Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Recent Advances in Strategies for Extracellular Matrix Degradation and Synthesis Inhibition for Improved Therapy of Solid Tumors

Author(s): Kamalpreet Kaur Sandha, Monu Kumar Shukla and Prem N. Gupta*

Volume 26, Issue 42, 2020

Page: [5456 - 5467] Pages: 12

DOI: 10.2174/1381612826666200728141601

Price: $65

Abstract

Despite a great deal of efforts made by researchers and the advances in the technology, the treatment of cancer is very challenging. Significant advances in the field of cancer therapeutics have been made but due to the complexity of solid tumor microenvironment, specially their dense extracellular matrix (which makes the conditions favorable for cancer growth, metastasis and acts as a barrier to the chemotherapeutic drugs as well as nanomedicine), the treatment of solid tumors is difficult. Overexpression of extracellular matrix components such as collagen, hyaluronan and proteoglycans in solid tumor leads to high interstitial fluid pressure, hypoxia, vascular collapse and poor perfusion which hinder the diffusion and convection of the drugs into the tumor tissue. This leads to the emergence of drug resistance and poor antitumor efficacy of chemotherapeutics. A number of approaches are being investigated in order to modulate this barrier for improved outcome of cancer chemotherapy. In this review, recent advances in the various approaches for the modulation of the extracellular matrix barrier of the solid tumor are covered and significant findings are discussed in an attempt to facilitate more investigations in this potential area to normalize the tumor extracellular matrix for improving drug exposure to solid tumor.

Keywords: Solid tumor, extracellular matrix, collagen, hyaluronic acid, interstitial fluid pressure, nanomedicine.

« Previous Next »
[1]
Jain RK, Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 2010; 7(11): 653-64.
[http://dx.doi.org/10.1038/nrclinonc.2010.139] [PMID: 20838415]
[2]
Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer 2006; 6(8): 583-92.
[http://dx.doi.org/10.1038/nrc1893] [PMID: 16862189]
[3]
Jain RK. Delivery of molecular and cellular medicine to solid tumors. Adv Drug Deliv Rev 2012; 64(Suppl.): 353-65.
[http://dx.doi.org/10.1016/j.addr.2012.09.011] [PMID: 24511174]
[4]
Li Y, Wang J, Wientjes MG, Au JLS. Delivery of nanomedicines to extracellular and intracellular compartments of a solid tumor. Adv Drug Deliv Rev 2012; 64(1): 29-39.
[http://dx.doi.org/10.1016/j.addr.2011.04.006] [PMID: 21569804]
[5]
Jain RK. Transport of molecules, particles, and cells in solid tumors. Annu Rev Biomed Eng 1999; 1: 241-63.
[http://dx.doi.org/10.1146/annurev.bioeng.1.1.241] [PMID: 11701489]
[6]
Choi IK, Strauss R, Richter M, Yun CO, Lieber A. Strategies to increase drug penetration in solid tumors. Front Oncol 2013; 3: 193.
[http://dx.doi.org/10.3389/fonc.2013.00193] [PMID: 23898462]
[7]
Nallanthighal S, Heiserman JP, Cheon DJ. The role of the extracellular matrix in cancer stemness. Front Cell Dev Biol 2019; 7: 86.
[http://dx.doi.org/10.3389/fcell.2019.00086] [PMID: 31334229]
[8]
Polydorou C, Mpekris F, Papageorgis P, Voutouri C, Stylianopoulos T. Pirfenidone normalizes the tumor microenvironment to improve chemotherapy. Oncotarget 2017; 8(15): 24506-17.
[http://dx.doi.org/10.18632/oncotarget.15534] [PMID: 28445938]
[9]
Stylianopoulos T, Martin JD, Chauhan VP, et al. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. Proc Natl Acad Sci USA 2012; 109(38): 15101-8.
