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 Gallinger; Raanan Berger

doi:10.1002/ijc.31292

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

Department of Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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 language	American English
Pages (from-to)	179-183
Number of pages	5
Journal	International Journal of Cancer
Volume	143
Issue number	1
DOIs	https://doi.org/10.1002/ijc.31292
State	Published - 1 Jul 2018

Bibliographical note

Funding Information:
Key words: pancreatic ductal adenocarcinoma, BRCA, patient-derived xenograft (PDX), PARP inhibitor, treatment na€ıve, treatment resistant Abbreviations: H&E: Hematoxylin and Eosin; HRD: homologous recombination deficient; I.P.: intra-peritoneal; LOH: loss of heterozygosity; NA: not applicable; OS: overall survival; PD: progressive disease; PDAC: pancreatic ductal adenocarcinoma; PDX: patient-derived xenograft; PR: partial response; RECIST: response evaluation criteria in solid tumors; RTV: relative tumor volume; SD: stable disease; SNV: single nucleotide variants; SPF: specific pathogen-free; SV: structural variants; WGS: whole genome sequencing Additional Supporting Information may be found in the online version of this article. *T.G. and C.S. contributed equally to this work Grant sponsor: The Ontario Institute for Cancer Research; Grant sponsor: The Canadian Friends of the Hebrew University (Alex U. Soyka) DOI: 10.1002/ijc.31292 This article was published online on 23 February 2018. An error was subsequently identified. This notice is included in the online and print versions to indicate that both have been corrected 02 March 2018. History: Received 11 Sep 2017; Accepted 23 Jan 2018; Online 3 Feb 2018 Correspondence to: Talia Golan, Medical Director Phase I Program, Oncology Institute, Sheba Medical Center, Tel Hashomer 52621, Israel, Tel.: 972-3-5307099, Fax: 972-3-5352214, E-mail: talia.golan@sheba.health.gov.il

Publisher Copyright:
© 2018 UICC

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/ijc.31292

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Golan, T., Stossel, C., Atias, D., Buzhor, E., Halperin, S., Cohen, K., Raitses-Gurevich, M., Glick, Y., Raskin, S., Yehuda, D., Feldman, A., Schvimer, M., Friedman, E., Karni, R., Wilson, J. M., Denroche, R. E., Lungu, I., Bartlett, J. M. S., Mbabaali, F., ... Berger, R. (2018). Recapitulating the clinical scenario of BRCA-associated pancreatic cancer in pre-clinical models. International Journal of Cancer, 143(1), 179-183. https://doi.org/10.1002/ijc.31292

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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 na{\"i}ve 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 na{\"i}ve to treatments; (2) stable-genome na{\"i}ve 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, na{\"i}ve 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 na{\"i}ve 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.",

keywords = "BRCA, PARP inhibitor, pancreatic ductal adenocarcinoma, patient-derived xenograft (PDX), treatment na{\"i}ve, treatment resistant",

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

note = "Funding Information: Key words: pancreatic ductal adenocarcinoma, BRCA, patient-derived xenograft (PDX), PARP inhibitor, treatment na€ıve, treatment resistant Abbreviations: H&E: Hematoxylin and Eosin; HRD: homologous recombination deficient; I.P.: intra-peritoneal; LOH: loss of heterozygosity; NA: not applicable; OS: overall survival; PD: progressive disease; PDAC: pancreatic ductal adenocarcinoma; PDX: patient-derived xenograft; PR: partial response; RECIST: response evaluation criteria in solid tumors; RTV: relative tumor volume; SD: stable disease; SNV: single nucleotide variants; SPF: specific pathogen-free; SV: structural variants; WGS: whole genome sequencing Additional Supporting Information may be found in the online version of this article. *T.G. and C.S. contributed equally to this work Grant sponsor: The Ontario Institute for Cancer Research; Grant sponsor: The Canadian Friends of the Hebrew University (Alex U. Soyka) DOI: 10.1002/ijc.31292 This article was published online on 23 February 2018. An error was subsequently identified. This notice is included in the online and print versions to indicate that both have been corrected 02 March 2018. History: Received 11 Sep 2017; Accepted 23 Jan 2018; Online 3 Feb 2018 Correspondence to: Talia Golan, Medical Director Phase I Program, Oncology Institute, Sheba Medical Center, Tel Hashomer 52621, Israel, Tel.: 972-3-5307099, Fax: 972-3-5352214, E-mail: talia.golan@sheba.health.gov.il Publisher Copyright: {\textcopyright} 2018 UICC",

