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Pancreatic Neoplasms: HELP
Articles by David W. Hedley
Based on 36 articles published since 2009
(Why 36 articles?)
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Between 2009 and 2019, D. Hedley wrote the following 36 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Comparison of Practice Guidelines, BRCAPRO, and Genetic Counselor Estimates to Identify Germline BRCA1 and BRCA2 Mutations in Pancreatic Cancer. 2018

Grant, Robert C / Holter, Spring / Borgida, Ayelet / Dhani, Neesha C / Hedley, David W / Knox, Jennifer J / Akbari, Mohammad R / Zogopoulos, George / Gallinger, Steven. ·Division of Medical Oncology, University of Toronto, Toronto, Canada. robert.grant@utoronto.ca. · Ontario Institute for Cancer Research, Toronto, Canada. robert.grant@utoronto.ca. · Princess Margaret Cancer Centre-Ontario Power Generation, 700 University Avenue, Work Station 7W460, Toronto, ON, M5G 1Z5, Canada. robert.grant@utoronto.ca. · Ontario Pancreas Cancer Study, Toronto, Canada. · Division of Medical Oncology, University of Toronto, Toronto, Canada. · Wallace McCain Centre for Pancreatic Cancer, University of Toronto, Toronto, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, Canada. · Women's College Research Institute, Toronto, Canada. · Research Institute of the McGill University Health Centre, Montreal, Canada. · Goodman Cancer Research Centre, McGill University, Montreal, Canada. · Ontario Institute for Cancer Research, Toronto, Canada. · Princess Margaret Cancer Centre-Ontario Power Generation, 700 University Avenue, Work Station 7W460, Toronto, ON, M5G 1Z5, Canada. · Division of General Surgery, University of Toronto, Toronto, Canada. ·J Genet Couns · Pubmed #29441441.

ABSTRACT: Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic ductal adenocarcinoma (PDAC) may benefit from precision therapies and their relatives should undergo tailored cancer prevention. In this study, we compared strategies to identify BRCA carriers with PDAC. Incident cases of PDAC were prospectively recruited for BRCA sequencing. Probands were evaluated using the National Comprehensive Cancer Network (NCCN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) guidelines. The probability of each proband carrying a mutation was estimated by surveying genetic counselors and using BRCAPRO. BRCA mutations were detected in 22/484 (4.5%) probands. 152/484 (31.2%) and 16/484 (3.3%) probands met the NCCN and MOHLTC guidelines, respectively. The NCCN guidelines had higher sensitivity than the MOHLTC guidelines (0.864 versus 0.227, P < 0.001) but lower specificity (0.712 versus 0.976, P < 0.001). One hundred and nineteen genetic counselors completed the survey. Discrimination was similar between genetic counselors and BRCAPRO (area-under-the-curve: 0.755 and 0.775, respectively, P = 0.702). Genetic counselors generally overestimated (P = 0.008), whereas BRCAPRO severely underestimated (P < 0.001), the probability that each proband carried a mutation. Our results indicate that the NCCN guidelines and genetic counselors accurately identify BRCA mutations in PDAC, while the MOHLTC guidelines and BRCAPRO should be updated to account for the association between BRCA and PDAC.

2 Review Emerging applications of flow cytometry in solid tumor biology. 2012

Chang, Qing / Hedley, David. ·Research Division, Ontario Cancer Institute and Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. ·Methods · Pubmed #22503773.

ABSTRACT: Despite considerable interest during the early clinical development of flow cytometry, its application to solid tumours has been largely ignored in recent years. However, with rapid progress in cancer biology and molecular therapeutics, linked to technical developments in the areas of flow cytometry instrumentation, reagents, and data analysis, it is timely to re-evaluate this role. This article places emphasis on the unique potential of flow cytometry to analyze heterogeneous cell populations, and to provide information on the functional status of regulatory processes by the simultaneous measurement of multiple key elements. Major obstacles to progress addressed include the acquisition of adequate clinical samples, tissue disaggregation to produce single cells suspensions suitable for flow cytometry, and protocols to label intracellular as well as cell surface antigens.

3 Clinical Trial A phase II study of the HSP90 inhibitor AUY922 in chemotherapy refractory advanced pancreatic cancer. 2016

Renouf, D J / Hedley, D / Krzyzanowska, M K / Schmuck, M / Wang, L / Moore, M J. ·British Columbia Cancer Agency, University of British Columbia, 600 West 10th Avenue, Vancouver, BC, V5Z4E6, Canada. drenouf@bccancer.bc.ca. · University Health Network-Princess Margaret Cancer Centre, Toronto, ON, Canada. · British Columbia Cancer Agency, University of British Columbia, 600 West 10th Avenue, Vancouver, BC, V5Z4E6, Canada. ·Cancer Chemother Pharmacol · Pubmed #27422303.

ABSTRACT: OBJECTIVES: AUY922 is a novel heat shock protein inhibitor with preclinical activity in pancreatic cancer. This phase II study evaluated the efficacy of AUY922 in patients with advanced pancreatic cancer previously treated with chemotherapy. METHODS: In this single-arm, Simon two-stage phase II trial, patients with metastatic or locally advanced pancreatic ductal adenocarcinoma who had progressed on at least one line of chemotherapy and were of good performances status (ECOG 0 or 1) were treated with AUY922 at a dose of 70 mg/m(2) IV weekly. The primary endpoint was disease control rate (objective response and stable disease ≥16 weeks). RESULTS: Twelve patients were accrued, all of whom received treatment. At least possibly related ≥grade 3 adverse events included fatigue (8 %) and AST elevation (8 %). Ten patients were evaluable for response with 1 (10 %) having stable disease and 9 (90 %) progressive disease. The median progression-free survival was 1.6 months, and the median overall survival was 2.9 months. CONCLUSIONS: AUY922 was not associated with significant efficacy in previously treated patients with advanced pancreatic cancer.