[http://dx.doi.org/10.1073/pnas.1213353109] [PMID: 22932871]
[10]
Zhang YR, Lin R, Li HJ, He WL, Du JZ, Wang J. Strategies to improve tumor penetration of nanomedicines through nanoparticle design. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2019; 11(1)e1519
[http://dx.doi.org/10.1002/wnan.1519] [PMID: 29659166]
[11]
Li X, Shepard HM, Cowell JA, et al. Parallel accumulation of tumor hyaluronan, collagen, and other drivers of tumor progression. Clin Cancer Res 2018; 24(19): 4798-807.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-3284] [PMID: 30084839]
[12]
Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012; 21(3): 418-29.
[http://dx.doi.org/10.1016/j.ccr.2012.01.007] [PMID: 22439937]
[13]
Erikson A, Tufto I, Bjønnum AB, Bruland ØS, Davies Cde L. The impact of enzymatic degradation on the uptake of differently sized therapeutic molecules. Anticancer Res 2008; 28(6A): 3557-66.
[PMID: 19189635]
[14]
Eikenes L, Tufto I, Schnell EA, Bjørkøy A, De Lange Davies C. Effect of collagenase and hyaluronidase on free and anomalous diffusion in multicellular spheroids and xenografts. Anticancer Res 2010; 30(2): 359-68.
[PMID: 20332440]
[15]
Tufto I, Hansen R, Byberg D, Nygaard KH, Tufto J, Davies Cde L. The effect of collagenase and hyaluronidase on transient perfusion in human osteosarcoma xenografts grown orthotopically and in dorsal skinfold chambers. Anticancer Res 2007; 27(3B): 1475-81.
[PMID: 17595764]
[16]
Eikenes L, Bruland ØS, Brekken C, Davies Cde L. Collagenase increases the transcapillary pressure gradient and improves the uptake and distribution of monoclonal antibodies in human osteosarcoma xenografts. Cancer Res 2004; 64(14): 4768-73.
[http://dx.doi.org/10.1158/0008-5472.CAN-03-1472] [PMID: 15256445]
[17]
Goodman TT, Olive PL, Pun SH. Increased nanoparticle penetration in collagenase-treated multicellular spheroids. Int J Nanomedicine 2007; 2(2): 265-74.
[PMID: 17722554]
[18]
Zinger A, Koren L, Adir O, et al. Collagenase nanoparticles enhance the penetration of drugs into pancreatic tumors. ACS Nano 2019; 13(10): 11008-21.
[http://dx.doi.org/10.1021/acsnano.9b02395] [PMID: 31503443]
[19]
Pan A, Wang Z, Chen B, et al. Localized co-delivery of collagenase and trastuzumab by thermosensitive hydrogels for enhanced antitumor efficacy in human breast xenograft. Drug Deliv 2018; 25(1): 1495-503.
[http://dx.doi.org/10.1080/10717544.2018.1474971] [PMID: 29943651]
[20]
Magzoub M, Jin S, Verkman AS. Enhanced macromolecule diffusion deep in tumors after enzymatic digestion of extracellular matrix collagen and its associated proteoglycan decorin. FASEB J 2008; 22(1): 276-84.
[http://dx.doi.org/10.1096/fj.07-9150com] [PMID: 17761521]
[21]
Choi J, Credit K, Henderson K, et al. Intraperitoneal immunotherapy for metastatic ovarian carcinoma: Resistance of intratumoral collagen to antibody penetration. Clin Cancer Res 2006; 12(6): 1906-12.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-2141] [PMID: 16551876]
[22]
Villegas MR, Baeza A, Vallet-Regí M. Hybrid collagenase nanocapsules for enhanced nanocarrier penetration in tumoral tissues. ACS Appl Mater Interfaces 2015; 7(43): 24075-81.
