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Pancreatic Cancer pp 1203–1217Cite as

Differential Therapy Based on Tumor Heterogeneity in Pancreatic Cancer

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Abstract

A major impediment to the effective treatment of patients with pancreatic ductal adenocarcinoma (PDAC) is its molecular heterogeneity, which is reflected in an equally diverse pattern of clinical outcomes and in response to therapies. An efficient strategy in which PDAC samples were collected by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) or surgery and preserved as patient-derived xenografts (PDX) and as a primary culture of epithelial cells was developed. Multiomics analysis, including transcriptomic and pharmacological studies, was performed on these PDX. As expected, significant molecular and phenotypic heterogeneity was observed. However, bioinformatic analysis was able to discriminate between patients with bad or better prognosis. Primary cultures of cells allowed to analyze their relative sensitivity to standard drugs (gemcitabine, 5FU, oxaliplatin, irinotecan active metabolite SN-38, and docetaxel), as well as more original anticancer drugs such as 5-aza-2′-deoxycytidine (5-AZA-dC) or the nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866. The establishment of chemograms in vitro allowed to identify individual profiles of drug sensitivity. Remarkably, the response was extremely heterogeneous and patient dependent. It was also found that transcriptome analysis predicts the anticancer drug sensitivity of PDAC cells. Furthermore, an original strategy to identify PDAC dependent on the MYC oncogene and consequently more sensitive to bromodomain and extraterminal inhibitors (BETi) was developed. In conclusion, using this original approach, it was found that multiomics analysis of PDX could predict the clinical outcome of patients, the sensitivity to anticancer drugs, and the pharmacological response to new therapeutic strategies. This opens up a future setting in individualized medicine, aiming to stratify patients in order to select the most appropriate treatments for each group.

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Authors and Affiliations

  1. Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France

    Juan Iovanna, Benjamin Bian, Martin Bigonnet & Nelson Dusetti

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  1. Juan Iovanna
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  2. Benjamin Bian
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  3. Martin Bigonnet
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  4. Nelson Dusetti
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Correspondence to Juan Iovanna .

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Editors and Affiliations

  1. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany

    John P. Neoptolemos

  2. Division of Research Department of Surgery and Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Raul Urrutia

  3. Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA

    James L. Abbruzzese

  4. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany

    Markus W. Büchler

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Iovanna, J., Bian, B., Bigonnet, M., Dusetti, N. (2018). Differential Therapy Based on Tumor Heterogeneity in Pancreatic Cancer. In: Neoptolemos, J., Urrutia, R., Abbruzzese, J., Büchler, M. (eds) Pancreatic Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-7193-0_94

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