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Pancreatic Neoplasms: HELP
Articles by Natalie Cook
Based on 17 articles published since 2009
(Why 17 articles?)
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Between 2009 and 2019, N. Cook wrote the following 17 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Drug development and clinical trial design in pancreatico-biliary malignancies. 2018

Harrington, Jennifer / Carter, Louise / Basu, Bristi / Cook, Natalie. ·Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, University of Manchester, Manchester, UK. · Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK; Department of Oncology, University of Cambridge, Cambridge, UK. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, University of Manchester, Manchester, UK. Electronic address: Natalie.cook@christie.nhs.uk. ·Curr Probl Cancer · Pubmed #29402439.

ABSTRACT: Pancreatico-biliary (P-B) tumors arise from the pancreas, bile duct, and ampulla of Vater. Despite their close anatomical location, they have different etiology and biology. However, they uniformly share a poor prognosis, with no major improvements observed in overall survival over decades, even in the face of progress in diagnostic imaging and surgical techniques, and advances in systemic and loco-regional radiation therapies. To date, cytotoxic treatment has been associated with modest benefits in the advanced disease setting, and survival for patients with stage IV disease has not exceeded a year. Therefore, there is a pressing need to identify better treatments which may impact more significantly. Frequently, encouraging signals of potential efficacy for novel agents in early phase clinical trials have been followed by disappointing failures in larger phase III trials, raising the valid question of how drug development can be optimized for patients with pancreatic adenocarcinoma and biliary tract malignancies. In this article we summarize the current therapeutic options for these patients and their limitations. The biological context of these cancers is reviewed, highlighting features that may make them resistant to standard chemotherapeutics and could be potential therapeutic targets. We discuss the role of early phase clinical trials, defined as phase I and non-randomised phase II trials, within the clinical context and current therapeutic landscape of P-B tumors and postulate how translational studies and trial design may enable better realization of emerging targets together with a proposed model for future patient management. A detailed summary of current phase I clinical trials in P-B tumors is provided.

2 Review The pancreas cancer microenvironment. 2012

Feig, Christine / Gopinathan, Aarthi / Neesse, Albrecht / Chan, Derek S / Cook, Natalie / Tuveson, David A. ·Cambridge Research Institute, Cancer Research UK. ·Clin Cancer Res · Pubmed #22896693.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a common and lethal malignancy resulting in more than 250,000 deaths per year worldwide. Despite extensive efforts, cytotoxic and targeted therapies have provided only limited efficacy for patients with PDA to date. One contributing factor to the failure of systemic therapies may be the abundant tumor stromal content that is the characteristic of PDA. The PDA stroma, aptly termed the tumor microenvironment, occupies the majority of the tumor mass, and consists of a dynamic assortment of extracellular matrix components and nonneoplastic cells including fibroblastic, vascular, and immune cells. Recent work has revealed that the PDA stroma supports tumor growth and promotes metastasis and simultaneously serves as a physical barrier to drug delivery. Accordingly, methods that alter stromal composition or function, for instance interference with the vasculature via Notch/Hedgehog pathway inhibition or relief of vascular compression by hyaluronidase, are under active investigation. Here, we will review our current understanding of the PDA tumor microenvironment, and highlight opportunities for further exploration that may benefit patients.

3 Review Stromal biology and therapy in pancreatic cancer. 2011

Neesse, Albrecht / Michl, Patrick / Frese, Kristopher K / Feig, Christine / Cook, Natalie / Jacobetz, Mike A / Lolkema, Martijn P / Buchholz, Malte / Olive, Kenneth P / Gress, Thomas M / Tuveson, David A. ·Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge, UK. ·Gut · Pubmed #20966025.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease. One explanation for the devastating prognosis is the failure of many chemotherapies, including the current standard of care therapy gemcitabine. Although our knowledge of the molecular events underlying multistep carcinogenesis in PDA has steadily increased, translation into more effective therapeutic approaches has been inefficient over the last several decades. Evidence for this innate resistance to systemic therapies was recently provided in an accurate mouse model of PDA by the demonstration that chemotherapies are poorly delivered to PDA tissues because of a deficient vasculature. This vascular deficiency correlated with the presence of a dense stromal matrix that is a prominent histological hallmark of PDA tumours. Therapeutic targeting of stromal cells decreased the stroma from pancreatic tumours, resulting in increased intratumoral perfusion and therapeutic delivery of gemcitabine. Stromal cells contained within the PDA tumour microenvironment therefore represent an additional constituent to neoplastic cells that should be critically evaluated for optimal therapeutic development in preclinical models and early clinical trials.