[http://dx.doi.org/10.1021/acsami.5b07116] [PMID: 26461206]
[23]
Murty S, Gilliland T, Qiao P, et al. Nanoparticles functionalized with collagenase exhibit improved tumor accumulation in a murine xenograft model. Part Part Syst Charact 2014; 31(12): 1307-12.
[http://dx.doi.org/10.1002/ppsc.201400169] [PMID: 26380538]
[24]
Zheng X, Goins BA, Cameron IL, et al. Ultrasound-guided intratumoral administration of collagenase-2 improved liposome drug accumulation in solid tumor xenografts. Cancer Chemother Pharmacol 2011; 67(1): 173-82.
[http://dx.doi.org/10.1007/s00280-010-1305-1] [PMID: 20306263]
[25]
Kato M, Hattori Y, Kubo M, Maitani Y. Collagenase-1 injection improved tumor distribution and gene expression of cationic lipoplex. Int J Pharm 2012; 423(2): 428-34.
[http://dx.doi.org/10.1016/j.ijpharm.2011.12.015] [PMID: 22197775]
[26]
Zhang W, Liu L, Su H, et al. Chimeric antigen receptor macrophage therapy for breast tumours mediated by targeting the tumour extracellular matrix. Br J Cancer 2019; 121(10): 837-45.
[http://dx.doi.org/10.1038/s41416-019-0578-3] [PMID: 31570753]
[27]
Curran S, Murray GI. Matrix metalloproteinases in tumour invasion and metastasis. J Pathol 1999; 189(3): 300-8.
[http://dx.doi.org/10.1002/(SICI)1096-9896(199911)189:3<300:AID-PATH456>3.0.CO;2-C] [PMID: 10547590]
[28]
Mok W, Boucher Y, Jain RK. Matrix metalloproteinases-1 and -8 improve the distribution and efficacy of an oncolytic virus. Cancer Res 2007; 67(22): 10664-8.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-3107] [PMID: 18006807]
[29]
Maneval DC, Caster CL, Derunes C, et al. Pegvorhyaluronidase alfa: a PEGylated recombinant human hyaluronidase PH20 for the treatment of cancers that accumulate hyaluronan. Polymer-Protein Conj 2020; pp. 175-204.
[30]
Eikenes L, Tari M, Tufto I, Bruland ØS, de Lange Davies C. Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx) in human osteosarcoma xenografts. Br J Cancer 2005; 93(1): 81-8.
[http://dx.doi.org/10.1038/sj.bjc.6602626] [PMID: 15942637]
[31]
Jacobetz MA, Chan DS, Neesse A, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 2013; 62(1): 112-20.
[http://dx.doi.org/10.1136/gutjnl-2012-302529] [PMID: 22466618]
[32]
Thompson CB, Shepard HM, O’Connor PM, et al. Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models. Mol Cancer Ther 2010; 9(11): 3052-64.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0470] [PMID: 20978165]
[33]
Jabłońska-Trypuć A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem 2016; 31(sup1): 177-83.
[http://dx.doi.org/10.3109/14756366.2016.1161620] [PMID: 27028474]
[34]
Cheng J, Sauthoff H, Huang Y, et al. Human matrix metalloproteinase-8 gene delivery increases the oncolytic activity of a replicating adenovirus. Mol Ther 2007; 15(11): 1982-90.
[http://dx.doi.org/10.1038/sj.mt.6300264] [PMID: 17653103]
[35]
Hong CS, Fellows W, Niranjan A, et al. Ectopic matrix metalloproteinase-9 expression in human brain tumor cells enhances oncolytic HSV vector infection. Gene Ther 2010; 17(10): 1200-5.
[http://dx.doi.org/10.1038/gt.2010.66] [PMID: 20463757]
[36]
Yang H, Jiang P, Liu D, et al. Matrix metalloproteinase 11 is a potential therapeutic target in lung adenocarcinoma. Mol Ther Oncolytics 2019; 14: 82-93.
