Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. CAS  This work was supported in part by R01CA181450 from the National Cancer Institute (HJZ and MTL) and by 1R35GM119526–01 (MDN). 2014;7(5):615–24. Neutrophils are also a source of tissue factor, as it is released during NET formation [25, 26]. We appreciate the efforts of Stacy Stull, Peter Adams and MACRO (Multidisciplinary Acute Care Research Organization) research, University of Pittsburgh, in running TEG samples. After establishing safety in a Phase I run-in, 112 patients were … NETs have been linked to thrombosis in autoimmune conditions and sterile inflammation [7, 8] and more recently implicated in cancer associated thrombosis [9,10,11]. © 2020 BioMed Central Ltd unless otherwise stated. Br Med J. Receptor for advanced glycation end products. 2014;73(10):1854–63. 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. Google ScholarÂ. Proc Natl Acad Sci U S A. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, et al. Incidence, outcome and risk stratification tools for venous thromboembolism in advanced pancreatic cancer - a retrospective cohort study. Diaz JA, Fuchs TA, Jackson TO, Kremer Hovinga JA, Lammle B, Henke PK, et al. We have for the first time also provided evidence that these pathways play a role in human pancreatic cancer. Murine whole blood was tested after submandibular bleed or cardiac puncture into 3.4% sodium citrated with 10 units/mL heparin. All together our findings support additional clinical trials with hydroxychloroquine to examine the ability of NET inhibition to lower the venous thromboembolism rate in patients with pancreatic and other cancer types. 2007;18(10):1660–5. 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. CQ treatment led to a decrease in circulating tissue factor in tumor bearing mice (d, 186.9 ± 5.6 vs. 228.2 ± 21 pg/mL, p < 0.05). Median duration of treatment for this study cohort was 34 days. We sought to further elucidate the mechanism of NET mediated hypercoagulability in pancreatic cancer and evaluate the role for NET inhibition with chloroquine in reversing this hypercoagulability. Epub 2014 May 12. The slides were incubated for 1 h at room temperature (RT) with primary antibodies for rabbit anti neutrophil elastase (ab68672, Abcam) at 1:200, sheep anti fibrinogen (ab61352, Abcam) 1:1000, and mouse anti tissue factor (ab17375, Abcam) 1:200, in 0.5% BSA solution. In patients who had elevated levels of pre-treatment tissue factor, HCQ treatment led to a significant reduction, suggesting that the greatest effect of HCQ is seen in patients who may have upregulation of NETs at baseline. Front Immunol. Thromboelastograms (TEGs) were performed to assess hypercoagulability and changes associated with treatment. Chloroquine inhibits NETs and diminishes hypercoagulability. Levels of circulating tissue factor, the initiator of extrinsic coagulation, were measured using ELISA. 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. Demers M, Wong SL, Martinod K, Gallant M, Cabral JE, Wang Y, et al. Google ScholarÂ. PAD4 KO tumor bearing mice demonstrated decreased platelet activation (Additional file 2: Figure S2A) and aggregation compared with WT tumor bearing controls (Fig. 1d). In both trials, hydroxychloroquine was initiated 48 h before the first dose of chemotherapy and continued until the day before surgery. Platelet aggregation was assessed using collagen-activated impedance aggregometry. That's a no. (DOCX 489 kb), Table S1. (DOCX 109 kb), Figure S3. All patients signed informed consent prior to participation in these clinical protocols. Furthermore, staining of resected human pancreatic tumors demonstrated focal areas of neutrophil and fibrinogen conjugates (Additional file 3: Figure S3), suggesting potential interaction between neutrophils and platelets in thrombosis within the pancreatic tumor microenvironment. 2013;123(8):3446–58. 2000;98(5):411–21. 1974;3(5923):94–5. Hydroxychloroquine may inactivate these pathways and results in the death of pancreatic cancer cells. Zohav E, Almog B, Cohen A, Levin I, Deutsch V, Many A, et al. Mean plasma DNA decreased with treatment in the HCQ group, consistent with potential NET inhibition (601 ± 129 vs. 539 ± 114 ng/mL, p < 0.05), but not in the gemcitabine/nab-paclitaxel alone group (588 ± 144 vs. 543 ± 166 ng/mL, p = 0.09). *p < 0.05. Circ Cardiovasc Genet. For general information, Learn About Clinical Studies. 2012;109(32):13076–81. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. 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]. It is possible that CQ may only serve a beneficial role in reducing hypercoagulability in the cancer burdened state, where NETs are upregulated. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. LY3214996 is an extracellular signal-regulated kinase (ERK) inhibitor. The addition of NET supernatant to RAGE knockout blood did not result in increased platelet aggregation. The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer. 2006;166(4):458–64. 