4 Clinical Trial A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. 2018

Cook, Natalie / Basu, Bristi / Smith, Donna-Michelle / Gopinathan, Aarthi / Evans, Jeffry / Steward, William P / Palmer, Daniel / Propper, David / Venugopal, Balaji / Hategan, Mirela / Anthoney, D Alan / Hampson, Lisa V / Nebozhyn, Michael / Tuveson, David / Farmer-Hall, Hayley / Turner, Helen / McLeod, Robert / Halford, Sarah / Jodrell, Duncan. ·Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK. · Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK. · Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow G12 0YN, United Kingdom. · Department of Oncology, University of Leicester, Leicester LE2 7LX, UK. · Clatterbridge Cancer Centre, Clatterbridge Road, Bebington, Wirral CH63 4JY, UK. · Bart's Cancer Institute, Queen Mary University of London EC1M 6BQ, London, UK. · Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK. · St James Institute of Oncology, University of Leeds & Leeds Teaching Hospitals Trust, Leeds LS9 7TF, UK. · Department of Mathematics and Statistics, Fylde College, Lancaster University, Lancaster LA1 4YF, UK. · Merck & Co., Inc., Kenilworth, NJ 07033, USA. · Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724, USA. ·Br J Cancer · Pubmed #29438372.

ABSTRACT: BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m RESULTS: Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. CONCLUSIONS: Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.

5 Article Exome-Wide Association Study of Pancreatic Cancer Risk. 2018

Grant, Robert C / Denroche, Robert E / Borgida, Ayelet / Virtanen, Carl / Cook, Natalie / Smith, Alyssa L / Connor, Ashton A / Wilson, Julie M / Peterson, Gloria / Roberts, Nicholas J / Klein, Alison P / Grimmond, Sean M / Biankin, Andrew / Cleary, Sean / Moore, Malcolm / Lemire, Mathieu / Zogopoulos, George / Stein, Lincoln / Gallinger, Steven. ·Ontario Institute for Cancer Research, Toronto, Canada. · Ontario Pancreas Cancer Study, Toronto, Canada. · Princess Margaret Genomics Centre, Toronto, Canada. · Research Institute of the McGill University Health Centre, Montreal, Canada. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, Australia. · Wohl Cancer Research Centre, Institute of, Cancer Sciences, University of Glasgow, Glasgow, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, Australia. · Ontario Institute for Cancer Research, Toronto, Canada; Ontario Pancreas Cancer Study, Toronto, Canada. · Ontario Institute for Cancer Research, Toronto, Canada; Ontario Pancreas Cancer Study, Toronto, Canada. Electronic address: steven.gallinger@uhn.ca. ·Gastroenterology · Pubmed #29074453.

ABSTRACT: We conducted a case-control exome-wide association study to discover germline variants in coding regions that affect risk for pancreatic cancer, combining data from 5 studies. We analyzed exome and genome sequencing data from 437 patients with pancreatic cancer (cases) and 1922 individuals not known to have cancer (controls). In the primary analysis, BRCA2 had the strongest enrichment for rare inactivating variants (17/437 cases vs 3/1922 controls) (P = 3.27x10

6 Article FOLFIRINOX for advanced pancreatic cancer: the Princess Margaret Cancer Centre experience. 2016

Chllamma, Muralidharan K / Cook, Natalie / Dhani, Neesha C / Giby, Kazim / Dodd, Anna / Wang, Lisa / Hedley, David W / Moore, Malcolm J / Knox, Jennifer J. ·Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2M9, Canada. · The Christie NHS Foundation Trust/Institute of Cancer Sciences, University of Manchester, Manchester M20 4BX, UK. · President, B.C. Cancer Agency, Vancouver, British Columbia V5Z 4E6, Canada. ·Br J Cancer · Pubmed #27467054.