4 Clinical Trial Analysis of the intra- and intertumoral heterogeneity of hypoxia in pancreatic cancer patients receiving the nitroimidazole tracer pimonidazole. 2015

Dhani, N C / Serra, S / Pintilie, M / Schwock, J / Xu, J / Gallinger, S / Hill, R P / Hedley, D W. ·Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9. · Department of Laboratory Medicine and Pathobiology, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9. · Department of Biostatistics, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, M5G 2M9. · Applied Molecular Profiling Laboratory, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9. · Division of Hepato-biliary Pancreatic Surgical Oncology, University Health Network and Mount Sinai Hospital, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9. · Radiation Medicine Program, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9. ·Br J Cancer · Pubmed #26325106.

ABSTRACT: BACKGROUND: Hypoxia is thought to be an adverse feature of pancreatic cancer, but direct measurement in patients is technically challenging. To address this, we characterised the intra/interpatient heterogeneity of hypoxia in surgical specimens from patients who received the 2-nitroimidazole tracer pimonidazole pre-operatively. METHODS: Pimondazole was given intravenously 16-20 h before pancreatectomy, and the extent and intratumoral heterogeneity of hypoxia determined by image analysis applied to multiple tissue blocks stained by immunohistochemistry. Intra/interpatient heterogeneity was estimated by variance component analysis. RESULTS: Pimonidazole staining was analysed in 10 tumours. The extent of labelling varied amongst patients (0-26%), with a broader range of hypoxia in the epithelial (1-39%) compared with the stromal (1-13%) compartments. Variance component analysis demonstrated greater inter- than intrapatient variability of hypoxia, and that multiple (4-5) tumour sections are required to provide a consistent evaluation of its extent in individual tumours. CONCLUSIONS: There is significant intra- and intertumoral heterogeneity of hypoxia in pancreatic cancers, and these do not appear to be generally more hypoxic than other cancer types. This study establishes the feasibility to assess hypoxia in pancreatic cancer patients using pimonidazole, but questions the reliability of measurements made using a single tissue section.

5 Clinical Trial A phase II study of erlotinib in gemcitabine refractory advanced pancreatic cancer. 2014

Renouf, D J / Tang, P A / Hedley, D / Chen, E / Kamel-Reid, S / Tsao, M S / Tran-Thanh, D / Gill, S / Dhani, N / Au, H J / Wang, L / Moore, M J. ·British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada. Electronic address: drenouf@bccancer.bc.ca. · Tom Baker Cancer Centre, Calgary, AB, Canada. · University Health Network-Princess Margaret Cancer Centre, Toronto, ON, Canada. · British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada. · Cross Cancer Institute, Edmonton, AB, Canada. ·Eur J Cancer · Pubmed #24857345.

ABSTRACT: BACKGROUND: Erlotinib induced skin toxicity has been associated with clinical benefit in several tumour types. This phase II study evaluated the efficacy of erlotinib, dose escalated to rash, in patients with advanced pancreatic cancer previously treated with gemcitabine. METHODS: Erlotinib was given at an initial dose of 150 mg/day, and the dose was escalated by 50mg every 2 weeks (to a maximum of 300 mg/day) until >grade 1 rash or other dose limiting toxicities occurred. Erlotinib pharmacokinetics were performed, and baseline tumour tissue was collected for mutational analysis and epidermal growth factor receptor (EGFR) expression. The primary end-point was the disease control rate (objective response and stable disease >8 weeks). RESULTS: Fifty-one patients were accrued, and 49 received treatment. Dose-escalation to 200-300 mg of erlotinib was possible in 9/49 (18%) patients. The most common ⩾ grade 3 adverse events included fatigue (6%), rash (4%) and diarrhoea (4%). Thirty-seven patients were evaluable for response, and the best response was stable disease in 12 patients (32% (95% confidence interval (CI) 17-47%)). Disease control was observed in nine patients (24% (95% CI: 10-38%)). Median survival was 3.8 months, and 6 month overall survival rate was 32% (95% CI 19-47%). Mutational analysis and EGFR expression were performed on 29 patients, with 93% having KRAS mutations, none having EGFR mutations, and 86% expressing EGFR. Neither KRAS mutational status nor EGFR expression was associated with survival. CONCLUSIONS: Erlotinib dose escalated to rash was well tolerated but not associated with significant efficacy in non-selected patients with advanced pancreatic cancer.

6 Clinical Trial Induction gemcitabine plus concurrent gemcitabine and radiotherapy for locally advanced unresectable or resected pancreatic cancer. 2014

Youl, M / Hashem, S / Brade, A / Cummings, B / Dawson, L A / Gallinger, S / Hedley, D / Jiang, H / Kim, J / Krzyzanowska, M K / Ringash, J / Wong, R / Brierley, J. ·Department of Radiation Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada. · Department of Surgical Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada. · Department of Medical Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada. · Department of Biostatistics, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada. · Department of Radiation Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada. Electronic address: James.Brierley@rmp.uhn.on.ca. ·Clin Oncol (R Coll Radiol) · Pubmed #24462333.