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. To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. DNA is released from neutrophils into the circulation during NET formation, therefore this data suggests that NETs may play a role in VTE in patients with pancreatic cancer. Cancer Res. Similarly, Razak et al. This phase I trial studies the best dose of hydroxychloroquine when given together with binimetinib in treating patients with KRAS gene mutated pancreatic cancer that has spread to other places in the body (metastatic). Molecular profiling studies have shown that pancreatic adenocarcinoma (PDAC) is a mutation-driven tumor type, with KRAS mutations found in approximately 90% of cases, which … Privacy Google ScholarÂ. While these findings point to extracellular DNA and RAGE promoting NET mediated platelet aggregation, there are many components released from NETs that may also have an impact on hypercoagulability and were not evaluated in the current analysis. Chloroquine reverses hypercoagulability in pancreatic cancer. Trials to test hydroxychloroquine, an inhibitor of autophagy, for pancreatic cancer are in progress. Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01273805. PubMed Central  Tissue factor, a transmembrane receptor in subendothelial cells, is a key initiator of the extrinsic coagulation cascade and is a contributor to hypercoagulability in pancreatic cancer [24]. Binimetinib may stop the growth of tumor cells … Patients without an event were censored at date of last disease evaluation. Next, we treated tumor bearing mice with DNase I and observed a significant reduction in platelet aggregation (Fig. 2b). Waterfall plot demonstrating individual treatment response to gemcitabine/nab-paclitaxel with and without hydroxychloroquine in patients with elevated preoperative levels (e). Data analysis was then performed using the aggrolink-8 software (ChronoLog). ], Overall Survival [ Time Frame: All patients were followed until death. Subsequent studies have established that HCQ has direct effects on platelet activation and aggregation [48, 49]. Nonetheless, these findings support a clinical trial designed specifically to study reduction in VTE by treatment of cancer patients with perioperative HCQ. The generation of these mice from a C57/Bl6 background has been previously described [16]. Mandala M, Reni M, Cascinu S, Barni S, Floriani I, Cereda S, et al. Recently, neutrophil extracellular traps (NETs), whereby activated neutrophils release their intracellular contents containing DNA, histones, tissue factor, high mobility group box 1 (HMGB1) and other components have been implicated in PDA and in cancer-associated thrombosis. 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. Since NETs are known to release tissue factor, we evaluated levels of circulating tissue factor in our murine models of pancreatic cancer. A 10 fold dilution was performed and mouse tissue factor levels were measured using the F3 / CD142 / Tissue factor ELISA per the manufacturer’s instruction (LS Bio, LS-F14709, Seattle, WA, USA). Pre and post-treatment results were compared using paired t-test. Article  Median duration of treatment for this study cohort was 34 days. J Exp Med. Both in vitro treatment of whole blood (Fig. 4a) and in vivo treatment of mice (Fig. 4b) with chloroquine resulted in decreased platelet aggregation and activation (Additional file 2: Figure S2C). FEBS J. 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. Part of The first trial was a dose escalation Phase I/II trial of preoperative gemcitabine with hydroxychloroquine for patients with high risk pancreatic adenocarcinoma (UPCI 09–122, IRB Protocol #10010028) [18]. 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. In the current study, inhibition of NETs with chloroquine resulted in decreased platelet aggregation and lower levels of circulating tissue factor. These findings implicate a role for DNA and RAGE in NET induced platelet aggregation. 2017;24(12):1600-6. 8). Tumor mice had an elevated coagulation index compared with sham controls, suggestive of hypercoagulability (Fig. 5a). Google ScholarÂ. NETs and down-stream signaling pathways represent a novel target for further research on cancer associated thrombosis [15]. Google ScholarÂ. PAD4 knockout tumor-burdened mice, unable to form NETs, had decreased aggregation and decreased circulating tissue factor. Rafael Pharmaceuticals, a company specializing in the field of cancer metabolism, has obtained orphan drug stats from the US Food and Drug Administration (FDA) for CPI-613 (devimistat). 