuscript for language editing by a native English speaker for enhanced clarity.

Author Response

"Please see the attachment."

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript provides a comprehensive review of the mechanisms leading to prostate cancer, the physiology underlying the development of resistance to therapies, in particular androgen therapy, ongoing therapeutic approaches, and future directions. I have only a few suggestions that the authors might want to consider for inclusion. 

1. The authors discuss the value of PET/CT PSMA imaging, and point out the limitation that many centers may not have the capability to perform PET/CT imaging. To circumvent this shortcoming, a number of [⁹⁹Tm] tracers have been developed for use with the more widely available SPECT/CT technology. A recent meta-analysis (Wang, Ketteler et al, BMC Cancer 2024) supports the potential of this approach.
2. In addition to the potential of replacing lutetium with alpha emitters in PSMA-directed theranostics, the beta-emitter terbium, [¹⁶¹Tb]Tb-PSMA-I&T is being tested in the Phase I/II VIOLET (Bureau et al, J Nucl Med 2024). [¹⁶¹Tb] emits Auger and conversion electrons that deposit a higher concentration of radiation over a shorter path, and shows superior in vitro and in vivo efficacy compared to ¹⁷⁷Lu.
3. Bipolar androgen therapy (BAT), the monthly administration of high dose testosterone to ADT-treated patients, has shown efficacy in patients progressing on abiraterone (TRANSFORMER, Denmeade et al, J Clin Oncol 2021). BAT provided meaningful clinical efficacy, and also sensitized patients to subsequent Enzalutamide treatment. A more recent Phase 2 study (COMBAT) has also shown efficacy of BAT plus  Nivolumab, and found that BAT induced pro-inflammatory gene expression changes in metastatic tumor biopsies that were restricted to patients achieving a clinical response (Markowski et al Nat Comm 2024).

Author Response

"Please see the attachment."

Author Response File: Author Response.pdf