ABSTRACT: BACKGROUND: FOLFIRINOX has been shown to significantly increase both overall survival (OS) and progression-free survival (PFS) in metastatic pancreas cancer. There is limited data regarding the treatment of locally advanced pancreatic cancer. We present a retrospective study of patients with both locally advanced and metastatic pancreas cancer using FOLFIRINOX as first-line therapy in our centre. METHODS: This is a retrospective review of patients treated with FOLFIRINOX for pancreatic cancer at Princess Margaret Cancer Centre, between December 2011 and July 2014. The primary objective was to evaluate the efficacy and safety of FOLFIRINOX when used with dose modifications. RESULTS: One hundred two patients were identified; 66 metastatic and 36 locally advanced. Sixty-eight per cent of patients initiated treatment with a dose reduction. The median (95% CI) OS in the metastatic group was 13.1 (6.3-16.1) months with full dose and 12.9 (10.3-30.1) months with modified dose. The median (95% CI) OS in the locally advanced group was 11.1 (6.1-not reached) months with full dose and 23 (not reached-not reached) months with modified dose. The median (95% CI) PFS in the metastatic group was 6.2 (4.9-15.2) months with full dose and 8.7 (5.7-12.9) months with modified dose. The median (95% CI) PFS in the locally advanced group was 11.1 (3.1-not reached) months with full dose and 10.4 (6.8-not reached) months with modified dose. Grade 3/4 haematologic adverse events were observed in 43% of patients. Grade 3/4 non-haematologic adverse events were observed in 28% of patients. Patient well-being significantly improved from baseline to cycle 4 (P=0.002). CONCLUSIONS: Efficacy was achievable with dose-modified FOLFIRINOX in daily setting. The safety of FOLFIRINOX remains a concern with a high rate of grades 3 and 4 neutropaenia despite dose reduction.

7 Article Endothelin-1 and endothelin B receptor expression in pancreatic adenocarcinoma. 2015

Cook, N / Brais, R / Qian, W / Hak, C Chan Wah / Corrie, P G. ·Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK CRUK Cancer Research Institute, University of Cambridge, Cambridge, UK. · Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. · Cambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. · School of Clinical Medicine, University of Cambridge, Cambridge, UK. · Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. ·J Clin Pathol · Pubmed #25572612.

ABSTRACT: BACKGROUND: Endothelin-1 (ET-1) acting through endothelin A and B receptors (ETAR and ETBR) has been implicated in the development of cancer. The endothelin axis has not previously been characterised in human pancreatic adenocarcinoma (PAC). METHODS: Expression of ET-1, ETAR, ETBR, vascular endothelial growth factor and microvessel density (MVD) was determined by immunohistochemistry in 45 surgically resected human PACs and 15 non-cancer human pancreas samples. RESULTS: PAC had the highest staining intensity for ET-1 and ETBR: 38% PAC samples scored 2+ or more compared with 7% non-cancer sample in ET-1; 58% PAC samples scored 2+ compared with 0% non-cancer samples in ETBR. MVD was significantly lower in PAC compared with non-cancer tissue (p<0.0001). CONCLUSIONS: PAC was characterised by greater expression of ET-1 and ETBR compared with normal pancreas.

8 Article Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo. 2014

Bapiro, T E / Frese, K K / Courtin, A / Bramhall, J L / Madhu, B / Cook, N / Neesse, A / Griffiths, J R / Tuveson, D A / Jodrell, D I / Richards, F M. ·Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Box 278, Robinson Way, Cambridge CB2 0RE, UK. · Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA. ·Br J Cancer · Pubmed #24874484.