2016;115(3):332–8. Br J Cancer. Learn More. Although designed and powered to study the effects of HCQ on pathologic treatment response and decrease in Ca 19–9, the reduction in VTE rate neared statistical significance. Tissue factor, a transmembrane receptor typically found in subendothelial cells that binds to factor VII to initiate the extrinsic pathway when the endothelium is damaged is also released from neutrophils during NET formation [25, 26]. Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). Hydroxychloroquine is approved for the treatment of non-cancerous illnesses such as rheumatoid arthritis and systemic lupus erythematous. Biochim Biophys Acta. C57/Bl6 wild-type mice (10–12-week female weighing 20–30 g) were purchased from Taconic (Hudson, NY, USA). We next assessed the rate of venous thromboembolism (VTE) in patients treated with pre-operative hydroxychloroquine as part of two separate clinical trial protocols. Tissue factor as a predictor of recurrent venous thromboembolism in malignancy: biomarker analyses of the CATCH trial. Maugeri N, Campana L, Gavina M, Covino C, De Metrio M, Panciroli C, et al. Oncoimmunology. 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. The 90 day VTE rate for patients treated with 2 cycles of preoperative gemcitabine/abraxane + HCQ was 9.1% (n = 3 of 33) compared to 30% (n = 9 of 30) in patients treated with gemcitabine/abraxane alone (c, p = 0.053). PLoS One. Int J Mol Sci. 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]. Autophagy mediates the delivery of thrombogenic tissue factor to neutrophil extracellular traps in human sepsis. Please remove one or more studies before adding more. 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. http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, https://doi.org/10.1186/s12885-018-4584-2, Infection, immunity and cancer vaccines’. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Demers M, Wagner DD. The Pancreatic Cancer Collective is an initiative of Lustgarten Foundation and Stand Up To Cancer to improve pancreatic cancer patient outcomes. Chloroquine and hydroxychloroquine decrease CXCL12-mediated proliferation in pancreatic cancer cell lines. Serum was collected after blood was allowed to clot and then spun at 1000 g for 10 min. RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA. Sections were blocked with 5% donkey serum in BSA solution for 45 min. Correlative data and samples from a randomized clinical trial of preoperative gemcitabine/nab-paclitaxel with and without hydroxychloroquine were studied and the impact of treatment on venous thromboembolism (VTE) rate was evaluated. 1975;41(12):761–6. Review of correlative data from patients treated on a randomized protocol of preoperative chemotherapy with and without hydroxychloroquine demonstrated a reduction in peri-operative VTE rate from 30 to 9.1% with hydroxychloroquine that neared statistical significance (p = 0.053) despite the trial not being designed to study VTE. Get the latest research information from NIH: You have reached the maximum number of saved studies (100). (DOCX 15 kb), Table S2. We have previously demonstrated that pancreatic cancer primes neutrophils to become more prone to NET formation and identified NETs within pancreatic tumors [13]. This phase I trial studies the best dose of hydroxychloroquine when given together with binimetinib in treating patients with KRAS gene mutated pancreatic cancer that has spread to other places in the body (metastatic). Funding was also graciously provided by philanthropic donors, including the Emma Clyde Hodge Memorial Fund. Thomas GM, Brill A, Mezouar S, Crescence L, Gallant M, Dubois C, et al. Plasma DNA is elevated in patients with deep vein thrombosis. Correspondence to Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. In a more recent randomized trial of preoperative gemcitabine and nab-paclitaxel with or without hydroxychloroquine, the VTE rate of patients treated with hydroxychloroquine was 9.1% compared to 30% in patients treated with gemcitabine/nab-paclitaxel alone (p = 0.053, Fig. 5c). For clinical outcomes, venous thromboembolism was defined as any venous thrombosis including deep vein thrombosis, pulmonary embolism, mesenteric thrombosis and catheter associated thrombosis. Platelet activation was assessed by analyzing expression of P-selectin (CD62P) by flow cytometry using an APC-conjugated anti-CD62P monoclonal antibody (2 μg/ml, mouse IgG1κ; eBioscience, San Diego, CA) or isotype control antibody (eBioscience) in platelet rich plasma (PRP), obtained by platelet isolation centrifugation. Shown that hydroxychloroquine, an average of 34 days Minano a, et al neutrophils are also a of. A. pancreatic cancer are in progress must agree to our Terms and,... Unfolding to form NETs had diminished platelet activation in murine pancreatic adenocarcinoma stained... To assess hypercoagulability and changes associated with NETs received 400 mg hydroxychloroquine twice... To aggregation 18, Article number:  678 ( 2018 ) Cite this article study population OH... 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