ABSTRACT: AIMS: To determine the efficacy of induction gemcitabine followed by biweekly gemcitabine concurrent with radiotherapy for locally advanced pancreatic cancer. MATERIALS AND METHODS: Between March 2001 and August 2009, 90 patients with unresectable (78) or resected (12) pancreatic cancer were treated with a standard treatment policy of induction gemcitabine (seven doses of weekly gemcitabine at 1000 mg/m(2)) followed by concurrent radiotherapy (52.5 Gy) and biweekly gemcitabine (40 mg/m(2)). RESULTS: After induction gemcitabine, 17.8% of patients did not proceed to chemoradiotherapy, due to either disease progression, performance status deterioration or gemcitabine toxicity. Of the patients who received chemoradiotherapy, 68.9% completed the course of 52.5 Gy, whereas 79.7% received more than 45 Gy. Chemoradiotherapy was stopped early due to treatment toxicity in 22.9% of patients. On intention to treat analysis, the median overall survival was 12.7 months in the locally advanced group and 18.2 months in the resected group. On multivariate analysis for the unresectable patients, a larger gross tumour volume was a significant poor prognostic factor for overall survival and local progression-free survival. CONCLUSION: This large series confirms, in a standard practice setting, similar efficacy and tolerability of treatment as previously reported in our phase I-II study. The benefit to patients with a gross tumour volume >48 cm(3) may be limited.

7 Clinical Trial A phase II study of the halichondrin B analog eribulin mesylate in gemcitabine refractory advanced pancreatic cancer. 2012

Renouf, Daniel J / Tang, Patricia A / Major, Pierre / Krzyzanowska, Monika K / Dhesy-Thind, Bindi / Goffin, John R / Hedley, David / Wang, Lisa / Doyle, L / Moore, Malcolm J. ·University Health Network-Princess Margaret Hospital, Toronto, ON, Canada. ·Invest New Drugs · Pubmed #21526355.

ABSTRACT: BACKGROUND: Eribulin mesylate is a halichondrin B analog that inhibits microtubule dynamics. Pre-clinical studies have suggested anti-tumor activity in pancreatic cancer. This phase II study of eribulin in patients with advanced pancreatic cancer previously treated with gemcitabine was conducted by the Princess Margaret Hospital Phase II consortium. PATIENTS AND METHODS: Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and previous treatment with gemcitabine. The study was a single arm phase II trial using a Simon 2-stage design. The primary endpoint was response rate, secondary endpoints included time to progression and overall survival. RESULTS: Fifteen patients were enrolled, 14 received treatment, and 12 were evaluable for response. The median age was 61, and the majority of patients were ECOG performance status 1. Grade 3 or greater adverse events included neutropenia (29%), fatigue (14%), peripheral neuropathy (7%) and thrombosis (7%). There were no complete or partial responses and therefore the study was closed after the first stage. The best response was stable disease in 5/12 (42%) of patients. Of these five patients, three had stable disease for 9 months or greater. Median time to progression was 1.4 months, and median overall survival was 6.1 months. CONCLUSION: Eribulin was well tolerated but did not result in any objective responses in gemcitabine refractory pancreatic cancer. However, several patients had prolonged stable disease, suggesting that further studies of eribulin in pancreatic cancer may be warranted.

8 Clinical Trial A phase I/II study of the Src inhibitor saracatinib (AZD0530) in combination with gemcitabine in advanced pancreatic cancer. 2012

Renouf, Daniel J / Moore, Malcolm J / Hedley, David / Gill, Sharlene / Jonker, Derek / Chen, Eric / Walde, David / Goel, Rakesh / Southwood, Bernadette / Gauthier, Isabelle / Walsh, Wendy / McIntosh, Lynn / Seymour, Lesley. ·Division of Medical Oncology and Hematology, Rm 5-708, Princess Margaret Hospital, 610 University Avenue, Toronto M5G2M9, Canada. ·Invest New Drugs · Pubmed #21170669.

ABSTRACT: AIM: This phase I/II study of saracatinib in combination with gemcitabine in patients with advanced pancreatic cancer was conducted by the NCIC Clinical Trials Group. The aims were to define the recommended phase II dose (RP2D) of saracatinib when combined with gemcitabine, and assess the efficacy of this combination in advanced pancreatic cancer. PATIENTS AND METHODS: Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and no prior chemotherapy. In phase I saracatinib was escalated in combination with gemcitabine (1000 mg/m(2)) to determine the recommended phase II dose (RP2D). The study was then expanded to a single arm phase II trial using a Simon 2-stage design. The primary endpoint was objective tumor response (OR) plus stable disease ≥ 4 months (SD4) rate; if ≥ 8 patients had OR+SD4, the study would proceed to stage 2. RESULTS: Thirteen patients were enrolled into the phase I portion of this study. Saracatinib 175 mg PO daily was chosen as the RP2D in combination with gemcitabine. Twenty-one additional patients were then enrolled at the RP2D (phase II). Of the 22 response evaluable patients treated at the RP2D, 9 patients (40.9%) had progressive disease, 6 patients (27.3%) had stable disease for less than 4 months, 5 patients (22.7%) had SD4, and 2 patients (9.1%) had a partial response to treatment. Objective criteria for continuing to stage 2 were thus not met and the trial was closed following the accrual of 34 patients. CONCLUSION: Saracatinib 175 mg daily in combination with gemcitabine is well tolerated but the combination did not improve efficacy over what would be expected from gemcitabine alone.

