Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer
, Arielle De La Cruz 1,2, Kelsey E. Huntington 1,2, Andrew George 1,2, Nicholas R. Liguori 1, Leiqing Zhang 1,2,3, Lanlan Zhou 1,2,3,4, Abbas E. Abbas 2,3,4,5, Christopher G. Azzoli 2,4,6 and Wafik S. El-Deiry 1,2,3,4,6,*
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
A very well written manuscript covering a novel aspects of potential PDAC treatment.
- Will be better if authors did deeper description of the implemented methodology. In particular, what software, laboratory methods were used for figure 6.
- Please consider comparing your study results to other similar published studies where the same agent was used for therapeutic purpose.
Author Response
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Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for Authors
You test the effect of lurbinectedin on pancreatic cancer cells in association with other classic drugs used for pancreatic cancer treatment. This has been done before and research in this sense has gone a step forward because it has been tested with patients in clinical trials with gemcitabine. See NCT01970553 and the publication by Cespedes M.V. et al. (Lurbinectedin induces depletion of tumor-associated macrophages...). Therefore, research is one step ahead of what you are publishing here. You need to establish in your paper why you are doing this research. Particularly, when you are associating Lurbinectedin with irinotecan and 5FU which will show OVERLAPING TOXICITY. This is an important issue that you omit commenting.
Lurbinectedin has been tested with gemcitabine, pegylated doxorubicin, and topotecan (Gaillard S. et al.) and also with paclitaxel (Calvo E. et al.).
Wouldn`t it be more logical to test this drug with a combination of nab-paclitaxel and gemcitabine which would have only little overlaping toxicity.
Please comment on NCT00877474.
Author Response
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Reviewer 3 Report
Comments and Suggestions for Authors
In the manuscript entitled “Preclinical Synergistic Combination Therapy of Lurbinectedin with Irinotecan and 5-Fluorouracil in Pancreatic Cancer”, Tummala and colleagues investigated the combination of lurbinectedin, irinotecan, and 5-FU as synergic treatment for pancreatic cancer. This work provided a potential new regimen of combination therapy and will unquestionably hold significance in the field. However, I have listed below a series of suggestions which would further improve the quality of the manuscript. The questions and concerns must be addressed before the publication of this paper.
1. Why did the authors describe the results in Discussion part? The Discussion part should be the part for potential mechanisms and alternative explanations. Please rewrite and revise the results and discussion.
2. The authors should still rerun the WB for Figure 4 since they are important data for revealing mechanisms of the synergy. Why there are no data as in 4B and 4D for the cell line HPAF-II, which is used in the following Figures 5 and 6? For the panel order, Figure 4B and 4D should be put before 4A and 4C, especially those 4A and 4C are inconclusive. The author should also mark the ATF4 or unspecific bands (upper or lower?).
3. There are no detail interpretation of some figures. For example, how to explain those cytokines in Figure 5? How to understand Figure 6B and C in details? Please try to explain all the panels shown in each figure.
4. Minor questions:
There are no scale bars in Figure 1.
Languages issues: line 202, “10 μM of with” should be “10 μM of irinotecan with”, etc.
Please double check the details in the manuscript.
Author Response
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Author Response File: Author Response.pdf
Round 2
Reviewer 3 Report
Comments and Suggestions for Authors
The authors have largely responded and addressed the major concerns. The manuscript quality was significantly improved.
However, I have listed below some suggestions for further revising the manuscript. When solved, I have no hesitation to suggest the publication of this paper.
Please still double check the new revisions including but not limit to:
In Figure 4A, should the measurement of p-ATR be the area above the dark band? Please confirm.
In Figure 4C, the Desitometry does not match the blot (4C cannot be the same as 4D), please correct.
In Figure 6A, “BxPC-3x” should be “BxPC-3”
Please be careful about all the details, especially the new revisions.
Author Response
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Author Response File: Author Response.pdf