ABSTRACT: BACKGROUND: The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRAS(G12D); p53(R172H); pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism. METHODS: LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay. RESULTS: In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite gemcitabine triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine triphosphate (CTP). In tumour homogenates in vitro, CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFdCTP for CTP:phosphocholine cytidylyltransferase (CCT). As the structure of GdPC precludes entry into cells, potential cytotoxicity was assessed by stimulating CCT activity using linoleate in KPC cells in vitro, leading to increased GdPC concentration and synergistic growth inhibition after dFdC addition. CONCLUSIONS: GdPC is an important element of the intra-tumoural dFdC metabolic pathway in vivo.

9 Article Anti-tumour efficacy of capecitabine in a genetically engineered mouse model of pancreatic cancer. 2013

Courtin, Aurélie / Richards, Frances M / Bapiro, Tashinga E / Bramhall, Jo L / Neesse, Albrecht / Cook, Natalie / Krippendorff, Ben-Fillippo / Tuveson, David A / Jodrell, Duncan I. ·Pharmacology and Drug Development Group, Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom. ·PLoS One · Pubmed #23840665.

ABSTRACT: Capecitabine (CAP) is a 5-FU pro-drug approved for the treatment of several cancers and it is used in combination with gemcitabine (GEM) in the treatment of patients with pancreatic adenocarcinoma (PDAC). However, limited pre-clinical data of the effects of CAP in PDAC are available to support the use of the GEMCAP combination in clinic. Therefore, we investigated the pharmacokinetics and the efficacy of CAP as a single agent first and then in combination with GEM to assess the utility of the GEMCAP therapy in clinic. Using a model of spontaneous PDAC occurring in Kras(G12D); p53(R172H); Pdx1-Cre (KPC) mice and subcutaneous allografts of a KPC PDAC-derived cell line (K8484), we showed that CAP achieved tumour concentrations (∼25 µM) of 5-FU in both models, as a single agent, and induced survival similar to GEM in KPC mice, suggesting similar efficacy. In vitro studies performed in K8484 cells as well as in human pancreatic cell lines showed an additive effect of the GEMCAP combination however, it increased toxicity in vivo and no benefit of a tolerable GEMCAP combination was identified in the allograft model when compared to GEM alone. Our work provides pre-clinical evidence of 5-FU delivery to tumours and anti-tumour efficacy following oral CAP administration that was similar to effects of GEM. Nevertheless, the GEMCAP combination does not improve the therapeutic index compared to GEM alone. These data suggest that CAP could be considered as an alternative to GEM in future, rationally designed, combination treatment strategies for advanced pancreatic cancer.

10 Article Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. 2013

Jacobetz, Michael A / Chan, Derek S / Neesse, Albrecht / Bapiro, Tashinga E / Cook, Natalie / Frese, Kristopher K / Feig, Christine / Nakagawa, Tomoaki / Caldwell, Meredith E / Zecchini, Heather I / Lolkema, Martijn P / Jiang, Ping / Kultti, Anne / Thompson, Curtis B / Maneval, Daniel C / Jodrell, Duncan I / Frost, Gregory I / Shepard, H M / Skepper, Jeremy N / Tuveson, David A. ·Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK. ·Gut · Pubmed #22466618.

ABSTRACT: OBJECTIVE: Pancreatic ductal adenocarcinoma (PDA) is characterised by stromal desmoplasia and vascular dysfunction, which critically impair drug delivery. This study examines the role of an abundant extracellular matrix component, the megadalton glycosaminoglycan hyaluronan (HA), as a novel therapeutic target in PDA. METHODS: Using a genetically engineered mouse model of PDA, the authors enzymatically depleted HA by a clinically formulated PEGylated human recombinant PH20 hyaluronidase (PEGPH20) and examined tumour perfusion, vascular permeability and drug delivery. The preclinical utility of PEGPH20 in combination with gemcitabine was assessed by short-term and survival studies. RESULTS: PEGPH20 rapidly and sustainably depleted HA, inducing the re-expansion of PDA blood vessels and increasing the intratumoral delivery of two chemotherapeutic agents, doxorubicin and gemcitabine. Moreover, PEGPH20 triggered fenestrations and interendothelial junctional gaps in PDA tumour endothelia and promoted a tumour-specific increase in macromolecular permeability. Finally, combination therapy with PEGPH20 and gemcitabine led to inhibition of PDA tumour growth and prolonged survival over gemcitabine monotherapy, suggesting immediate clinical utility. CONCLUSIONS: The authors demonstrate that HA impedes the intratumoral vasculature in PDA and propose that its enzymatic depletion be explored as a means to improve drug delivery and response in patients with pancreatic cancer.