9 Article Whole genomes define concordance of matched primary, xenograft, and organoid models of pancreas cancer. 2019

Gendoo, Deena M A / Denroche, Robert E / Zhang, Amy / Radulovich, Nikolina / Jang, Gun Ho / Lemire, Mathieu / Fischer, Sandra / Chadwick, Dianne / Lungu, Ilinca M / Ibrahimov, Emin / Cao, Ping-Jiang / Stein, Lincoln D / Wilson, Julie M / Bartlett, John M S / Tsao, Ming-Sound / Dhani, Neesha / Hedley, David / Gallinger, Steven / Haibe-Kains, Benjamin. ·Centre for Computational Biology, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom. · School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom. · PanCuRx Translational Research Initiative, Ontario Institute of Cancer Research (OICR), Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Princess Margaret Living Biobank Core, University Health Network, Toronto, Ontario, Canada. · Department of Statistical Science, University of Toronto, Toronto, Ontario, Canada. · Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. · UHN Program in BioSpecimen Sciences, Department of Pathology, University Health Network, Toronto, Ontario, Canada. · Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. · Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. · Vector Institute, Toronto, Ontario, Canada. ·PLoS Comput Biol · Pubmed #30629588.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC. For these preclinical disease models to be effective, they should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities. To date however, deep characterization of the molecular heterogeneity of PDAC PDX and PDO models and comparison with matched human tumour remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of 16 whole-genome pairs of tumours and matched PDX, from primary PDAC and liver metastasis, including a unique cohort of 5 'trios' of matched primary tumour, PDX, and PDO. We developed a pipeline to score concordance between PDAC models and their paired human tumours for genomic events, including mutations, structural variations, and copy number variations. Tumour-model comparisons of mutations displayed single-gene concordance across major PDAC driver genes, but relatively poor agreement across the greater mutational load. Genome-wide and chromosome-centric analysis of structural variation (SV) events highlights previously unrecognized concordance across chromosomes that demonstrate clustered SV events. We found that polyploidy presented a major challenge when assessing copy number changes; however, ploidy-corrected copy number states suggest good agreement between donor-model pairs. Collectively, our investigations highlight that while PDXs and PDOs may serve as tractable and transplantable systems for probing the molecular properties of PDAC, these models may best serve selective analyses across different levels of genomic complexity.

10 Article Panitumumab Modified with Metal-Chelating Polymers (MCP) Complexed to 2018

Aghevlian, Sadaf / Lu, Yijie / Winnik, Mitchell A / Hedley, David W / Reilly, Raymond M. ·Department of Pharmaceutical Sciences , University of Toronto , 144 College Street , Toronto , ON M5S 3M2 , Canada. · Department of Chemistry , University of Toronto , 80 St. George Street , Toronto , ON M5S 3H6 , Canada. · Department of Medical Oncology, Princess Margaret Cancer Centre , 610 University Avenue , Toronto , ON M5G 2M9 , Canada. · Department of Medical Imaging , University of Toronto , 263 McCaul Street , Toronto , ON M5T 1W7 , Canada. · Toronto General Research Institute and Joint Department of Medical Imaging , University Health Network , 200 Elizabeth Street , Toronto , ON M5G 2C4 , Canada. ·Mol Pharm · Pubmed #29314858.

ABSTRACT: A metal-chelating polymer (MCP) with a polyglutamide (PGlu) backbone presenting on average 13 DOTA (tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelators for complexing

11 Article Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial. 2018

Aung, Kyaw L / Fischer, Sandra E / Denroche, Robert E / Jang, Gun-Ho / Dodd, Anna / Creighton, Sean / Southwood, Bernadette / Liang, Sheng-Ben / Chadwick, Dianne / Zhang, Amy / O'Kane, Grainne M / Albaba, Hamzeh / Moura, Shari / Grant, Robert C / Miller, Jessica K / Mbabaali, Faridah / Pasternack, Danielle / Lungu, Ilinca M / Bartlett, John M S / Ghai, Sangeet / Lemire, Mathieu / Holter, Spring / Connor, Ashton A / Moffitt, Richard A / Yeh, Jen Jen / Timms, Lee / Krzyzanowski, Paul M / Dhani, Neesha / Hedley, David / Notta, Faiyaz / Wilson, Julie M / Moore, Malcolm J / Gallinger, Steven / Knox, Jennifer J. ·Wallace McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario, Institute for Cancer Research, Toronto, Ontario, Canada. · UHN Biobank, University Health Network, Toronto, Ontario, Canada. · Genomics, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Diagnostic Development, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. · Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York. · Department of Surgery, University of North Carolina, Chapel Hill, North Carolina. · British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Wallace McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. Jennifer.Knox@uhn.ca. ·Clin Cancer Res · Pubmed #29288237.

ABSTRACT:

12 Article Activity of the novel polo-like kinase 4 inhibitor CFI-400945 in pancreatic cancer patient-derived xenografts. 2017

Lohse, Ines / Mason, Jacqueline / Cao, Pinjiang Mary / Pintilie, Melania / Bray, Mark / Hedley, David W. ·Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. · Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. ·Oncotarget · Pubmed #27902970.

ABSTRACT: BACKGROUND: Polo-like kinase 4 (PLK4) plays a key role in centriole replication. Hence PLK4 inhibition disrupts mitosis, and offers a novel approach to treating chromosomally unstable cancers, including pancreatic cancer. CFI-400945 is a first in class small molecule PLK4 inhibitor, currently undergoing early phase clinical trials. RESULTS: Treatment with CFI-400945 significantly reduced tumor growth and increased survival in four out of the six models tested. Consistent with PLK4 inhibition, we observed reduced expression of the proliferation marker Ki-67 associated with an increase in nuclear diameter during treatment with CFI-400945. Additionally, treatment with CFI-400945 resulted in a significant reduction of tumor-initiating cells. DISCUSSION: These results support the further investigation of PLK4 as a drug target in pancreatic cancer. METHODS: Sensitivity to CFI-400945 was tested in a series of six patient-derived pancreatic cancer xenografts, selected to represent the range of growth characteristics, genetic features, and hypoxia found in pancreatic cancer patients.

