Dynamic changes during the treatment of pancreatic cancer

Robert A. Wolff, Andrea Wang-Gillam, Hector Alvarez, Hervé Tiriac, Dannielle Engle, Shurong Hou, Abigail F. Groff, Anthony San Lucas, Vincent Bernard, Kelvin Allenson, Jonathan Castillo, Dong Kim, Feven Mulu, Jonathan Huang, Bret Stephens, Ignacio I. Wistuba, Matthew Katz, Gauri Varadhachary, Young Kyu Park, James HicksArul Chinnaiyan, Louis Scampavia, Timothy Spicer, Chiara Gerhardinger, Anirban Maitra, David Tuveson, John Rinn, Gregory Lizee, Cassian Yee, Arnold J. Levine

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)14764-14790
Number of pages27
JournalOncotarget
Volume9
Issue number19
DOIs
StatePublished - 2018

Keywords

  • Epithelial-mesenchymal transition
  • Genomic instability
  • Organoids
  • Pancreatic cancer

ASJC Scopus subject areas

  • Oncology

Fingerprint

Dive into the research topics of 'Dynamic changes during the treatment of pancreatic cancer'. Together they form a unique fingerprint.

Cite this