Targeting Mitochondria for Treatment of Chemoresistant Ovarian Cancer

Round 1

Reviewer 1 Report

This is a nice review focusing on the metabolic role of the tumor microenvironment in the aggressiveness of ovarian cancer. 

1- Introduction section (first paragraph): Please don't focus on the USA only when providing epidemiological data. You can update based on the recently launched GLOBOCAN 2018. Check here: https://onlinelibrary.wiley.com/doi/full/10.3322/caac.21492

2-Introduction section: This part is important to shed light on the problem of resistance in ovarian cancer as well as the role of tumor microenvironment in this perspective which is the key objective of your review. Please update and focus on this matter. 

These recent  reviews may be useful (suggestions): 

https://www.tandfonline.com/doi/abs/10.1080/10408363.2017.1313190

https://link.springer.com/article/10.1007%2Fs10555-013-9456-2

https://www.sciencedirect.com/science/article/pii/S0959804915011600

Moreover, you will discuss the OXPHOS deregulation in cancer and it is suitable to add a historical note about the Warburg effect. 

3- Section 3: please discuss the perspective of using intraperitoneal chemotherapy (HIPEC) to eliminate poorly vascularized tumors and this based on clinical trials published until this time. 

4- Section 6: This part needs supporting references (you cited only one!).

5- Section 7: I strongly recommend adding a table summarizing these OXPHOS inhibitors along with the tumor models used and the limitations of each study. This will be interesting for clinicians working in the area of cancer drug discovery. 

Section 7 (figure 3): is this supported by published evidence or it is just your hypothesis?. Provide references if any ! if no reports until this time then add the term "hypothesis" in this figure.

8- To be complete your review needs to have a chapter about the characterization of these spheroids based on ascites to predict chemoresistance and to test effective drugs (such as the published chemoresponse assay).

Minor comments:

Figures must be provided as TIFF and with high quality.

Author Response

Point by Point Response to Reviewer's comments

This is a nice review focusing on the metabolic role of the tumor microenvironment in the aggressiveness of ovarian cancer. 

1- Introduction section (first paragraph): Please don't focus on the USA only when providing epidemiological data. You can update based on the recently launched GLOBOCAN 2018. Check here: https://onlinelibrary.wiley.com/doi/full/10.3322/caac.21492

We have now provided epidemiological data relative to the most recently launched GLOBOCAN 2018 and properly referenced that.

2-Introduction section: This part is important to shed light on the problem of resistance in ovarian cancer as well as the role of tumor microenvironment in this perspective which is the key objective of your review. Please update and focus on this matter. 

These recent  reviews may be useful (suggestions): 

https://www.tandfonline.com/doi/abs/10.1080/10408363.2017.1313190

https://link.springer.com/article/10.1007%2Fs10555-013-9456-2

https://www.sciencedirect.com/science/article/pii/S0959804915011600

Moreover, you will discuss the OXPHOS deregulation in cancer and it is suitable to add a historical note about the Warburg effect. 

We have now more clearly highlighted the problems associate with chemoresistance in ovarian cancer relative to both, cancer cells’ intrinsic resistance and effects of the ovarian cancer tumor microenvironment. We have also added an historical note about the Warburg effect and provided with appropriate references.

3- Section 3: please discuss the perspective of using intraperitoneal chemotherapy (HIPEC) to eliminate poorly vascularized tumors and this based on clinical trials published until this time. 

We have now discussed and referenced the perspective of using intraperitoneal chemotherapy (HIPEC) in ovarian cancer including clinical trials.

4- Section 6: This part needs supporting references (you cited only one!).

We have added additional references.

5- Section 7: I strongly recommend adding a table summarizing these OXPHOS inhibitors along with the tumor models used and the limitations of each study. This will be interesting for clinicians working in the area of cancer drug discovery. 

We have now added a summarizing table.

Section 7 (figure 3): is this supported by published evidence or it is just your hypothesis?. Provide references if any ! if no reports until this time then add the term "hypothesis" in this figure.

We have added the term “hypothesis” to this Figure as it represents the potential of targeting mitochondria for ovarian cancer treatment.

8- To be complete your review needs to have a chapter about the characterization of these spheroids based on ascites to predict chemoresistance and to test effective drugs (such as the published chemoresponse assay).

We have now dedicated a separate chapter to spheroids and their use for testing of chemotherapy agents.

Minor comments:

Figures must be provided as TIFF and with high quality.

High quality figures are now provided.

Reviewer 2 Report

The review targeting mitochondrial addiction of chemoresistant tumor cells is timely and a very relevant topic clinically offering insights into potential novel therapies for poor prognostic patients. However, it focuses too narrowly on cancer stem-like cells, OXPHOS rates, and OXPHOS inhibitors. It should be mentioned that unlike somatic stem cells, ovarian cancer stem cells are not quiescent as described throughout the text, many studies have described them as having a high rate of proliferation similar to other tumor cells but being characterized by selective chemoresistance pathways and markers. This has to be fixed or further clarified. Furthermore, if OXPHOS and OXPHOS inhibition is in fact the subject of the proposed review, then the title should be changed and the scope of the review should be more clearly identified. If the title stays the same however, then the paper needs to be a more comprehensive review of the current literature and include a balanced discussion on various mitochondrial changes in intrinsic platinum resistant versus acquired platinum resistant EOC. In addition, do various EOC subtypes show mitochondrial differences perhaps leading to personalized treatments for patients? Finally, the review has to describe clinical studies already done or detail the ongoing and planned clinical trials targeting mitochondria. If not in EOC, have these types of therapies shown clinical efficacy for other cancers?

Author Response

Point by Point Response to Reviewer's comments

The review targeting mitochondrial addiction of chemoresistant tumor cells is timely and a very relevant topic clinically offering insights into potential novel therapies for poor prognostic patients. However, it focuses too narrowly on cancer stem-like cells, OXPHOS rates, and OXPHOS inhibitors. It should be mentioned that unlike somatic stem cells, ovarian cancer stem cells are not quiescent as described throughout the text, many studies have described them as having a high rate of proliferation similar to other tumor cells but being characterized by selective chemoresistance pathways and markers. This has to be fixed or further clarified.

We have now clarified throughout the text and referenced that unlike somatic stem cells, ovarian cancer stem cells are not quiescent and are characterized by specific chemoresistance pathways and markers.

Furthermore, if OXPHOS and OXPHOS inhibition is in fact the subject of the proposed review, then the title should be changed and the scope of the review should be more clearly identified. If the title stays the same however, then the paper needs to be a more comprehensive review of the current literature and include a balanced discussion on various mitochondrial changes in intrinsic platinum resistant versus acquired platinum resistant EOC.

We have now rephrased the title in “Targeting mitochondria for treatment of chemoresistant ovarian cancer” to more properly represent the intent and the content of this Review.

In addition, do various EOC subtypes show mitochondrial differences perhaps leading to personalized treatments for patients?

We have now clarified that targeting of mitochondrial pathways could lead to personalized treatments for patients including for patients affected by ovarian clear cell carcinoma, of ovarian endometrioid carcinomas and Small cell carcinoma of the ovary, hypercalcemic type.

Finally, the review has to describe clinical studies already done or detail the ongoing and planned clinical trials targeting mitochondria. If not in EOC, have these types of therapies shown clinical efficacy for other cancers?

We now mention phase I studies in the text where relevant.

Round 2

Reviewer 2 Report

No additional comments