13 Article Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma. 2017

Connor, Ashton A / Denroche, Robert E / Jang, Gun Ho / Timms, Lee / Kalimuthu, Sangeetha N / Selander, Iris / McPherson, Treasa / Wilson, Gavin W / Chan-Seng-Yue, Michelle A / Borozan, Ivan / Ferretti, Vincent / Grant, Robert C / Lungu, Ilinca M / Costello, Eithne / Greenhalf, William / Palmer, Daniel / Ghaneh, Paula / Neoptolemos, John P / Buchler, Markus / Petersen, Gloria / Thayer, Sarah / Hollingsworth, Michael A / Sherker, Alana / Durocher, Daniel / Dhani, Neesha / Hedley, David / Serra, Stefano / Pollett, Aaron / Roehrl, Michael H A / Bavi, Prashant / Bartlett, John M S / Cleary, Sean / Wilson, Julie M / Alexandrov, Ludmil B / Moore, Malcolm / Wouters, Bradly G / McPherson, John D / Notta, Faiyaz / Stein, Lincoln D / Gallinger, Steven. ·PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada5Department of Statistical Science, University of Toronto, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada6Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · University of Liverpool, Liverpool, England. · Heidelberg University Hospital, Heidelberg, Germany. · Mayo Clinic, Rochester, Minnesota. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts. · University of Nebraska Medical Centre, Omaha, Nebraska. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. · Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada16Department of Pathology, University Health Network, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada18BioSpecimen Sciences Program, University Health Network, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico20Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico. · Department of Pathology, University Health Network, Toronto, Ontario, Canada. · Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. ·JAMA Oncol · Pubmed #27768182.

ABSTRACT: Importance: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. Objective: To classify PDAC according to distinct mutational processes, and explore their clinical significance. Design, Setting, and Participants: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens. Main Outcomes and Measures: Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies. Results: The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes-BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2,3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens. Conclusions and Relevance: Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.

14 Article Effects of Combined Treatment with Ionizing Radiation and the PARP Inhibitor Olaparib in BRCA Mutant and Wild Type Patient-Derived Pancreatic Cancer Xenografts. 2016

Lohse, Ines / Kumareswaran, Ramya / Cao, Pinjiang / Pitcher, Bethany / Gallinger, Steven / Bristow, Robert G / Hedley, David W. ·Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. · Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada. · Translational Research Initiative in Pancreas Cancer, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. · Department of Medical Oncology and Haematology, Princess Margaret Cancer Center, Toronto, Ontario, Canada. ·PLoS One · Pubmed #28033382.

ABSTRACT: BACKGROUND: The BRCA2 gene product plays an important role in DNA double strand break repair. Therefore, we asked whether radiation sensitivity of pancreatic cancers developing in individuals with germline BRCA2 mutations can be enhanced by agents that inhibit poly (ADP-ribose) polymerase (PARP). METHODS: We compared the sensitivity of two patient-derived pancreatic cancer xenografts, expressing a truncated or wild type BRCA 2, to ionizing radiation alone or in combination with olaparib (AZD-2281). Animals were treated with either a single dose of 12Gy, 7 days of olaparib or 7 days of olaparib followed by a single dose of 12Gy. Response was assessed by tumour growth delay and the activation of damage response pathways. RESULTS: The BRCA2 mutated and wild type tumours showed similar radiation sensitivity, and treatment with olaparib did not further sensitize either model when compared to IR alone. CONCLUSIONS: While PARP inhibition has been shown to be effective in BRCA-mutated breast and ovarian cancers, it is less well established in pancreatic cancer patients. Our results show no radiosensitization in a germline BRCA 2 mutant and suggest that combining PARP inhibition and IR may not be beneficial in BRCA 2 related pancreatic tumors.

15 Article Biodistribution of cisplatin revealed by imaging mass cytometry identifies extensive collagen binding in tumor and normal tissues. 2016

Chang, Qing / Ornatsky, Olga I / Siddiqui, Iram / Straus, Rita / Baranov, Vladimir I / Hedley, David W. ·Fluidigm Canada Inc., 1380 Rodick Road, Markham, Ontario L3R 4G5, Canada. · Department of Pathology, Hospital for Sick Children, 555 University Avenue, Ontario M5G 1X8, Canada. · Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. ·Sci Rep · Pubmed #27812005.

ABSTRACT: Imaging mass cytometry was used for direct visualization of platinum localization in tissue sections from tumor and normal tissues of cisplatin-treated mice bearing pancreas cancer patient-derived xenografts. This recently-developed technology enabled simultaneous detection of multiple markers to define cell lineage, DNA damage response, cell proliferation and functional state, providing a highly detailed view of drug incorporation in tumor and normal tissues at the cellular level. A striking and unanticipated finding was the extensive binding of platinum to collagen fibers in both tumor and normal mouse tissues. Time course experiments indicated the slow release of stroma-bound platinum, although it is currently unclear if released platinum retains biological activity. Imaging mass cytometry offers a unique window into the in vivo effects of platinum compounds, and it is likely that this can be extended into the clinic in order to optimize the use of this important class of agent.

16 Article Quantifying hypoxia in human cancers using static PET imaging. 2016

Taylor, Edward / Yeung, Ivan / Keller, Harald / Wouters, Bradley G / Milosevic, Michael / Hedley, David W / Jaffray, David A. ·Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Techna Institute, University Health Network, Toronto, Canada. ·Phys Med Biol · Pubmed #27779123.

