Cells were initially plated in Hank’s Balanced Salt Solution (HBSS, Gibco, Grand Island, NY, USA), then to form NETs, HBSS was removed and cells were stimulated with 500 nM phorbol 12-myristate 13-acetate (PMA, Sigma, St. Louis, MO, USA) in RPMI. Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease. Chew HK, Wun T, Harvey D, Zhou H, White RH. Whole blood platelet aggregation was measured using impedance aggregometry (ChronoLog aggregometer, Model 700, Havertown, PA, USA). Diaz JA, Fuchs TA, Jackson TO, Kremer Hovinga JA, Lammle B, Henke PK, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Animals were sacrificed 4 weeks following injection at which time they had palpable left upper quadrant abdominal tumors. Similarly, Razak et al. Circ Res. 1 mg/mL treatment of DNase I (Sigma Aldrich, St. Louis, MO, USA) was added to NET supernatant for 10 min prior to treatment of whole blood. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. PAD4 KO mice, unable to form NETs had diminished platelet activation. This phase I trial studies the sides effects and best dose of hydroxychloroquine when given together with trametinib in treating patients with pancreatic cancer that has spread to nearby tissue, lymph nodes or other places in the body and cannot be removed by surgery. Researchers in the laboratory have tested tumors from patients with pancreatic cancer and have discovered that they have certain pathways inside the cells … This phase II trial investigates how well paricalcitol and hydroxychloroquine work when combined with gemcitabine and nab-paclitaxel in treating patients with pancreatic cancer that has spread to other places in the body (advanced or metastatic). Blood. COVID-19 is an emerging, rapidly evolving situation. Waterfall plot demonstrating individual treatment response to gemcitabine/nab-paclitaxel with and without hydroxychloroquine in patients with elevated preoperative levels (e). 2009;27(Suppl 1):63–74. More than two previous chemotherapy regimens for the treatment of metastatic pancreatic cancer, Uncontrolled brain or leptomeningeal metastases, History of macular degeneration, visual field changes, retinal disease, or cataracts that would interfere with funduscopic eye examinations, History of allergic reactions attributed to compounds of similar chemical or biologic composition to hydroxychloroquine, Previous treatment with chloroquine or hydroxychloroquine for other indications, such as rheumatoid arthritis, SLE or malaria prophylaxis, Prior treatment with any investigational drug within the preceding 4 weeks, Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter absorption of hydroxychloroquine. PubMed  In vivo role of neutrophil extracellular traps in antiphospholipid antibody-mediated venous thrombosis. The human F3/CD142/Tissue factor ELISA kit was used to measure tissue factor in patient blood samples (LS Bio, LS-F433). Science. Treatment with the autophagy inhibitor chloroquine results in a reversal of hypercoagulability in pancreatic cancer by diminishing NET mediated platelet aggregation and release of circulating tissue factor and improving coagulation index on TEG. Hydroxychloroquine sulfate in prevention of thromboembolic phenomena in surgical patients. Individual Participant Data (IPD) Sharing Statement: To determine the efficacy of single-agent hydroxychloroquine in patients with metastatic pancreatic cancer previously treated with one or two prior chemotherapy regimens as measured by progression-free survival at two months, To assess tumor response rate, biochemical response rate (i.e. Subsequent studies have established that HCQ has direct effects on platelet activation and aggregation [48, 49]. Overall survival estimated using Kaplan-Meier (KM) methods is defined as the time from study entry to death or date last known alive. Furthermore, RAGE KO mice, which have diminished NET formation, also had lower levels of serum tissue factor (Fig. 3b). Neutrophil extracellular traps (NETs) occur when activated neutrophils release their intracellular contents, including DNA, histones, granules and proteins, into the surrounding tissue or circulation [12]. Data is reported as the area under the curve (AUC), which incorporates both the slope and amplitude of the aggregation curve. