Recapitulating the clinical scenario of BRCA-associated pancreatic cancer in pre-clinical models

Talia Golan*, Chani Stossel, Dikla Atias, Ella Buzhor, Sharon Halperin, Keren Cohen, Maria Raitses-Gurevich, Yulia Glick, Stephen Raskin, Daniel Yehuda, Anna Feldman, Michael Schvimer, Eitan Friedman, Rotem Karni, Julie M. Wilson, Robert E. Denroche, Ilinca Lungu, John M.S. Bartlett, Faridah Mbabaali, Steven GallingerRaanan Berger

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. BRCA-associated PDAC comprises a clinically relevant subtype. A portion of these patients are highly susceptible to DNA damaging therapeutics, however, responses are heterogeneous and clinical resistance evolves. We have developed unique patient-derived xenograft (PDX) models from metastatic lesions of germline BRCA-mutated patients obtained at distinct time points; before treatment and at progression. Thus, closely mimicking clinical scenarios, to further investigate treatment naïve and resistant patients. DNA was isolated from six BRCA-mutated PDXs and classified by whole-genome sequencing to stable-genome or homologous recombination deficient (HRD)-genome. The sensitivity to DNA-damaging agents was evaluated in vivo in three BRCA-associated PDAC PDXs models: (1) HRD-genome naïve to treatments; (2) stable-genome naïve to treatment; (3) HRD-genome resistant to treatment. Correlation between disease course at tissue acquisition and response to PARP inhibitor (PARPi)/platinum was demonstrated in PDXs in vivo. Only the HRD-genome PDX, naïve to treatment, was sensitive to PARP inhibitor/cisplatin treatments. Our results demonstrate heterogeneous responses to DNA damaging agents/PARPi in BRCA-associated PDX thus reflecting the wide clinical spectrum. An HRD-genome PDX generated from a naïve to treatment biopsy was sensitive to platinum/PARPi whereas no benefit was observed in treating a HRD-genome PDXs generated from a patient that had acquired resistance nor stable-genome PDXs.

Original languageEnglish
Pages (from-to)179-183
Number of pages5
JournalInternational Journal of Cancer
Volume143
Issue number1
DOIs
StatePublished - 1 Jul 2018

Funding

FundersFunder number
Hebrew University of Jerusalem
Ontario Institute for Cancer Research

    Keywords

    • BRCA
    • PARP inhibitor
    • pancreatic ductal adenocarcinoma
    • patient-derived xenograft (PDX)
    • treatment naïve
    • treatment resistant

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