PONE-D-19-19723

The Role of Survivin in the Progression of Pancreatic Ductal Adenocarcinoma (PDAC) and a Novel Survivin-Targeted Therapeutic for PDAC

PLOS ONE

Dear Dr Pham,

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Reviewer #1: Yes

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Reviewer #1: No

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: The authors present data validating survivin as a target in pancreatic adenocarcinoma using TCGA data and histologic evaluation of primary tissues compared to histologic normal tissue. There have been earlier publications showing survivin is upregulated in pancreatic cancer (Satoh. Cancer 2001;92:271–278) and its inhibition using knockdown sensitizes pancreatic CA to radiation (Kami. Surgery 2005;138:299–305).

The authors use unique patient derived cell line models-one is from the primary cancer and other is derived from a metastatic pancreatic cancer lesion. It would be interesting to see at what stage in transformation this protein is upregulated in pancreatic adenoCA, looking at the continuum of adenomas, in situ and invasive carcinoma-primary or metastatic lesions. Moreover with these 2 different cell lines differences seen in the efficacy of the survivin inhibition may be related to differences in the relevance of this protein in primary versus metastatic lesion.

Another novelty of this research is the use of UFSHR a novel derivative of YM155 which is a known survivin inhibitor by destabilizing the transcriptional complex at the BIRC promoter.

However the authors have not confirmed the mechanism by which this drug is inhibiting survivin –there is no examination of survivin gene expression to confirm transcriptional repression of BIRC5. Are there differences in BIRC8 which is upregulated by YM155as an off target effect? Do the 2 drugs differ in their effects on survivin splice variants that are responsible for the anti-apoptotic effects of this gene

The concept of inhibiting survivin in this cancer is not novel- a peptide survivin vaccine in combination with interferon in a phase 1 trial in pancreatic cancer was published in Cancer Science in 2018. The PDX animal data is compelling. This drug is inhibiting tumor growth and suppressing the target in vivo. Whether survivin is critical to this anticancer activity of UFSHR should be proven by overexpressing survivin to reverse the apoptotic phenotype because destabilizing a transcriptional complex could have multiple effects.

Statistics have not been shown to justify the size of the animal experiments nor is there any mention of any statistical tests used in the in vitro experiments.

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Reviewer #1: No

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The Role of Survivin in the Progression of Pancreatic Ductal Adenocarcinoma (PDAC) and a Novel Survivin-Targeted Therapeutic for PDAC

PONE-D-19-19723R1

Dear Dr. Pham,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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Andrei L. Gartel

Academic Editor

PLOS ONE

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