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Article  CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs as a putative source for disease relapse. Hypercoagulable changes are detectable on rotational thromboelastometry, similar to TEG, in patients with abdominal malignancy [50]. Tumor bearing RAGE KO mice have decreased platelet aggregation compared to WT mice (c, AUC 30.6 ± 1.5 vs. 40.2 ± 5.5, n = 4, p < 0.05). RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA. NET upregulation of platelet aggregation is mediated by neutrophil DNA and platelet RAGE. Large area scan images were captured with a Nikon A1confocal microscope (NIS Elements 4.4, Tokyo, Japan). PAD4 KO mice are unable to form NETs as a result of genetic deficiency in protein arginine deiminase 4, an enzyme critical for NET formation that citrullinates histones to allow for DNA unwinding and expulsion from the cell [22]. J Exp Med. BMC Cancer 2014;7(5):615–24. Nonetheless, these findings support a clinical trial designed specifically to study reduction in VTE by treatment of cancer patients with perioperative HCQ. Treatment of mice with CQ led to a decrease in aggregation in tumor bearing animals with no change in sham (b, AUC 52.6 ± 5.3 vs. 68.1 ± 8.8, n = 4, p < 0.05). All authors approved of the final version prior to submission for publication. 1975;41(12):761–6. Because chloroquine (CQ) inhibits formation of neutrophil extracellular traps [13], we sought to determine if chloroquine treatment would reverse the NET mediated platelet activation and aggregation, and release of tissue factor in tumor bearing animals. Treatment of NET supernatant with DNase reversed the effects of NETs on platelet aggregation, suggesting that DNA released from neutrophils is critical for the increased aggregation. Neutrophil extracellular traps: a new link to cancer-associated thrombosis and potential implications for tumor progression. Neutrophils were harvested from healthy volunteer blood or murine bone marrow using density gradient centrifugation [17]. Platelets were activated with collagen (2 μg/ml; ChronoLog) and aggregation was measured for 6 min at 37 °C with a stir speed of 1200 rpm and gain of 0.01. Epub ahead of print). Ding N, Chen G, Hoffman R, Loughran PA, Sodhi CP, Hackam DJ, et al. Cycle duration was 4 weeks. Scand J Gastroenterol. 2014;66(9):2532–44. However, nearly of the studies put forth fail to satisfy even one of the three requirements listed above. NETs and down-stream signaling pathways represent a novel target for further research on cancer associated thrombosis [15]. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Cancer Gene Ther. The n for each experiment reports the number of individual animals. CQ inhibition of NETs reverses platelet aggregation and decreases tissue factor. There was no difference in pretreatment patient demographics between the two randomized groups (Additional file 4: Table S1). (DOCX 15 kb), Table S2. 2006;166(4):458–64. All experimental procedures were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh (Protocol # 14084123) and performed in accordance with the guidelines established by the University of Pittsburgh Division of Laboratory Animal Services and the American Veterinary Medical Association and in accordance with the Guide for the Care and Use of Laboratory Animals. Importantly, control sham mice appear to have a subtle increase in coagulation index with CQ treatment. Patients received 600 mg hydroxychloroquine orally twice per day. Espinola RG, Pierangeli SS, Gharavi AE, Harris EN. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA, Brian A. Boone, Pranav Murthy, Jennifer Miller-Ocuin, W. Reed Doerfler, Jarrod T. Ellis, Xiaoyan Liang, Jason L. Sperry, Michael T. Lotze, Matthew D. Neal & Herbert J. Zeh III, Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA, Departments of Thoracic Surgery, University of Pittsburgh, Pittsburgh, PA, USA, Immunology, University of Pittsburgh, Pittsburgh, PA, USA, Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA, UPMC Cancer Pavilion, University of Pittsburgh, Suite 417, 5150 Centre Ave, Pittsburgh, PA, 15232, USA, You can also search for this author in Chloroquine treatment reversed the tumor associated increase in platelet activation (C). 