[http://dx.doi.org/10.1016/j.omto.2019.03.012] [PMID: 31024988]
[37]
Radisky ES, Raeeszadeh-Sarmazdeh M, Radisky DC. Therapeutic potential of matrix metalloproteinase inhibition in breast cancer. J Cell Biochem 2017; 118(11): 3531-48.
[http://dx.doi.org/10.1002/jcb.26185] [PMID: 28585723]
[38]
Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010; 141(1): 52-67.
[http://dx.doi.org/10.1016/j.cell.2010.03.015] [PMID: 20371345]
[39]
Winer A, Adams S, Mignatti P. Matrix metalloproteinase inhibitors in cancer therapy: turning past failures into future successes. Mol Cancer Ther 2018; 17(6): 1147-55.
[http://dx.doi.org/10.1158/1535-7163.MCT-17-0646] [PMID: 29735645]
[40]
Lv Y, Zhao X, Zhu L, et al. Targeting intracellular MMPs efficiently inhibits tumor metastasis and angiogenesis. Theranostics 2018; 8(10): 2830-45.
[http://dx.doi.org/10.7150/thno.23209] [PMID: 29774078]
[41]
Fields GB. The rebirth of matrix metalloproteinase inhibitors: moving beyond the dogma. Cells 2019; 8(9): 984.
[http://dx.doi.org/10.3390/cells8090984] [PMID: 31461880]
[42]
Razai AS, Eckelman BP, Salvesen GS. Selective inhibition of matrix metalloproteinase 10 (MMP10) with a single-domain antibody. J Biol Chem 2020; 295(8): 2464-72.
[http://dx.doi.org/10.1074/jbc.RA119.011712] [PMID: 31953328]
[43]
Overall CM, Kleifeld O. Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 2006; 6(3): 227-39.
[http://dx.doi.org/10.1038/nrc1821] [PMID: 16498445]
[44]
Cathcart J, Pulkoski-Gross A, Cao J. Targeting matrix metalloproteinases in cancer: bringing new life to old ideas. Genes Dis 2015; 2(1): 26-34.
[http://dx.doi.org/10.1016/j.gendis.2014.12.002] [PMID: 26097889]
[45]
Giussani M, Triulzi T, Sozzi G, Tagliabue E. Tumor extracellular matrix remodeling: new perspectives as a circulating tool in the diagnosis and prognosis of solid tumors. Cells 2019; 8(2): 81.
[http://dx.doi.org/10.3390/cells8020081] [PMID: 30678058]
[46]
Nissen NI, Karsdal M, Willumsen N. Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology. J Exp Clin Cancer Res 2019; 38(1): 115.
[http://dx.doi.org/10.1186/s13046-019-1110-6] [PMID: 30841909]
[47]
Papageorgis P, Polydorou C, Mpekris F, et al. Tranilast-induced stress alleviation in solid tumors improves the efficacy of chemo- and nanotherapeutics in a size-independent manner. Sci Rep 2017; 7: 46140.
[http://dx.doi.org/10.1038/srep46140] [PMID: 28393881]
[48]
Mpekris F, Voutouri C, Papageorgis P, Stylianopoulos T. Stress alleviation strategy in cancer treatment: Insights from a mathematical model. ZAMM‐J Appl Math Mech 2018; 98(12): 2295-306.
[http://dx.doi.org/10.1002/zamm.201700270]
[49]
Mediavilla-Varela M, Boateng K, Noyes D, Antonia SJ. The anti-fibrotic agent pirfenidone synergizes with cisplatin in killing tumor cells and cancer-associated fibroblasts. BMC Cancer 2016; 16(1): 176.
[http://dx.doi.org/10.1186/s12885-016-2162-z] [PMID: 26935219]
[50]
Kozono S, Ohuchida K, Eguchi D, et al. Pirfenidone inhibits pancreatic cancer desmoplasia by regulating stellate cells. Cancer Res 2013; 73(7): 2345-56.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-3180] [PMID: 23348422]
[51]
Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci USA 2011; 108(7): 2909-14.
