Losartan as a mechanotherapeutic adjuvant: Remodeling the breast tumor microenvironment to improve treatment efficacy

Mutaz Dwairy; Alaa Yehya; Feras M. Mohammad; Hiba Alzoubi

doi:10.1371/journal.pone.0328196

Peer Review History

Original SubmissionMay 4, 2025
Decision Letter - Hean Teik Ong, Editor Dear Dr. Dwairy, Please submit your revised manuscript by Jul 21 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. 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Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: I Don't Know ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: Although this study is highly theoretical, it demonstrates strong biological relevance, offers novel insights into tumor microenvironment modulation, and is a valuable contribution worthy of publication. Reviewer #2: My Main Supporting Suggestions 1. This is a well-designed paper based on mathematical modeling, much in line with physical laws, utilizing COMSOL Multiphysics simulations that has been successfully applied in various other fields especially in research. 2. Conclusions in this paper do reflect the proposed objectives of the Mathematical Modeling. 3. A follow-up of this paper with further Clinical Trials, may contribute to the study of the complex Tumor Microenvironment (TME) that is so relevant to tumor growth, and its response and resistance to treatment. My Main Concerns 1. Although the Laws of Physics apply universally, effects resulting from these Laws may be different in macro vs micro scales. 2. Mathematical Modeling may not reflect actual observable results in Clinical Trials, in relation to emphasis placed on Deterministic Vs Stochastic modeling. 3. Malignant Cellular adaptive mechanisms to survive when faced with treatment challenges may be evident during Clinical Trials. 4. The population of subjects selected for Clinical Trials may need to be of a certain target group, because of time constraints in relation to the disease progression versus the time needed for the contributory effects of Losartan to take effect. 5. The Mathematical Model, which reflects local disease control and progression, may not have taken into consideration the importance of metastatic disease which may ultimately determine prognosis, and metastases as we know, occur quite early before the disease can be clinically detected. ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? 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If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org Attachments Attachment Submitted filename: Manuscript Review_ Losartan.docx https://doi.org/10.1371/journal.pone.0328196.r001
Revision 1
14 Jun 2025 Author Response We sincerely thank the editor and the reviewers for their thoughtful and constructive comments. We have carefully addressed all comments and revised the manuscript accordingly. Below, we provide our detailed point-by-point responses. Reviewer #1: Although this study is highly theoretical, it demonstrates strong biological relevance, offers novel insights into tumor microenvironment modulation, and is a valuable contribution worthy of publication. Response: We sincerely thank the reviewer for this encouraging and positive evaluation of our work. Reviewer #2: 1. Although the Laws of Physics apply universally, effects resulting from these Laws may be different in macro vs micro scales. Response: We thank the reviewer for this valuable comment. Our original manuscript already acknowledges this limitation in the Discussion. Specifically, we have stated that: “The framework operates at a single spatial scale (macroscale) and does not incorporate multi-scale (cellular-to-tissue level) interactions, thus potentially missing important cross-scale dynamics.” 2. Mathematical modeling may not reflect actual observable results in Clinical Trials, in relation to emphasis placed on Deterministic Vs Stochastic modeling. Response: In the original manuscript, we acknowledged that by stating: “In addition, many model parameters (e.g., tissue stiffness, drug efficacy) were estimated from preclinical studies due to the limited availability of patient-specific data, which may introduce uncertainty and reduce predictive accuracy.” To further address the reviewer’s concern about deterministic versus stochastic modeling, we have expanded the Discussion section to explicitly recognize that: “In addition, many model parameters (e.g., tissue stiffness, drug efficacy) were estimated from preclinical studies due to the limited availability of patient-specific data. Consequently, the deterministic nature of our computational model fails to capture the biological variability and patient heterogeneity observed in clinical settings, which may introduce uncertainty and reduce predictive accuracy.” 3. Malignant Cellular adaptive mechanisms to survive when faced with treatment challenges may be evident during Clinical Trials. Response: In the original manuscript, we did not explicitly consider tumor adaptations (such as the development of drug resistance) that could allow cancer cells to survive therapy. To address this point, we have added a statement to the Discussion, highlighting that our model does not include dynamic resistance mechanisms. We acknowledge that cancer cells in patients may adapt over time. Specifically, we have added the following statement to the Discussion section: “Our model also does not account for tumor adaptive resistance mechanisms (e.g., genetic or phenotypic changes that enable cancer cells to survive therapy). As a result, it may overestimate treatment efficacy, since in clinical settings, cancer cells can adapt and develop resistance during prolonged therapy.” 4. The population of subjects selected for Clinical Trials may need to be of a certain target group, because of time constraints in relation to the disease progression versus the time needed for the contributory effects of Losartan to take effect. Response: We thank the reviewer for highlighting this important point about the timing of losartan’s effects in relation to disease progression. In response, we have added a statement to the Discussion section to address this clinical consideration. Specifically, we have added the following statement to the Discussion section: “Because losartan’s stromal normalization effects develop gradually over several weeks, patients with more aggressive or rapidly progressing disease may not fully benefit if the tumor progresses before sufficient remodeling occurs.” 5. The Mathematical Model, which reflects local disease control and progression, may not have taken into consideration the importance of metastatic disease which may ultimately determine prognosis, and metastases as we know, occur quite early before the disease can be clinically detected. Response: The original study focused only on the local tumor microenvironment and did not account for metastasis. We agree that this omission is a significant limitation. We have added text to the Discussion section explicitly acknowledging that our model is limited to the primary tumor and does not capture metastatic spread, which may critically influence outcomes. Specifically, we have added the following statement to the Discussion section: “Finally, the current model focuses only on the primary tumor and does not account for metastasis, even though metastatic spread often occurs early, sometimes even before the primary tumor becomes clinically detectable.” Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0328196.r002
Decision Letter - Hean Teik Ong, Editor Losartan as a mechanotherapeutic adjuvant: remodeling the breast tumor microenvironment to improve treatment efficacy PONE-D-25-24060R1 Dear Dr. Dwairy, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Hean Teik Ong, FRCP, FACC Academic Editor PLOS ONE Additional Editor Comments (optional): Thank you for addressing the comments of reviewers. The article can be accepted. Please fulfill any requirements of the administrative editor to get the article in the correct format necessary. Reviewers' comments: https://doi.org/10.1371/journal.pone.0328196.r003
Formally Accepted
Acceptance Letter - Hean Teik Ong, Editor PONE-D-25-24060R1 PLOS ONE Dear Dr. Dwairy, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Hean Teik Ong Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0328196.r004

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