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Golan, T, Stossel, C, Atias, D, Buzhor, E, Halperin, S, Cohen, K, Raitses-Gurevich, M, Glick, Y, Raskin, S, Yehuda, D, Feldman, A, Schvimer, M, Friedman, E, Karni, R, Wilson, JM, Denroche, RE, Lungu, I, Bartlett, JMS, Mbabaali, F, Gallinger, S & Berger, R 2018, 'Recapitulating the clinical scenario of BRCA-associated pancreatic cancer in pre-clinical models', International Journal of Cancer, vol. 143, no. 1, pp. 179-183. https://doi.org/10.1002/ijc.31292

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T1 - Recapitulating the clinical scenario of BRCA-associated pancreatic cancer in pre-clinical models

AU - Golan, Talia

AU - Stossel, Chani

AU - Atias, Dikla

AU - Buzhor, Ella

AU - Halperin, Sharon

AU - Cohen, Keren

AU - Raitses-Gurevich, Maria

AU - Glick, Yulia

AU - Raskin, Stephen

AU - Yehuda, Daniel

AU - Feldman, Anna

AU - Schvimer, Michael

AU - Friedman, Eitan

AU - Karni, Rotem

AU - Wilson, Julie M.

AU - Denroche, Robert E.

AU - Lungu, Ilinca

AU - Bartlett, John M.S.

AU - Mbabaali, Faridah

AU - Gallinger, Steven

AU - Berger, Raanan

N1 - Funding Information: Key words: pancreatic ductal adenocarcinoma, BRCA, patient-derived xenograft (PDX), PARP inhibitor, treatment na€ıve, treatment resistant Abbreviations: H&E: Hematoxylin and Eosin; HRD: homologous recombination deficient; I.P.: intra-peritoneal; LOH: loss of heterozygosity; NA: not applicable; OS: overall survival; PD: progressive disease; PDAC: pancreatic ductal adenocarcinoma; PDX: patient-derived xenograft; PR: partial response; RECIST: response evaluation criteria in solid tumors; RTV: relative tumor volume; SD: stable disease; SNV: single nucleotide variants; SPF: specific pathogen-free; SV: structural variants; WGS: whole genome sequencing Additional Supporting Information may be found in the online version of this article. *T.G. and C.S. contributed equally to this work Grant sponsor: The Ontario Institute for Cancer Research; Grant sponsor: The Canadian Friends of the Hebrew University (Alex U. Soyka) DOI: 10.1002/ijc.31292 This article was published online on 23 February 2018. An error was subsequently identified. This notice is included in the online and print versions to indicate that both have been corrected 02 March 2018. History: Received 11 Sep 2017; Accepted 23 Jan 2018; Online 3 Feb 2018 Correspondence to: Talia Golan, Medical Director Phase I Program, Oncology Institute, Sheba Medical Center, Tel Hashomer 52621, Israel, Tel.: 972-3-5307099, Fax: 972-3-5352214, E-mail: talia.golan@sheba.health.gov.il Publisher Copyright: © 2018 UICC

PY - 2018/7/1

Y1 - 2018/7/1

N2 - 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.

AB - 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.

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KW - PARP inhibitor

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KW - patient-derived xenograft (PDX)

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KW - treatment resistant

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JO - International Journal of Cancer

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ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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