11 Article nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. 2012

Frese, Kristopher K / Neesse, Albrecht / Cook, Natalie / Bapiro, Tashinga E / Lolkema, Martijn P / Jodrell, Duncan I / Tuveson, David A. ·Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK. · Department of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Baldingerstr, 35043 Marburg, Germany. · Department of Oncology, University of Cambridge, Cambridge, UK. · Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. ·Cancer Discov · Pubmed #22585996.

ABSTRACT: SIGNIFICANCE: This study provides mechanistic insight into the clinical cooperation observed between gemcitabine and nab-paclitaxel in the treatment of pancreatic cancer.

12 Article A novel Phase I/IIa design for early phase oncology studies and its application in the evaluation of MK-0752 in pancreatic cancer. 2012

Whitehead, John / Thygesen, Helene / Jaki, Thomas / Davies, Scot / Halford, Sarah / Turner, Helen / Cook, Natalie / Jodrell, Duncan. ·Medical and Pharmaceutical Statistics Research Unit, Lancaster University, U.K. j.whitehead@lancaster.ac.uk ·Stat Med · Pubmed #22495759.

ABSTRACT: The Cancer Research UK study CR0720-11 is a trial to determine the tolerability and effect on survival of using two agents in combination in patients with advanced pancreatic cancer. In particular, the trial is designed first to identify the most suitable combination of doses of the two agents in terms of the incidence of dose-limiting toxicities. Then, the survival of all patients who have received that dose combination in the study so far, together with additional patients assigned to that dose combination to ensure that the total number is sufficient, will be analysed. If the survival outcomes show promise, then a definitive randomised study of that dose combination will be recommended. The first two patients in the trial will be treated with the lowest doses of each agent in combination. An adaptive Bayesian procedure based only on monotonicity constraints concerning the risks of toxicity at different dose levels will then be used to suggest dose combinations for subsequent patients. The survival analysis will concern only patients who received the chosen dose combination, and will compare observed mortality with that expected from an exponential model based on the known survival rates associated with current treatment. In this paper, the Bayesian dose-finding procedure is described and illustrated, and its properties are evaluated through simulation. Computation of the appropriate sample size for the survival investigation is also discussed.

13 Article Direct histological processing of EUS biopsies enables rapid molecular biomarker analysis for interventional pancreatic cancer trials. 2012

Brais, Rebecca J / Davies, Susan E / O'Donovan, Maria / Simpson, Ben W / Cook, Natalie / Darbonne, Walter C / Chilcott, Sian / Lolkema, Martijn P / Neesse, Albrecht / Lockley, Michelle / Corrie, Pippa G / Jodrell, Duncan I / Praseedom, Raaj K / Huguet, Emmanuel L / Jah, Asif / Jamieson, Neville V / de Sauvage, Frederic J / Tuveson, David A / Carroll, Nicholas R. ·Department of Histopathology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom. ·Pancreatology · Pubmed #22487467.