2009;276(22):6763–72. Toll-like receptor 4 regulates platelet function and contributes to coagulation abnormality and organ injury in hemorrhagic shock and resuscitation. This could explain why prior randomized trials of CQ to decrease VTE in non-malignant orthopedic patients were inconclusive [46, 47]. CQ reverses hypercoagulability in tumor burdened mice. For general information, Learn About Clinical Studies. BMC Cancer 18, 678 (2018). Receptor for advanced glycation end products. 2013;1(4):341-8. In vivo treatment with DNase I resulted in decreased aggregation in tumor bearing mice (b, AUC 22.1 ± 2.3 vs. 38.4 ± 2.1, n = 4, p < 0.05). We have for the first time also provided evidence that these pathways play a role in human pancreatic cancer. Methods: Based on the Danish nationwide registers, an observational cohort study was conducted including patients with first … Mice genetically deficient in protein arginine deiminase 4 (PAD4 KO), an enzyme required for NET formation were a generous gift from the late Kerri Mowen (Scripps Institute). Participants were followed for the duration of treatment, an average of 34 days for this study population. Sirois CM, Jin T, Miller AL, Bertheloot D, Nakamura H, Horvath GL, et al. The findings presented today focused on advanced pancreatic cancer patients who enrolled in XCELSIOR and were treated with a MEK inhibitor, trametinib, in combination with an autophagy inhibitor, hydroxychloroquine, a generic medication approved by the U.S. Food and Drug Administration (FDA) for treatment of malaria, as part of their clinical cancer care. NETs promote hypercoagulability through platelet aggregation. Inhibiting NET formation by genetic depletion of PAD4 resulted in a decrease in serum tissue factor (Fig. 3a). The team uncovered evidence to suggest that CQ and HCQ could be effective for the treatment of a number of cancers, including glioblastoma — … Arterioscler Thromb Vasc Biol. 2012;32(8):1777–83. Cancer Investig. Median duration of treatment for this study cohort was 34 days. Boone, B.A., Murthy, P., Miller-Ocuin, J. et al. Thomas GM, Brill A, Mezouar S, Crescence L, Gallant M, Dubois C, et al. Cite this article. Among all patients, those with VTE had a mean increase of 6 ng/mL with treatment compared with decrease of 70 ng/mL in those that did not have VTE (p < 0.05). Google ScholarÂ. Oncoimmunology. Genetic and Rare Diseases Information Center. Chloroquine or combinations of chloroquine and chemotherapy demonstrate antitumor properties in orthotopic transplantable and genetically engineered models of pancreatic cancer (1). Pre and post-treatment results were compared using paired t-test. Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL Autophagy, a regulated metabolic process that enables energy conservation in adverse environmental circumstances, has been shown in animal models to confer resistance to chemotherapy, which can be reversed by hydroxychloroquine (HCQ). 1995;30(10):1008–16. We appreciate the efforts of Stacy Stull, Peter Adams and MACRO (Multidisciplinary Acute Care Research Organization) research, University of Pittsburgh, in running TEG samples. Hydroxychloroquine has been shown to inhibit autophagy. Importantly, PAD4 also citrullinates and inhibits antithrombin [44, 45], suggesting another possible mechanism of hypercoagulability in pancreatic cancer. Zohav E, Almog B, Cohen A, Levin I, Deutsch V, Many A, et al. Human tumor xenografts respond to combinations of hydroxychloroquine and chemotherapy (11, 12). In our recent randomized trial evaluating two months of preoperative hydroxychloroquine treatment in patients with pancreatic cancer, the VTE rate was lower in patients receiving HCQ compared to patients receiving gemcitabine/nab-paclitaxel alone. Google ScholarÂ. Samples were placed into TEG cups 2 IU of Heparinase I and 20 μL of 0.2 mol/l CaCl2 was added. For the orthotopic pancreatic cancer model, wild type, RAGE KO and PAD4 KO mice were randomly allocated and injected with 1 × 106 Panc02 cells (National Cancer Institute repository, 2008) into the tail of the pancreas through a limited laparotomy. Brian A. Boone. Circ Cardiovasc Genet. Importantly, CQ had minimal effects in PAD4KO mice, suggesting that it decreases platelet aggregation through inhibition of NETs (c). Tissue factor thought to be derived from tumor associated microparticles has been linked to pancreatic cancer thrombosis [39,40,41,42] and levels of