Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. Issue 12 (28th October 2017)

• Record Type: Journal Article
• Authors: Chou, Angela; Froio, Danielle; Nagrial, Adnan M; Parkin, Ashleigh; Murphy, Kendelle J; Chin, Venessa T; Wohl, Dalia; Steinmann, Angela; Stark, Rhys; Drury, Alison; Walters, Stacey N; Vennin, Claire; Burgess, Andrew; Pinese, Mark; Chantrill, Lorraine A; Cowley, Mark J; Molloy, Timothy J; Waddell, Nicola; Johns, Amber; Grimmond, Sean M; Chang, David K; Biankin, Andrew V; Sansom, Owen J; Morton, Jennifer P; Grey, Shane T; Cox, Thomas R; Turchini, John; Samra, Jaswinder; Clarke, Stephen J; Timpson, Paul; Gill, Anthony J; Pajic, Marina;
• Other Names: Biankin Andrew V author non-byline.; Johns Amber L author non-byline.; Axford Catherine J author non-byline.; Pajic Marina author non-byline.; Chang David K author non-byline.; Scarlett Christopher J author non-byline.; Brancato Mary-anne L author non-byline.; Mawson Amanda author non-byline.; Simpson Skye H author non-byline.; Smith Mona Martyn- author non-byline.; Chantrill Lorraine A author non-byline.; Chin Venessa T author non-byline.; Chou Angela author non-byline.; Cowley Mark J author non-byline.; Humphris Jeremy L author non-byline.; Mead R Scott author non-byline.; Nagrial Adnan M author non-byline.; Pettit Jessica author non-byline.; Pinese Mark author non-byline.; Rooman Ilse author non-byline.; Wu Jianmin author non-byline.; Watson Clare author non-byline.; Steinmann Angela author non-byline.; Lee Hong Ching author non-byline.; Wong Rachel author non-byline.; Pinho Andreia V author non-byline.; Giry-laterriere Marc author non-byline.; Daly Roger J author non-byline.; Musgrove Elizabeth A author non-byline.; Sutherland sean m grimmond Robert L author non-byline.; Waddell Nicola author non-byline.; Kassahn Karin S author non-byline.; Miller David K author non-byline.; Wilson Peter J author non-byline.; Patch Ann-marie author non-byline.; Song Sarah author non-byline.; Harliwong Ivon author non-byline.; Idrisoglu Senel author non-byline.; Nourse Craig author non-byline.; Nourbakhsh Ehsan author non-byline.; Manning Suzanne author non-byline.; Wani Shivangi author non-byline.; Gongora Milena author non-byline.; Anderson Matthew author non-byline.; Holmes Oliver author non-byline.; Leonard Conrad author non-byline.; Taylor Darrin author non-byline.; Wood Scott author non-byline.; Xu Christina author non-byline.; Nones Katia author non-byline.; Fink J Lynn author non-byline.; Christ Angelika author non-byline.; Bruxner Tim author non-byline.; Cloonan Nicole author non-byline.; Newell Felicity author non-byline.; Pearson John V author non-byline.; Bailey Peter author non-byline.; Quinn Michael author non-byline.; Nagaraj Shivashankar author non-byline.; Kazakoff Stephen author non-byline.; Waddell Nick author non-byline.; Krisnan Keerthana author non-byline.; Quek Kelly author non-byline.; Jaswinder s samra David Wood author non-byline.; Gill Anthony J author non-byline.; Pavlakis Nick author non-byline.; Guminski Alex author non-byline.; Ray asghari Christopher Toon author non-byline.; Merrett Neil D author non-byline.; Pavey Darren author non-byline.; Peter h cosman Amitabha Das author non-byline.; Ismail Kasim author non-byline.; O'connnor Chelsie author non-byline.; Lam Vincent W author non-byline.; Mcleod Duncan author non-byline.; Pleass Henry C author non-byline.; Richardson Arthur author non-byline.; James Virginia author non-byline.; Kench James G author non-byline.; Cooper Caroline L author non-byline.; Joseph David author non-byline.; Sandroussi Charbel author non-byline.; Crawford Michael author non-byline.; Michael texler James Gallagher author non-byline.; Forest Cindy author non-byline.; Laycock Andrew author non-byline.; Epari Krishna P author non-byline.; Ballal Mo author non-byline.; Fletcher David R author non-byline.; Nigel a spry Sanjay Mukhedkar author non-byline.; Deboer Bastiaan author non-byline.; Nikolajs zeps Ming Chai author non-byline.; Beilin Maria author non-byline.; Nan q nguyen Kynan Feeney author non-byline.; Ruszkiewicz Andrew R author non-byline.; Worthley Chris author non-byline.; Tan john chen Chuan P author non-byline.; Brooke-smith Mark E author non-byline.; Henry tang Virginia Papangelis author non-byline.; Barbour envoi pathology andrew d clouston Andrew P author non-byline.; Thomas j o'rourke Patrick Martin author non-byline.; Fawcett Jonathan W author non-byline.; Slater Kellee author non-byline.; Yeung Shinn author non-byline.; Hatzifotis Michael author non-byline.; Christopher christophi Peter Hodgkinson author non-byline.; Nikfarjam Mehrdad author non-byline.; Mountain Angela author non-byline.; Scarpa Aldo author non-byline.; Lawlor Rita T author non-byline.; Sperandio Nicola author non-byline.; Bonizzato Giada author non-byline.; Grimaldi Sonia author non-byline.; Cantù Cinzia author non-byline.; Merlini Paola author non-byline.; Turri Giona author non-byline.; Pea Antonio author non-byline.; Pedrazzani Corrado author non-byline.; Ruzzenente Andrea author non-byline.; Gobbo Stefano author non-byline.; Guido Martignoni author non-byline.; Andrew v biankin Roberto Girelli author non-byline.; Grimmond Sean M author non-byline.; Chang David K author non-byline.; Musgrove Elizabeth A author non-byline.; Jones Marc D author non-byline.; B jamieson Craig Nourse, nigel author non-byline.; S Janet author non-byline.; Graham Janet S author non-byline.; Biankin Andrew V author non-byline.; Chang David K author non-byline.; Jones Marc D author non-byline.; Jamieson Nigel B author non-byline.; Graham Janet S author non-byline.;
• Is Part Of: Gut. Volume 67:Issue 12(2018)
• Page Start: 2142
• Page End: 2155
• Publication Date: 2017-10-28
• Subjects: pancreatic cancer -- extracellular matrix -- molecular mechanisms -- cell cycle; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2017-315144
• Languages: English
• ISSNs: 0017-5749

Abstract

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.