Research Papers:
Dynamic changes during the treatment of pancreatic cancer
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Abstract
Robert A. Wolff1,*, Andrea Wang-Gillam2,*, Hector Alvarez8,*, Hervé Tiriac3,*, Dannielle Engle3,*, Shurong Hou4,*, Abigail F. Groff6,*, Anthony San Lucas9, Vincent Bernard10, Kelvin Allenson11, Jonathan Castillo8, Dong Kim8, Feven Mulu8, Jonathan Huang8, Bret Stephens8, Ignacio I. Wistuba9, Matthew Katz11, Gauri Varadhachary1, YoungKyu Park3, James Hicks3, Arul Chinnaiyan5, Louis Scampavia4, Timothy Spicer4, Chiara Gerhardinger6, Anirban Maitra8, David Tuveson3, John Rinn6,13, Gregory Lizee12, Cassian Yee12 and Arnold J. Levine7
1 Department of Gastrointestinal (GI) Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
2 Division of Oncology, Washington University, St. Louis, MO, USA
3 Cold Spring Harbor Laboratory, New York, NY, USA
4 Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, USA
5 Center for Translational Pathology, University of Michigan Medical Center, Ann Arbor, MI, USA
6 Department of Molecular and Cellular Biology, Harvard University, The Broad Institute, Cambridge, MA, USA
7 Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ, USA
8 Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA
9 Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX, USA
10 Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA
11 Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA
12 Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
13 Current address: University of Colorado Boulder, BioFrontiers Institute, Boulder, CO, USA
* These authors have contributed equally to this paper
Correspondence to:
Arnold J. Levine, email:
Keywords: pancreatic cancer; genomic instability; organoids; epithelial-mesenchymal transition
Received: December 20, 2017 Accepted: February 01, 2018 Epub: February 13, 2018 Published: March 13, 2018
Abstract
This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments. When an unusual drug response was detected, an extensive RNA sequencing analysis was employed to establish novel mechanisms of action of this drug. Organoid cell cultures were employed to identify possible antigens associated with the tumor and the patient’s T-cells were expanded against one of these antigens. Similar and identical T-cell receptor sequences were observed in the initial biopsy and the expanded T-cell population. Immunotherapy treatment failed to shrink the tumor, which had undergone an epithelial to mesenchymal transition prior to therapy. A warm autopsy of the metastatic lung tumor permitted an extensive analysis of tumor heterogeneity over five years of treatment and surgery. This detailed analysis of the clinical descriptions, imaging, pathology, molecular and cellular evolution of the tumors, treatments, and responses to chemotherapy, targeted therapies, and immunotherapies, as well as attempts at the development of personalized medical treatments for a single patient should provide a valuable guide to future directions in cancer treatment.
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