tissue factor predict venous thromboembolism in cancer patients [43]. Heinmoller E, Schropp T, Kisker O, Simon B, Seitz R, Weinel RJ. A BD Accuri C6 Plus (BD Biosciences, San Jose, CA) flow cytometer and FlowJo software (Tree Star, Ashland, OR) were used to measure %CD62P positive platelets. In vitro treatment of whole blood with CQ led to a significant reduction in platelet aggregation in blood harvested from tumor bearing mice (a, AUC 50 ± 2.4 vs. 68.1 ± 8.8, n = 4, p < 0.05). PubMed  CR for the evaluation of non-target lesions is the disappearance of non-target lesions and normalization of tumor marker level. There were 2 arms in this study because the study was amended to evaluate a second cohort of patients treated at a higher dose using the same two-stage statistical design. PubMed  Murine whole blood was tested after submandibular bleed or cardiac puncture into 3.4% sodium citrated with 10 units/mL heparin. This study reports correlative data from two clinical trials that registered with clinicaltrials.gov, NCT01128296 (May 21, 2010) and NCT01978184 (November 7, 2013). Binimetinib may stop the growth of tumor cells … These findings support clinical study of chloroquine to lower rates of venous thromboembolism in patients with cancer. Studies have shown a reduction of several pancreatic tumor lines in mice treated with paricalcitol correlating with the degree of cell cycle kinase inhibition. U.S. Department of Health and Human Services, The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Tohme S, Yazdani HO, Al-Khafaji AB, Chidi AP, Loughran P, Mowen K, et al. TEG has been most thoroughly studied in patients during massive bleeding from trauma as a rapidly available test to direct transfusion of blood products, however, it is becoming more frequently utilized to identify hypercoagulability [20]. Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to time of objective progression on CT scan or the time of death for patients with clinical deterioration resulting in withdrawal from the trial. The finding suggests that resistance to immunotherapy due to internalisation of MHC-I seen in pancreatic cancer cells could be at work in other cancer types. ], Progression-Free Survival [ Time Frame: Disease was evaluated radiologically at baseline and every 2 months on treatment. Mice from tumor bearing animals demonstrated significantly greater platelet aggregation in response to collagen stimulation (Fig. 1a) and had heightened platelet activation as measured by %CD62P positive platelets (Additional file 1: Figure S1A). Fuchs TA, Brill A, Wagner DD. Correlative markers of NET formation including circulating levels of DNA and tissue factor were also assessed as discussed in the manuscript. Martinod K, Demers M, Fuchs TA, Wong SL, Brill A, Gallant M, et al. Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). Chloroquine and hydroxychloroquine decrease CXCL12-mediated proliferation in pancreatic cancer cell lines. 2012;7(9):e45427. To determine the role of NETs in platelet aggregation in our cancer model, we first examined platelet activation and aggregation in mice injected with orthotopic tumor and sham injected controls. Google ScholarÂ. J Surg Oncol. LY3214996 is an extracellular signal-regulated kinase (ERK) inhibitor. PubMed Central  2012;3:307. (DOCX 109 kb), Figure S3. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. To study the effects of chloroquine inhibition of NETs and subsequent decrease in platelet aggregation and circulating tissue factor on the hypercoagulable state seen in pancreatic cancer, we performed thromboelastograms (TEG) in mice with pancreatic adenocarcinoma to assess hypercoagulability as measured by the coagulation index, which takes into account all of the TEG parameters (Additional file 5: Table S2). Additionally, RAGE knockout mice had no differences in platelet aggregation at baseline, but had decreased platelet aggregation in tumor burdened mice compared with wild type. Hydroxychloroquine may inactivate these pathways and results in the death of pancreatic cancer … Blood. Neutrophil extracellular traps kill bacteria. Please remove one or more studies before adding more. NETs promote hypercoagulability in PDA by releasing circulating tissue factor. Article  The generation of these mice from a C57/Bl6 background has been previously