[http://dx.doi.org/10.1073/pnas.1018892108] [PMID: 21282607]
[52]
Stylianopoulos T, Munn LL, Jain RK. Reengineering the physical microenvironment of tumors to improve drug delivery and efficacy: from mathematical modeling to bench to bedside. Trends Cancer 2018; 4(4): 292-319.
[http://dx.doi.org/10.1016/j.trecan.2018.02.005] [PMID: 29606314]
[53]
Liu J, Liao S, Diop-Frimpong B, et al. TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc Natl Acad Sci USA 2012; 109(41): 16618-23.
[http://dx.doi.org/10.1073/pnas.1117610109] [PMID: 22996328]
[54]
Chen Y, Liu X, Yuan H, et al. Therapeutic remodeling of the tumor microenvironment enhances nanoparticle delivery. Adv Sci (Weinh) 2019; 6(5)1802070
[http://dx.doi.org/10.1002/advs.201802070] [PMID: 30886813]
[55]
Beyer I, Li Z, Persson J, et al. Controlled extracellular matrix degradation in breast cancer tumors improves therapy by trastuzumab. Mol Ther 2011; 19(3): 479-89.
[http://dx.doi.org/10.1038/mt.2010.256] [PMID: 21081901]
[56]
Brown E, McKee T, diTomaso E, et al. Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation. Nat Med 2003; 9(6): 796-800.
[http://dx.doi.org/10.1038/nm879] [PMID: 12754503]
[57]
Kim JH, Lee YS, Kim H, Huang JH, Yoon AR, Yun CO. Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy. J Natl Cancer Inst 2006; 98(20): 1482-93.
[http://dx.doi.org/10.1093/jnci/djj397] [PMID: 17047197]
[58]
Ganesh S, Gonzalez Edick M, Idamakanti N, et al. Relaxin-expressing, fiber chimeric oncolytic adenovirus prolongs survival of tumor-bearing mice. Cancer Res 2007; 67(9): 4399-407.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-4260] [PMID: 17483354]
[59]
Rossow L, Veitl S, Vorlová S, et al. LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy. Oncogene 2018; 37(36): 4921-40.
[http://dx.doi.org/10.1038/s41388-018-0320-2] [PMID: 29780168]
[60]
Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 2010; 16(9): 1009-17.
[http://dx.doi.org/10.1038/nm.2208] [PMID: 20818376]
[61]
Voutouri C, Stylianopoulos T. Accumulation of mechanical forces in tumors is related to hyaluronan content and tissue stiffness. PLoS One 2018; 13(3)e0193801
[http://dx.doi.org/10.1371/journal.pone.0193801] [PMID: 29561855]
[62]
Kakizaki I, Kojima K, Takagaki K, et al. A novel mechanism for the inhibition of hyaluronan biosynthesis by 4-methylumbelliferone. J Biol Chem 2004; 279(32): 33281-9.
[http://dx.doi.org/10.1074/jbc.M405918200] [PMID: 15190064]
[63]
Cheng XB, Sato N, Kohi S, Koga A, Hirata K. 4-Methylumbelliferone inhibits enhanced hyaluronan synthesis and cell migration in pancreatic cancer cells in response to tumor-stromal interactions. Oncol Lett 2018; 15(5): 6297-301.
[http://dx.doi.org/10.3892/ol.2018.8147] [PMID: 29725394]
[64]
Adamia S, Maxwell CA, Pilarski LM. Hyaluronan and hyaluronan synthases: potential therapeutic targets in cancer. Curr Drug Targets Cardiovasc Haematol Disord 2005; 5(1): 3-14.
[http://dx.doi.org/10.2174/1568006053005056] [PMID: 15720220]
[65]
Kohli AG, Kivimäe S, Tiffany MR, Szoka FC. Improving the distribution of Doxilβ in the tumor matrix by depletion of tumor hyaluronan. J Control Release 2014; 191: 105-14.