ABSTRACT: OBJECTIVE: Current practice to diagnose pancreatic cancer is accomplished by endoscopic ultrasound guided fine needle aspiration (EUS-FNA) using a cytological approach. This method is time consuming and often fails to provide suitable specimens for modern molecular analyses. Here, we compare the cytological approach with direct formalin fixation of pancreatic EUS-FNA micro-cores and evaluate the potential to perform molecular biomarker analysis on these specimen. METHODS: 130 specimens obtained by EUS-FNA with a 22G needle were processed by the standard cytological approach and compared to a separate cohort of 130 specimens that were immediately formalin fixed to preserve micro-cores of tissue prior to routine histological processing. RESULTS: We found that direct formalin fixation significantly shortened the time required for diagnosis from 3.6 days to 2.9 days (p<0.05) by reducing the average time (140 vs 33 min/case) and number of slides (9.65 vs 4.67 slides/case) for histopathological processing. Specificity and sensitivity yielded comparable results between the two approaches (82.3% vs 77% and 90.9% vs 100%). Importantly, EUS-FNA histology preserved the tumour tissue architecture with neoplastic glands embedded in stroma in 67.89% of diagnostic cases compared to 27.55% with the standard cytological approach (p < 0.001). Furthermore, micro-core samples were suitable for molecular studies including the immunohistochemical detection of intranuclear Hes1 in malignant cells, and the laser-capture microdissection-mediated measurement of Gli-1 mRNA in tumour stromal myofibroblasts. CONCLUSIONS: Direct formalin fixation of pancreatic EUS-FNA micro-cores demonstrates superiority regarding diagnostic delay, costs, and specimen suitability for molecular studies. We advocate this approach for future investigational trials in pancreatic cancer patients.

14 Article Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma. 2012

Cook, Natalie / Frese, Kristopher K / Bapiro, Tashinga E / Jacobetz, Michael A / Gopinathan, Aarthi / Miller, Jodi L / Rao, Sudhir S / Demuth, Tim / Howat, William J / Jodrell, Duncan I / Tuveson, David A. ·Cancer Research UK Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE, England, UK. ·J Exp Med · Pubmed #22351932.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease that is refractory to medical intervention. Notch pathway antagonism has been shown to prevent pancreatic preneoplasia progression in mouse models, but potential benefits in the setting of an established PDA tumor have not been established. We demonstrate that the gamma secretase inhibitor MRK003 effectively inhibits intratumoral Notch signaling in the KPC mouse model of advanced PDA. Although MRK003 monotherapy fails to extend the lifespan of KPC mice, the combination of MRK003 with the chemotherapeutic gemcitabine prolongs survival. Combination treatment kills tumor endothelial cells and synergistically promotes widespread hypoxic necrosis. These results indicate that the paucivascular nature of PDA can be exploited as a therapeutic vulnerability, and the dual targeting of the tumor endothelium and neoplastic cells by gamma secretase inhibition constitutes a rationale for clinical translation.

15 Article Cathepsin B promotes the progression of pancreatic ductal adenocarcinoma in mice. 2012

Gopinathan, Aarthi / Denicola, Gina M / Frese, Kristopher K / Cook, Natalie / Karreth, Florian A / Mayerle, Julia / Lerch, Markus M / Reinheckel, Thomas / Tuveson, David A. ·Li Ka Shing Centre, Cancer Research UK Cambridge Research Institute, Cambridge, UK. ·Gut · Pubmed #22157328.

ABSTRACT: OBJECTIVE: The lysosomal protease cathepsin B is upregulated in human pancreatic ductal adenocarcinoma (PDA) and represents a potential therapeutic target. Loss of cathepsin B delays tumour progression in mouse models of islet, mammary and intestinal carcinoma and decreases invasion and metastasis. This study examines the role of cathepsin B in the initiation, progression and metastasis of PDA. METHODS: Cathepsin B germline knockout mice were crossed with animals expressing an endogenous Kras(G12D) allele in the pancreas, and mice were aged to evaluate the role of cathepsin B in pancreatic intraepithelial neoplasia (PanIN). A survival study was also performed with mice carrying an additional heterozygous conditional Trp53(R172H) allele. Cell lines derived from tumours were used to investigate the role of cathepsin B in vitro, and subcutaneous allografts investigated the cell autonomous and non-cell autonomous roles of cathepsin B in pancreatic cancer. RESULTS: Constitutive cathepsin B loss resulted in delayed progression of both PanIN and PDA and a significant survival advantage in mice. Cathepsin B-deficient PDA cells and PanIN showed decreased proliferation and mitogen-activated protein (MAP) kinase signalling. The reconstitution of deficient cells with cathepsin B reversed these findings, which correlated with decreased levels of the active forms of the related protease cathepsin L. Conversely, acute ablation of cathepsin L activated the MAP kinase cascade in PDA cells. CONCLUSIONS: These results confirm that cathepsin B plays an important cell autonomous role in the progression of PDA and suggest that the regulation of cathepsin L by cathepsin B may be a means of stimulating cell proliferation in neoplasia.

