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Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived xenograft (PDX) model

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Summary

Despite the significant progress in the field of cancer therapeutics, the incidence of pancreatic cancer (PC) has continuously increased. One possible mechanism for this increasing burden is impaired drug delivery and drug resistance resulting from a unique tumor microenvironment and genetic mutations. Apratoxins are potent anticancer agents and cotranslational translocation inhibitors with potential therapeutic applications to treat cancers with active secretory pathways. Here, we developed apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent which potently inhibited the growth of both established and patient-derived primary pancreatic cancer cells. We validated its mechanism of action on pancreatic cancer cells by demonstrating the downregulation of multiple receptor tyrosine kinases and inhibition of growth factor and cytokine secretion. Apra S10 also inhibited a number of cytokines secreted by stromal cells, suggesting that Apra S10 not only inhibited pancreatic cancer cell secretion, but also reduced the level of factors secreted by other cell types active within the tumor microenvironment. As Apra S10 tissue distribution indicated its high enrichment in pancreas tissue, an orthotopic pancreatic patient-derived xenograft mouse model that closely mimics the human pancreatic tumor microenvironment was for the first time used in apratoxin studies. Apra S10 showed promising antitumor effect in this pancreatic cancer model and this effect was mediated through anti-proliferation properties.

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Author information

W.C., experimental design, tissue distribution and PK study in mice, LC-MS/MS analysis, efficacy study in mice and manuscript writing; R.R. experimental design for in vitro assays (viability, RTKs, cytokine profiling) and edited manuscript; M.H.G., in vivo study and edited manuscript; J.G.T., supervised in vivo studies. Q.Y.C., scale-up total synthesis. Y.Y., PK parameter analysis and simulation study; H.D., supervised PK parameter analysis and simulation study. H.L., designed and supervised the study and edited the manuscript.

Funding

Research was supported in part by the National Institutes of Health, NCI grant R01CA172310, Ocala Royal Dames for Cancer Research, Inc., NCI Research Specialist Award R50CA211487 (R.R) and the Debbie and Sylvia DeSantis Chair professorship (H.L.).

Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida, 32610, USA

    Weijing Cai, Ranjala Ratnayake, Qi-Yin Chen & Hendrik Luesch

  2. Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, Florida, 32610, USA

    Weijing Cai, Ranjala Ratnayake, Qi-Yin Chen & Hendrik Luesch

  3. Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, 32610, USA

    Michael H. Gerber & Jose G. Trevino

  4. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, 32610, USA

    Yichao Yu & Hartmut Derendorf

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  1. Weijing Cai
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  2. Ranjala Ratnayake
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  8. Hendrik Luesch
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Correspondence to Hendrik Luesch.

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Conflict of interest

The authors declare the following competing financial interest(s): H. Luesch is co-founder of Oceanyx Pharmaceuticals, Inc., which has licensed patents and patent applications related to the subject matter.

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All applicable international, national, and /or institutional guidelines for the care and use of animals were followed.

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Cai, W., Ratnayake, R., Gerber, M.H. et al. Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived xenograft (PDX) model. Invest New Drugs 37, 364–374 (2019). https://doi.org/10.1007/s10637-018-0647-0

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