ABSTRACT: Compared to FDG, the signal of

17 Article Porphysome nanoparticles for enhanced photothermal therapy in a patient-derived orthotopic pancreas xenograft cancer model: a pilot study. 2016

MacLaughlin, Christina M / Ding, Lili / Jin, Cheng / Cao, Pingjiang / Siddiqui, Iram / Hwang, David M / Chen, Juan / Wilson, Brian C / Zheng, Gang / Hedley, David W. ·University Health Network, Princess Margaret Cancer Center, 101 College Street, Toronto, Ontario M5G 1L7, CanadabUniversity of Toronto, Department of Medical Biophysics, 101 College Street, Toronto, Ontario M5G 1L7, CanadacPrincess Margaret Hospital, Department of Medical Oncology and Hematology, 610 University Avenue, Toronto, Ontario M5T 2M9, Canada. · University Health Network, Princess Margaret Cancer Center, 101 College Street, Toronto, Ontario M5G 1L7, Canada. · University Health Network, Princess Margaret Cancer Center, 101 College Street, Toronto, Ontario M5G 1L7, CanadabUniversity of Toronto, Department of Medical Biophysics, 101 College Street, Toronto, Ontario M5G 1L7, CanadadUniversity of Toronto, Department of Pharmaceutical Sciences, 144 College Street, Toronto, Ontario M5T 2M9, Canada. · University Health Network, Department of Pathology, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada. ·J Biomed Opt · Pubmed #27552306.

ABSTRACT: Local disease control is a major challenge in pancreatic cancer treatment, because surgical resection of the primary tumor is only possible in a minority of patients and radiotherapy cannot be delivered in curative doses. Despite the promise of photothermal therapy (PTT) for focal ablation of pancreatic tumors, this approach remains underinvestigated. Using photothermal sensitizers in combination with laser light irradiation for PTT can result in more efficient conversion of light energy to heat and improved spatial confinement of thermal destruction to the tumor. Porphysomes are self-assembled nanoparticles composed mainly of pyropheophorbide-conjugated phospholipids, enabling the packing of ∼80,000 porphyrin photosensitizers per particle. The high-density porphyrin loading imparts enhanced photonic properties and enables high-payload tumor delivery. A patient-derived orthotopic pancreas xenograft model was used to evaluate the feasibility of porphysome-enhanced PTT for pancreatic cancer. Biodistribution and tumor accumulation were evaluated using fluorescence intensity measurements from homogenized tissues and imaging of excised organs. Tumor surface temperature was recorded using IR optical imaging during light irradiation to monitor treatment progress. Histological analyses were conducted to determine the extent of PTT thermal damage. These studies may provide insight into the influence of heat-sink effect on thermal therapy dosimetry for well-perfused pancreatic tumors.

18 Article Novel regulatory role of neuropilin-1 in endothelial-to-mesenchymal transition and fibrosis in pancreatic ductal adenocarcinoma. 2016

Matkar, Pratiek N / Singh, Krishna Kumar / Rudenko, Dmitriy / Kim, Yu Jin / Kuliszewski, Michael A / Prud'homme, Gerald J / Hedley, David W / Leong-Poi, Howard. ·Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada. · Institute of Medical Science, University of Toronto, Toronto, Canada. · Division of Vascular Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada. · Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada. · Division of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada. · Division of Medical Oncology and Hematology, Ontario Cancer Institute, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, Toronto, Canada. ·Oncotarget · Pubmed #27542226.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an intense fibrotic reaction termed tumor desmoplasia, which is in part responsible for its aggressiveness. Endothelial cells have been shown to display cellular plasticity in the form of endothelial-to-mesenchymal transition (EndMT) that serves as an important source of fibroblasts in pathological disorders, including cancer. Angiogenic co-receptor, neuropilin-1 (NRP- 1) actively binds TGFβ1, the primary mediator of EndMT and is involved in oncogenic processes like epithelial-to-mesenchymal transition (EMT). NRP-1 and TGFβ1 signaling have been shown to be aberrantly up-regulated in PDAC. We report herein a positive correlation between NRP-1 levels, EndMT and fibrosis in human PDAC xenografts. Loss of NRP-1 in HUVECs limited TGFβ1-induced EndMT as demonstrated by gain of endothelial and loss of mesenchymal markers, while maintaining endothelial cell architecture. Knockdown of NRP-1 down-regulated TGFβ canonical signaling (pSMAD2) and associated pro-fibrotic genes. Overexpression of NRP-1 exacerbated TGFβ1-induced EndMT and up-regulated TGFβ signaling and expression of pro-fibrotic genes. In vivo, loss of NRP-1 attenuated tumor perfusion and size, accompanied by reduction in EndMT and fibrosis. This study defines a previously unrecognized role of NRP-1 in regulating TGFβ1-induced EndMT and fibrosis, and advocates NRP-1 as a therapeutic target to reduce tumor fibrosis and PDAC progression.

19 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.

20 Article Targeting hypoxic microenvironment of pancreatic xenografts with the hypoxia-activated prodrug TH-302. 2016

Lohse, Ines / Rasowski, Joanna / Cao, Pinjiang / Pintilie, Melania / Do, Trevor / Tsao, Ming-Sound / Hill, Richard P / Hedley, David W. ·Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. · Department of Radiation Medicine Program, Toronto, Ontario, Canada. · Department of STTARR Innovation Center, Toronto, Ontario, Canada. · Department of Pathology, University Health Network, Toronto, Ontario, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. · Department of Medical Biophysics, Toronto, Ontario, Canada. · Department of Radiation Oncology, Toronto, Ontario, Canada. · Department of Medicine, University of Toronto, Toronto, Ontario, Canada. · Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. ·Oncotarget · Pubmed #27248663.

ABSTRACT: Previous reports have suggested that the hypoxic microenvironment provides a niche that supports tumor stem cells, and that this might explain clinical observations linking hypoxia to metastasis. To test this, we examined the effects of a hypoxia-activated prodrug, TH-302, on the tumor-initiating cell (TIC) frequency of patient-derived pancreatic xenografts (PDX).The frequencies of TIC, measured by limiting dilution assay, varied widely in 11 PDX models, and were correlated with rapid growth but not with the levels of hypoxia. Treatment with either TH-302 or ionizing radiation (IR), to target hypoxic and well-oxygenated regions, respectively, reduced TIC frequency, and the combination of TH-302 and IR was much more effective in all models tested. The combination was also more effective than TH-302 or IR alone controlling tumor growth, particularly treating the more rapidly-growing/hypoxic models. These findings support the clinical utility of hypoxia targeting in combination with radiotherapy to treat pancreatic cancers, but do not provide strong evidence for a hypoxic stem cell niche.