[http://dx.doi.org/10.1016/j.jconrel.2014.05.019] [PMID: 24852095]
[66]
Nakazawa H, Yoshihara S, Kudo D, et al. 4-methylumbelliferone, a hyaluronan synthase suppressor, enhances the anticancer activity of gemcitabine in human pancreatic cancer cells. Cancer Chemother Pharmacol 2006; 57(2): 165-70.
[http://dx.doi.org/10.1007/s00280-005-0016-5] [PMID: 16341905]
[67]
Hajime M, Shuichi Y, Makoto N, et al. Inhibitory effect of 4-methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice. Int J Cancer 2007; 120(12): 2704-9.
[http://dx.doi.org/10.1002/ijc.22349] [PMID: 17354230]
[68]
Adiseshaiah PP, Crist RM, Hook SS, McNeil SE. Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer. Nat Rev Clin Oncol 2016; 13(12): 750-65.
[http://dx.doi.org/10.1038/nrclinonc.2016.119] [PMID: 27531700]
[69]
Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009; 324(5933): 1457-61.
[http://dx.doi.org/10.1126/science.1171362] [PMID: 19460966]
[70]
Khawar IA, Kim JH, Kuh HJ. Improving drug delivery to solid tumors: priming the tumor microenvironment. J Control Release 2015; 201: 78-89.
[http://dx.doi.org/10.1016/j.jconrel.2014.12.018] [PMID: 25526702]
[71]
Mpekris F, Papageorgis P, Polydorou C, et al. Sonic-hedgehog pathway inhibition normalizes desmoplastic tumor microenvironment to improve chemo- and nanotherapy. J Control Release 2017; 261: 105-12.
[http://dx.doi.org/10.1016/j.jconrel.2017.06.022] [PMID: 28662901]
[72]
LaGory EL, Giaccia AJ. The ever-expanding role of HIF in tumour and stromal biology. Nat Cell Biol 2016; 18(4): 356-65.
[http://dx.doi.org/10.1038/ncb3330] [PMID: 27027486]
[73]
Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer 2011; 11(6): 393-410.
[http://dx.doi.org/10.1038/nrc3064] [PMID: 21606941]
[74]
Sainio A, Järveläinen H. Extracellular matrix macromolecules: potential tools and targets in cancer gene therapy. Mol Cell Ther 2014; 2(1): 14.
[http://dx.doi.org/10.1186/2052-8426-2-14] [PMID: 26056582]
[75]
Köninger J, Giese NA, di Mola FF, et al. Overexpressed decorin in pancreatic cancer: potential tumor growth inhibition and attenuation of chemotherapeutic action. Clin Cancer Res 2004; 10(14): 4776-83.
