Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/124425
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
Type: | Journal article |
Title: | Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer |
Author: | Chou, A. Froio, D. Nagrial, A.M. Parkin, A. Murphy, K.J. Chin, V.T. Wohl, D. Steinmann, A. Stark, R. Drury, A. Walters, S.N. Vennin, C. Burgess, A. Pinese, M. Chantrill, L.A. Cowley, M.J. Molloy, T.J. Waddell, N. Johns, A. Grimmond, S.M. et al. |
Citation: | Gut, 2018; 67(12):2142-2155 |
Publisher: | BMJ Journals |
Issue Date: | 2018 |
ISSN: | 0017-5749 1468-3288 |
Statement of Responsibility: | Angela Chou, Danielle Froio, Adnan M Nagrial, Ashleigh Parkin, Kendelle J Murphy ... Shane T Grey ... et al. |
Abstract: | OBJECTIVE:Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4. DESIGN:Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens). RESULTS:Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach. CONCLUSION:This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context. |
Keywords: | Pancreatic Neoplasms |
Rights: | © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. s This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/ |
DOI: | 10.1136/gutjnl-2017-315144 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1081312 http://purl.org/au-research/grants/nhmrc/1105640 http://purl.org/au-research/grants/nhmrc/1060522 http://purl.org/au-research/grants/nhmrc/1100722 |
Published version: | http://dx.doi.org/10.1136/gutjnl-2017-315144 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.