16 Article Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice. 2011

Maniati, Eleni / Bossard, Maud / Cook, Natalie / Candido, Juliana B / Emami-Shahri, Nia / Nedospasov, Sergei A / Balkwill, Frances R / Tuveson, David A / Hagemann, Thorsten. ·Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. ·J Clin Invest · Pubmed #22056382.

ABSTRACT: The majority of human pancreatic cancers have activating mutations in the KRAS proto-oncogene. These mutations result in increased activity of the NF-κB pathway and the subsequent constitutive production of proinflammatory cytokines. Here, we show that inhibitor of κB kinase 2 (Ikk2), a component of the canonical NF-κB signaling pathway, synergizes with basal Notch signaling to upregulate transcription of primary Notch target genes, resulting in suppression of antiinflammatory protein expression and promotion of pancreatic carcinogenesis in mice. We found that in the Kras(G12D)Pdx1-cre mouse model of pancreatic cancer, genetic deletion of Ikk2 in initiated pre-malignant epithelial cells substantially delayed pancreatic oncogenesis and resulted in downregulation of the classical Notch target genes Hes1 and Hey1. Tnf-α stimulated canonical NF-κB signaling and, in collaboration with basal Notch signals, induced optimal expression of Notch targets. Mechanistically, Tnf-α stimulation resulted in phosphorylation of histone H3 at the Hes1 promoter, and this signal was lost with Ikk2 deletion. Hes1 suppresses expression of Pparg, which encodes the antiinflammatory nuclear receptor Pparγ. Thus, crosstalk between Tnf-α/Ikk2 and Notch sustains the intrinsic inflammatory profile of transformed cells. These findings reveal what we believe to be a novel interaction between oncogenic inflammation and a major cell fate pathway and show how these pathways can cooperate to promote cancer progression.

17 Article Impact of pancreatic leaks on survival following pancreaticoduodenectomy. 2010

Ausania, Fabio / Cook, Natalie / Jamieson, Neville / Huguet, Emanuel / Jah, Asif / Praseedom, Raaj. ·Hepato-Pancreato-Biliary Surgery, Addenbrooke's Hospital, NIHR Comprehensive Biomedical Research Centre, Cambridge, United Kingdom. ·JOP · Pubmed #20442516.

ABSTRACT: CONTEXT: Pancreatic leak following pancreaticoduodenectomy has a major impact on postoperative mortality. However, it is not clear whether pancreatic leaks affect long term survival in patients with pancreatic ductal adenocarcinoma. OBJECTIVE: The aim of this study is to compare the long term outcome in patients who underwent pancreaticoduodenectomy, with and without postoperative pancreatic leak. PATIENTS: All 133 patients who underwent a pancreaticoduodenectomy at the HepatoPancreatoBiliary Unit, Addenbrooke's Hospital, Cambridge, between June 2002 and June 2007 were identified from a prospectively held database. The study was restricted to 47 patients who had a confirmed diagnosis of pancreatic ductal adenocarcinoma. SETTING: Pancreatic leak was defined as drain fluid amylase more than three times the serum level for more than 3 days post operatively. MAIN OUTCOME MEASURE: Long term survival of patients with and without leaks were compared using Kaplan-Meier curves and significance was measured using the log-rank test. RESULTS: Median follow-up was 30.8 months. The median actuarial survival of all ductal adenocarcinoma patients was 19 months. Pancreatic leaks occurred in 9 patients (19.1%). There were no significant differences in the overall survival or presence of recurrence between the two groups. CONCLUSIONS: Pancreatic leak following pancreaticoduodenectomy does not appear to impact on long-term outcome of patients with pancreatic ductal adenocarcinoma.