21 Article Cytokinetic effects of Wee1 disruption in pancreatic cancer. 2016

Chang, Qing / Chandrashekhar, Megha / Ketela, Troy / Fedyshyn, Yaroslav / Moffat, Jason / Hedley, David. ·a Ontario Cancer Institute/Princess Margaret Cancer Center , Toronto , Ontario , Canada. · b Donnelly Centre for Cellular and Biomolecular Research, Department of Molecular Genetics , University of Toronto , Toronto , Ontario , Canada. ·Cell Cycle · Pubmed #26890070.

ABSTRACT: The Wee1 kinase, which is activated in response to DNA damage, regulates exit from G2 through inhibitory phosphorylation of Cdk1/Cdc2, and is an attractive drug target. However, recent work has highlighted effects of Cdk2 phosphorylation by Wee1 on movement through S-phase, suggesting the potential to sensitize to S-phase specific agents by Wee1 inhibitors. In this paper we applied multiparametric flow cytometry to patient-derived pancreatic cancer xenograft tumor cells to study the cell cycle perturbations of Wee1 disruption via the small molecule inhibitor MK-1775, and genetic knockdown. We find that in vitro treatment with MK-1775, and to a lesser degree, Wee1 RNA transcript knockdown, results in the striking appearance of S-phase cells prematurely entering into mitosis. This effect was not seen in vivo in any of the models tested. Here, although we noted an increase of S-phase cells expressing the damage response marker γH2AX, treatment with MK-1775 did not significantly sensitize cells to the cytidine analog gemcitabine. Treatment with MK-1775 did result in a transient but large increase in cells expressing the mitotic marker phosphorylated H3S10 that reached a peak 4 hours after treatment. This suggests a role for Wee1 regulating the progression of genomically unstable cancer cells through G2 in the absence of extrinsically-applied DNA damage. A single dose of 8Gy ionizing radiation resulted in the time-dependent accumulation of Cyclin A2 positive/phosphorylated H3S10 negative cells at the 4N position, which was abrogated by treatment with MK-1775. Consistent with these findings, a genome-scale pooled RNA interference screen revealed that toxic doses of MK-1775 are suppressed by CDK2 or Cyclin A2 knockdown. These findings support G2 exit as the more significant effect of Wee1 inhibition in pancreatic cancers.

22 Article Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on 18F-Fluoroazomyin Arabinoside Uptake. 2016

Metran-Nascente, Cristiane / Yeung, Ivan / Vines, Douglass C / Metser, Ur / Dhani, Neesha C / Green, David / Milosevic, Michael / Jaffray, David / Hedley, David W. ·Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; and. · Department of Medical Imaging, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada david.hedley@uhn.ca. ·J Nucl Med · Pubmed #26769863.

ABSTRACT: METHODS: We tested the potential for minimally invasive imaging of hypoxia in pancreatic cancer patients, using the 2-nitroimidazole PET tracer (18)F-fluoroazomycin arabinoside (or (18)F-1-α-D-[5-fluoro-5-deoxyarabinofuranosyl]-2-nitroimidazole [(18)F-FAZA]). Dynamic and static scans were obtained in 21 patients with either locally advanced or metastatic disease. The hypoxic fraction was determined in the 2-h static scans as the percentage of voxels with SUVs more than 3 SDs from the mean values obtained for skeletal muscle. RESULTS: Hypoxia was detected in 15 of 20 evaluable patients, with the hypoxic fraction ranging from less than 5% to greater than 50%. Compartmental analysis of the dynamic scans allowed us to approximate the tumor perfusion as mL/min/g of tissue, a value that is independent of the extent of hypoxia derived from tracer uptake in the 2-h static scan. There was no significant correlation between tumor perfusion and hypoxia; nor did we see an association between tumor volume and hypoxia. CONCLUSION: Although pancreatic cancers can be highly hypoxic, a substantial proportion appears to be well oxygenated. Therefore, we suggest that a minimally invasive technique such as the one described in this study be used for patient stratification in future clinical trials of hypoxia-targeting agents.

23 Article BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts. 2015

Lohse, I / Borgida, A / Cao, P / Cheung, M / Pintilie, M / Bianco, T / Holter, S / Ibrahimov, E / Kumareswaran, R / Bristow, R G / Tsao, M-S / Gallinger, S / Hedley, D W. ·Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9. · Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9. · 1] Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9 [2] Translational Research Initiative in Pancreas Cancer, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 2M9. · 1] Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 [2] Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9. · 1] Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 [2] Department of Pathology, University Health Network, Toronto, Ontario, Canada M5G 2M9 [3] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5G 2M9. · 1] Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 [2] Translational Research Initiative in Pancreas Cancer, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 2M9 [3] Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada M5G 2M9. ·Br J Cancer · Pubmed #26180923.

