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Molecular Cancer Therapeutics
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Cancer Biology and Translational Studies

A Patient-derived Xenograft Model of Pancreatic Neuroendocrine Tumors Identifies Sapanisertib as a Possible New Treatment for Everolimus-resistant Tumors

Chester E. Chamberlain, Michael S. German, Katherine Yang, Jason Wang, Henry VanBrocklin, Melanie Regan, Kevan M. Shokat, Gregory S. Ducker, Grace E. Kim, Byron Hann, David B. Donner, Robert S. Warren, Alan P. Venook, Emily K. Bergsland, Danny Lee, Yucheng Wang and Eric K. Nakakura
Chester E. Chamberlain
1Center for Regeneration Medicine, University of California, San Francisco, California.
2Diabetes Center, University of California, San Francisco, California.
3Department of Medicine, University of California, San Francisco, California.
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  • For correspondence: eric.nakakura@ucsf.edu chester.chamberlain@ucsf.edu
Michael S. German
1Center for Regeneration Medicine, University of California, San Francisco, California.
2Diabetes Center, University of California, San Francisco, California.
3Department of Medicine, University of California, San Francisco, California.
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Katherine Yang
1Center for Regeneration Medicine, University of California, San Francisco, California.
2Diabetes Center, University of California, San Francisco, California.
3Department of Medicine, University of California, San Francisco, California.
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Jason Wang
1Center for Regeneration Medicine, University of California, San Francisco, California.
2Diabetes Center, University of California, San Francisco, California.
3Department of Medicine, University of California, San Francisco, California.
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Henry VanBrocklin
4Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.
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Melanie Regan
4Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.
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Kevan M. Shokat
5Department of Cellular Molecular Pharmacology, University of California, San Francisco, California.
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  • ORCID record for Kevan M. Shokat
Gregory S. Ducker
5Department of Cellular Molecular Pharmacology, University of California, San Francisco, California.
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Grace E. Kim
6Department of Pathology, University of California, San Francisco, California.
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Byron Hann
7Helen Diller Family HDF Comprehensive Cancer Center, University of California, San Francisco, California.
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David B. Donner
7Helen Diller Family HDF Comprehensive Cancer Center, University of California, San Francisco, California.
8Department of Surgery, University of California, San Francisco, California.
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Robert S. Warren
7Helen Diller Family HDF Comprehensive Cancer Center, University of California, San Francisco, California.
8Department of Surgery, University of California, San Francisco, California.
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Alan P. Venook
3Department of Medicine, University of California, San Francisco, California.
7Helen Diller Family HDF Comprehensive Cancer Center, University of California, San Francisco, California.
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Emily K. Bergsland
3Department of Medicine, University of California, San Francisco, California.
7Helen Diller Family HDF Comprehensive Cancer Center, University of California, San Francisco, California.
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Danny Lee
7Helen Diller Family HDF Comprehensive Cancer Center, University of California, San Francisco, California.
8Department of Surgery, University of California, San Francisco, California.
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Yucheng Wang
7Helen Diller Family HDF Comprehensive Cancer Center, University of California, San Francisco, California.
8Department of Surgery, University of California, San Francisco, California.
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Eric K. Nakakura
7Helen Diller Family HDF Comprehensive Cancer Center, University of California, San Francisco, California.
8Department of Surgery, University of California, San Francisco, California.
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  • For correspondence: eric.nakakura@ucsf.edu chester.chamberlain@ucsf.edu
DOI: 10.1158/1535-7163.MCT-17-1204 Published December 2018
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    Figure 1.

    Generation and characterization of the patient-derived xenograft model of PNET (PDX-PNET). A, nondiagnostic portion of metastasized PNETs were removed during the hepatic resection and expanded in a cohort of female athymic nude mice. Comparison of neuroendocrine biomarkers in original patient tumor and passage-6 PDX-PNET using RNA sequencing (B) and immunofluorescence (C). In B, a “+” means a gene is expressed. In C, DNA is in blue while CHGA, INS, and 5-HT are in green.

