Organoid profiling identifies common responders to chemotherapy in pancreatic cancer

Tiriac, H., Belleau, P., Engle, D. D., Plenker, D., Deschenes, A., Somerville, T., Froeling, F. E. M., Burkhart, R. A., Denroche, R. E., Jang, G. H., Miyabayashi, K., Young, C. M., Patel, H., Ma, M., LaComb, J. F., Palmaira, R. L. D., Javed, A. A., Huynh, J. A., Johnson, M., Arora, K., Robine, N., Shah, M., Sanghvi, R., Goetz, A. B., Lowder, C. Y., Martello, L., Driehuis, E., Lecomte, N., Askan, G., Iacobuzio-Donahue, C. A., Clevers, H., Wood, L. D., Hruban, R. H., Thompson, E. D., Aguirre, A. J., Wolpin, B. M., Sasson, A., Kim, J., Wu, M., Bucobo, J. C., Allen, P. J., Sejpal, D. V., Nealon, W., Sullivan, J. D., Winter, J. M., Gimotty, P. A., Grem, J. L., DiMaio, D. J., Buscaglia, J. M., Grandgenett, P. M., Brody, J. R., Hollingsworth, M. A., O'Kane, G. M., Notta, F., Kim, E. J., Crawford, J. M., Devoe, C. E., Ocean, A., Wolfgang, C. L., Yu, K. H., Li, E., Vakoc, C. R., Hubert, B., Fischer, S. E., Wilson, J. M., Moffitt, R. A., Knox, J. J., Krasnitz, A., Gallinger, S., Tuveson, D. A. (2018) Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. Cancer Discovery. ISSN 21598274

URL: https://www.ncbi.nlm.nih.gov/pubmed/29853643
DOI: 10.1158/2159-8290.cd-18-0349

Abstract

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we find that PDO therapeutic profiles paralleled patient outcomes and that PDOs enable longitudinal assessment of chemo-sensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemo-sensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemo-refractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.

Item Type: Paper
Subjects: Investigative techniques and equipment > cell culture > cancer organoids
diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Krasnitz lab
CSHL labs > Tuveson lab
CSHL labs > Vakoc lab
Depositing User: Matt Covey
Date Deposited: 15 Jun 2018 14:03
Last Modified: 21 Sep 2018 18:52
PMCID: PMC6125219
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36724

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