[http://dx.doi.org/10.1158/1078-0432.CCR-1190-03] [PMID: 15269152]
[76]
NCT01928030. Recombinant human hyaluronidase in treating lymphedema in patients with cancer Available from: https://ClinicalTrials.gov/show/NCT01928030
[77]
NCT02346370. A Phase 1b Study of PEGylated recombinant human hyaluronidase (PEGPH20) combined with docetaxel in subjects with recurrent previously treated locally advanced or metastatic NSCLC. Available from: https://ClinicalTrials.gov/show/NCT02346370
[78]
NCT02563548. A study of PEGylated recombinant human hyaluronidase (PEGPH20) with pembrolizumab in participants with selected hyaluronan high solid tumors. Available from: https://ClinicalTrials.gov/show/NCT02563548
[79]
NCT03267940. Study of PEGPH20 with cisplatin (CIS) and gemcitabine (GEM); PEGPH20 with atezolizumab (ATEZO), CIS, and GEM; and CIS and GEM Alone in participants with previously untreated, unresectable, locally advanced, or metastatic intrahepatic and extrahepatic cholangiocarcinoma and gallbladder. Available from: https://ClinicalTrials.gov/show/NCT03267940
[80]
NCT01453153. Study of gemcitabine + PEGPH20 vs gemcitabine alone in stage IV previously untreated pancreatic cancer https://ClinicalTrials.gov/show/NCT01453153
[81]
NCT02753595. Study of eribulin mesylate in combination with PEGylated recombinant human hyaluronidase (PEGPH20) versus eribulin mesylate alone in subjects with human epidermal growth factor receptor 2 (HER2)-negative, High-hyaluronan (HA) Metastatic Breast Cancer Available from: https://ClinicalTrials.gov/show/NCT02753595
[82]
NCT02715804. A study of PEGylated recombinant human hyaluronidase in combination with nab-paclitaxel plus gemcitabine compared with placebo plus nab-paclitaxel and gemcitabine in participants with hyaluronan-high stage IV previously untreated pancreatic ductal adenocarcinoma Available from: https://ClinicalTrials.gov/show/NCT02715804
[83]
NCT00318643. Safety study of recombinant human hyaluronidase (chemophase) in combination with mitomycin in patients with superficial bladder cancer Available from: https://ClinicalTrials.gov/show/NCT00318643
[84]
NCT03481920. A trial of PEGPH20 in combination with avelumab in chemotherapy resistant pancreatic cancer Available from: https://ClinicalTrials.gov/show/NCT03481920
[85]
NCT01170897. Study of PEGPH20 with initial dexamethasone premedication given intravenously to patients with advanced solid tumors Available from: https://ClinicalTrials.gov/show/NCT01170897
[86]
NCT02910882. PEGPH20 Plus gemcitabine with radiotherapy in patients with localized, unresectable pancreatic cancer Available from: https://ClinicalTrials.gov/show/NCT02910882
[87]
NCT03634332. Second-line study of PEGPH20 and pembro for HA high metastatic PDAC Available from: https://ClinicalTrials.gov/show/ NCT03634332
[88]
NCT03281369. A study of multiple immunotherapy-based treatment combinations in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction cancer (G/GEJ) (Morpheus-gastric cancer Available from: https://ClinicalTrials.gov/show/NCT03281369
[89]
NCT03177291. Pirfenidone combined with standard first-line chemotherapy in advanced-stage lung NSCLC Available from: https://ClinicalTrials.gov/show/NCT03177291
[90]
NCT00020631. Pirfenidone in treating patients with fibrosis caused by radiation therapy for cancer Available from: https://ClinicalTrials.gov/show/NCT00020631
[91]
NCT03563248. Losartan and nivolumab in combination with FOLFIRINOX and SBRT in localized pancreatic cancer Available from: https://ClinicalTrials.gov/show/NCT03563248
[92]
NCT01821729. Proton w/FOLFIRINOX- losartan for Pancreatic cancer Available from: https://ClinicalTrials.gov/show/NCT01821729
[93]
Tissue pharmacokinetics of intraoperative gemcitabine in resectable adenocarcinoma of the pancreas Available from: https://ClinicalTrials.gov/show/
[94]
NCT03951142. Imaging perfusion restrictions from extracellular solid stress - An open-label losartan study Available from: https://ClinicalTrials.gov/show/NCT03951142
[95]
NCT03900793. Losartan+sunitinib in treatment of osteosarcoma Available from: https://ClinicalTrials.gov/show/NCT03900793
[96]
NCT01383538. FOLFIRINOX plus IPI-926 for advanced pancreatic adenocarcinoma Available from: https://ClinicalTrials.gov/show/NCT01383538
[97]
NCT01130142. A study evaluating IPI-926 in combination with gemcitabine in patients with metastatic pancreatic cancer Available from: https://ClinicalTrials.gov/show/NCT01130142

Rights & Permissions Print Cite
Article Metrics
15
© 2024 Bentham Science Publishers | Privacy Policy