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    Figure 2.

    68Ga-DOTATATE PET-CT imaging of the PDX-PNET model. A, 3D rendered PET/CT image showing flank tumor tracer uptake. B, Axial view at the level of the tumor. C, Relationship between tumor size and normalized 68Ga-DOTATATE PET/CT counts.

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    Figure 3.

    PDX-PNETs harbor mutations in genes commonly associated with PNETs and mTOR pathway activation. A, Whole-exome sequencing of PDX-PNET reveals mutations in genes commonly found in PNET. B, Two frameshift mutations were identified in PTEN. Green, phosphatase domain; blue, C2 domain; red, PDZ-binding domain.

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    Figure 4.

    Response of PDX-PNETs to the mTOR inhibitor drugs everolimus and sapanisertib. A, Growth chart of PDX-PNETs treated with vehicle control, everolimus, or sapanisertib for 28 days (vehicle control n = 5, everolimus n = 6, sapanisertib n = 6). The P values were calculated by two-tailed Student t test (*, P < 0.05, **, P < 0.01). Error bars indicate the SD from the mean. B, Western blot analysis of mTOR pathway targets in PDX-PNETs harvested after 28 days of treatment with either vehicle control, everolimus, or sapanisertib. Each lane represents a single xenograft harvested from a unique mouse.

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    Figure 5.

    Response of everolimus-resistant PDX-PNETs to sapanisertib. A, The best response of tumors treated with everolimus, as compared with pretreatment baseline (n = 34). Numbers along the x-axis indicate arbitrarily assigned animal numbers in order of increasing percentage response to everolimus. The bars indicate the percent change in tumor burden from baseline. B, The best response to sapanisertib in 10 animals with everolimus-resistant PDX-PNETs. Selected tumor characteristics are listed in the table below the graph. Animals are listed in order of increasing percentage response to sapanisertib, with listed numbers corresponding to those in Fig. 5A. Sapanisertib treatment ended when tumors either regressed (n = 1), developed sapanisertib resistance, and exceeded five times the original volume (n = 6), or animals died (n = 3). Underlined numbers indicate animals that died during treatment.

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    • Supplementary Figure 1 - Pharmacodynamic studies of everolimus and sapanisertib treated PDX-PNETs using Western blot analysis of mTOR pathway targets.
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Molecular Cancer Therapeutics: 17 (12)
December 2018
Volume 17, Issue 12
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A Patient-derived Xenograft Model of Pancreatic Neuroendocrine Tumors Identifies Sapanisertib as a Possible New Treatment for Everolimus-resistant Tumors
Chester E. Chamberlain, Michael S. German, Katherine Yang, Jason Wang, Henry VanBrocklin, Melanie Regan, Kevan M. Shokat, Gregory S. Ducker, Grace E. Kim, Byron Hann, David B. Donner, Robert S. Warren, Alan P. Venook, Emily K. Bergsland, Danny Lee, Yucheng Wang and Eric K. Nakakura
Mol Cancer Ther December 1 2018 (17) (12) 2702-2709; DOI: 10.1158/1535-7163.MCT-17-1204

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A Patient-derived Xenograft Model of Pancreatic Neuroendocrine Tumors Identifies Sapanisertib as a Possible New Treatment for Everolimus-resistant Tumors
Chester E. Chamberlain, Michael S. German, Katherine Yang, Jason Wang, Henry VanBrocklin, Melanie Regan, Kevan M. Shokat, Gregory S. Ducker, Grace E. Kim, Byron Hann, David B. Donner, Robert S. Warren, Alan P. Venook, Emily K. Bergsland, Danny Lee, Yucheng Wang and Eric K. Nakakura
Mol Cancer Ther December 1 2018 (17) (12) 2702-2709; DOI: 10.1158/1535-7163.MCT-17-1204
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Molecular Cancer Therapeutics
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