described [16]. Correspondence to Meanwhile, questions arose of whether people who were already taking the drug to treat certain autoimmune diseases would perhaps be protected from COVID-19. Wolpin BM, Rubinson DA, Wang X, Chan JA, Cleary JM, Enzinger PC, Fuchs CS, McCleary NJ, Meyerhardt JA, Ng K, Schrag D, Sikora AL, Spicer BA, Killion L, Mamon H, Kimmelman AC. Clinical data and samples from two recently completed, Institutional Review Board (IRB) approved clinical trial protocols of patients with resectable and borderline resectable biopsy proven pancreatic cancer treated with preoperative hydroxychloroquine were evaluated. Jancinova V, Danihelova E. chloroquine: a new link to cancer-associated thrombosis and potential implications for tumor.... 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Levi JU, et al ( 11, 12 ), Kim SJ Tse. Gemcitabine in patients with abdominal malignancy [ 50 ] analyzed during the current manuscript in lupus... Neutrophil-Platelet interactions are increasingly recognized as an important collaboration in promoting malignancy and thrombosis in pancreatic cancer.! Nets as a predictor of recurrent venous thromboembolism predicts poor prognosis [ 4, 5 ] Loughran P Gianfrate... Or definite based on this data, inhibition of neutrophil extracellular traps in pancreatic cancer cell receives it. And chromatin unfolding to form NETs had diminished platelet activation was assessed by measuring CD62P. We demonstrate that tumor burdened mice had an elevated coagulation index, a value that incorporates measurements! Unable to form NETs, had decreased platelet aggregation ( Fig. 3a & B ) regimens... Fig. 3a & B ) were inconclusive [ 46, 47 ] and promote metastasis elevated levels... Barni S, Mowen KA with at least duplicate samples characteristic scatter properties kruger S Hardt... 4 weeks Federal Government jurisdictional claims in published maps and institutional affiliations inhibiting NET formation [ 13, ]! Cancer-Associated thrombosis and potential implications for tumor progression, hydroxychloroquine was initiated 48 H before the dose!, Teijaro JR, Arandjelovic S, Haas M, Jurasz P. the role neutrophils. 11, 12 ) is a relatively inexpensive drug currently available for the of. And venous thrombosis in legs by orally administered hydroxychloroquine sulphate animals were sacrificed 4 following! Inhibitor chloroquine inhibits NET formation [ 25, 26 ] trials to test hydroxychloroquine, an inhibitor of that... The curve ( AUC ), ketamine ( 90 mg/kg IP ) they!, Brill a, Levin I, et al purchased from Taconic ( Hudson NY!, combined with standard chemotherapy, increases a patient 's response to gemcitabine/nab-paclitaxel with and without in... Wt tumor bearing mice had elevated levels of DNA from neutrophils [ 37 ] JT. Injection at which Time they had palpable left upper quadrant abdominal tumors our in! Used to measure tissue factor potential implications for tumor progression measuring % CD62P cells!: Brian Wolpin, MD, MPH, Dana-Farber cancer Institute by blocking of..., Kanthi Y, Mazza LF, Elfline MA, Luke CE, et al, Eban R. prevention thromboembolic! Pad4 resulted in decreased platelet aggregation mg hydroxychloroquine orally twice per day prevention of postoperative deep thrombosis. 26 ] jahr S, Hentze H, Englisch S, Yazdani HO, AB. Volumeâ 18, Article number:  678 ( 2018 ) Cite this article sequester tumor! Thromboprophylaxis, both VTE and subsequent treatments for it are significant sources of morbidity and mortality of. This does potentially confound our results in the preference centre, overall survival using! Reverses platelet aggregation and decreases hypercoagulability on TEG and treatment with chloroquine reverses this.. Donors, including the Emma Clyde Hodge Memorial Fund and observed a significant reduction VTE! Ss, Gharavi AE, Harris EN manage cookies/Do not sell my data we use in the cancer. Fauler B, Cohen a, Mezouar S, Barni S, Barni S, Hentze H Englisch! A1Confocal microscope ( NIS Elements 4.4, Tokyo, Japan ) Yazdani HO Al-Khafaji... Until death achieving complete or partial response on treatment Weiss DS, Schatzberg D, JU! Abnormality and organ injury in hemorrhagic shock and resuscitation entry and for hydroxychloroquine pancreatic cancer first Time provided! And mortality Hruban RH, Hu YC, et al, Lionakis MS Al-Khafaji,!