Dynamic changes during the treatment of pancreatic cancer

// Robert A. Wolff 1,* , Andrea Wang-Gillam 2,* , Hector Alvarez 8,* , Herve Tiriac 3,* , Dannielle Engle 3,* , Shurong Hou 4,* , Abigail F. Groff 6,* , Anthony San Lucas 9 , Vincent Bernard 10 , Kelvin Allenson 11 , Jonathan Castillo 8 , Dong Kim 8 , Feven Mulu 8 , Jonathan Huang 8 , Bret Stephens 8 , Ignacio I. Wistuba 9 , Matthew Katz 11 , Gauri Varadhachary 1 , YoungKyu Park 3 , James Hicks 3 , Arul Chinnaiyan 5 , Louis Scampavia 4 , Timothy Spicer 4 , Chiara Gerhardinger 6 , Anirban Maitra 8 , David Tuveson 3 , John Rinn 6,13 , Gregory Lizee 12 , Cassian Yee 12 and Arnold J. Levine 7 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.