ABSTRACT: BACKGROUND: Germline mutations of the BRCA tumour suppressors have been associated with increased risk of pancreatic cancer. Clinical evidence suggests that these patients may be more sensitive to treatment with cisplatin. As the frequency of germline BRCA mutations is low, definitive experimental data to support the clinical observations are still missing. METHODS: We tested gemcitabine and cisplatin sensitivity of four BRCA1 and BRCA2 mutant and three BRCA1 and BRCA2 wild-type (WT) patient-derived pancreatic cancer xenografts. RESULTS: We observed treatment sensitivity to gemcitabine and cisplatin in the BRCA WT and mutant models. The BRCA1 and BRCA2 mutant xenografts were significantly more sensitive to cisplatin although these models also showed sensitivity to gemcitabine. The BRCA1 and BRCA2 WT models showed sensitivity to gemcitabine but not cisplatin. Treatment sensitivity in the xenograft models closely resembled treatment response in the corresponding patients. DISCUSSION: We have characterised a panel of xenografts derived from pancreatic cancer patients carrying germline BRCA mutations, and shown that their genetic features resemble the patient donor. Our results support further clinical testing of treatment regimens combining gemcitabine and platinum drugs in this patient population, as well as preclinical research aiming to identify mechanisms of cisplatin resistance in BRCA mutant pancreatic cancers.

24 Article Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma. 2015

Holter, Spring / Borgida, Ayelet / Dodd, Anna / Grant, Robert / Semotiuk, Kara / Hedley, David / Dhani, Neesha / Narod, Steven / Akbari, Mohammad / Moore, Malcolm / Gallinger, Steven. ·Spring Holter, Ayelet Borgida, Robert Grant, Kara Semotiuk, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital · Anna Dodd, David Hedley, Neesha Dhani, Malcolm Moore, and Steven Gallinger, McCain Pancreatic Cancer Centre, University Health Network · and Steven Narod and Mohammad Akbari, Women's College Research Institute, Toronto, Ontario, Canada. ·J Clin Oncol · Pubmed #25940717.

ABSTRACT: PURPOSE: The main purpose of this study was to determine the prevalence of pathogenic BRCA1 and BRCA2 mutations in a consecutively ascertained clinic-based cohort of patients with pancreatic ductal adenocarcinoma and describe the clinical and family history characteristics. PATIENTS AND METHODS: Unselected, consecutive, incident patients with pancreatic ductal adenocarcinoma were recruited at a single cancer center over a 2-year period. Participants provided blood for DNA analysis and cancer family history, and cancer treatment records were reviewed. DNA from all patients was analyzed by Sanger sequencing and multiplex ligation-dependent probe amplification for germline variants in BRCA1 and BRCA2. RESULTS: Three hundred six patients were eligible for analysis. Pathogenic germline BRCA mutations were identified in 14 patients (4.6%; 95% CI, 2.2% to 6.9%), including 11 patients with a BRCA2 mutation and three patients with a BRCA1 mutation. Having a cancer family history that met genetic testing criteria of the National Comprehensive Cancer Network or the Ontario Ministry of Health and Long-Term Care or self-reporting as Ashkenazi Jewish was significantly associated with BRCA mutation carrier status (P=.02, P<.001, and P=.05, respectively). However, the majority of the BRCA mutation-positive patients did not actually meet these genetic testing criteria. CONCLUSION: Pathogenic BRCA mutations were identified in 4.6% of a large cohort of clinic-based patients. Considering the implications for family members of BRCA carriers, and possibly tailored chemotherapeutic treatment of patients, our finding has implications for broader BRCA genetic testing for patients with pancreatic ductal adenocarcinoma.

25 Article Targeting of metastasis-promoting tumor-associated fibroblasts and modulation of pancreatic tumor-associated stroma with a carboxymethylcellulose-docetaxel nanoparticle. 2015

Ernsting, Mark J / Hoang, Bryan / Lohse, Ines / Undzys, Elijus / Cao, Pinjiang / Do, Trevor / Gill, Bethany / Pintilie, Melania / Hedley, David / Li, Shyh-Dar. ·Drug Discovery Program, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada; Faculty of Engineering and Architectural Science, Ryerson University, Toronto, Ontario M5B 1Z2, Canada. · Drug Discovery Program, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada. · Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, Ontario M5G 2M9, Canada. · Spatio-Temporal Targeting and Amplification of Radiation Response (STTARR) Program, Princess Margaret Hospitals Radiation Medicine Program, Toronto, Ontario M5G 2M9, Canada. · Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, Ontario M5G 2M9, Canada; Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Drug Discovery Program, Ontario Institute for Cancer Research, 101 College Street, Suite 800, Toronto, Ontario M5G 0A3, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address: shyh-dar.li@ubc.ca. ·J Control Release · Pubmed #25804872.

ABSTRACT: Pancreatic ductal adenocarcinomas are characterized by the desmoplastic reaction, a dense fibrous stroma that has been shown to be supportive of tumor cell growth, invasion, and metastasis, and has been associated with resistance to chemotherapy and reduced patient survival. Here, we investigated targeted depletion of stroma for pancreatic cancer therapy via taxane nanoparticles. Cellax-DTX polymer is a conjugate of docetaxel (DTX), polyethylene glycol (PEG), and acetylated carboxymethylcellulose, a construct which condenses into well-defined 120nm particles in an aqueous solution, and is suitable for intravenous injection. We examined Cellax-DTX treatment effects in highly stromal primary patient-derived pancreatic cancer xenografts and in a metastatic PAN02 mouse model of pancreatic cancer, focusing on specific cellular interactions in the stroma, pancreatic tumor growth and metastasis. Greater than 90% of Cellax-DTX particles accumulate in smooth muscle actin (SMA) positive cancer-associated fibroblasts which results in long-term depletion of this stromal cell population, an effect not observed with Nab-paclitaxel (Nab-PTX). The reduction in stromal density leads to a >10-fold increase in tumor perfusion, reduced tumor weight and a reduction in metastasis. Consentingly, Cellax-DTX treatment increased survival when compared to treatment with gemcitabine or Nab-PTX in a metastatic PAN02 mouse model. Cellax-DTX nanoparticles interact with the tumor-associated stroma, selectively interacting with and depleting SMA positive cells and macrophage, effects of which are associated with significant changes in tumor progression and metastasis.

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