Towards extracellular matrix normalization for improved treatment of solid tumors
Identifieur interne : 000B11 ( Pmc/Curation ); précédent : 000B10; suivant : 000B12Towards extracellular matrix normalization for improved treatment of solid tumors
Auteurs : Hoda Soleymani Abyaneh [Canada] ; Maximilian Regenold [Canada] ; Trevor D. Mckee [Canada] ; Christine Allen [Canada] ; Marc A. Gauthier [Canada]Source :
- Theranostics [ 1838-7640 ] ; 2020.
Abstract
It is currently challenging to eradicate cancer. In the case of solid tumors, the dense and aberrant extracellular matrix (ECM) is a major contributor to the heterogeneous distribution of small molecule drugs and nano-formulations, which makes certain areas of the tumor difficult to treat. As such, much research is devoted to characterizing this matrix and devising strategies to modify its properties as a means to facilitate the improved penetration of drugs and their nano-formulations. This contribution presents the current state of knowledge on the composition of normal ECM and changes to ECM that occur during the pathological progression of cancer. It also includes discussion of strategies designed to modify the composition/properties of the ECM as a means to enhance the penetration and transport of drugs and nano-formulations within solid tumors. Moreover, a discussion of approaches to image the ECM, as well as ways to monitor changes in the ECM as a function of time are presented, as these are important for the implementation of ECM-modifying strategies within therapeutic interventions. Overall, considering the complexity of the ECM, its variability within different tissues, and the multiple pathways by which homeostasis is maintained (both in normal and malignant tissues), the available literature - while promising - suggests that improved monitoring of ECM remodeling
Url:
DOI: 10.7150/thno.39995
PubMed: 32042347
PubMed Central: 6993244
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Towards extracellular matrix normalization for improved treatment of solid tumors</title><author><name sortKey="Abyaneh, Hoda Soleymani" sort="Abyaneh, Hoda Soleymani" uniqKey="Abyaneh H" first="Hoda Soleymani" last="Abyaneh">Hoda Soleymani Abyaneh</name><affiliation wicri:level="1"><nlm:aff id="A1">Institut National de la Recherche Scientifique (INRS), EMT Research Center, 1650 boul. Lionel-Boulet, Varennes, J3X 1S2, Canada.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Canada</country><wicri:regionArea>Institut National de la Recherche Scientifique (INRS), EMT Research Center, 1650 boul. 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Mckee</name><affiliation wicri:level="1"><nlm:aff id="A3">STTARR Innovation Centre, University Health Network, 101 College Street Room 7-504, Toronto, Ontario M5G 1L7, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>STTARR Innovation Centre, University Health Network, 101 College Street Room 7-504, Toronto, Ontario M5G 1L7</wicri:regionArea></affiliation></author><author><name sortKey="Allen, Christine" sort="Allen, Christine" uniqKey="Allen C" first="Christine" last="Allen">Christine Allen</name><affiliation wicri:level="1"><nlm:aff id="A2">Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Canada</country><wicri:regionArea>Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2</wicri:regionArea></affiliation></author><author><name sortKey="Gauthier, Marc A" sort="Gauthier, Marc A" uniqKey="Gauthier M" first="Marc A." last="Gauthier">Marc A. Gauthier</name><affiliation wicri:level="1"><nlm:aff id="A1">Institut National de la Recherche Scientifique (INRS), EMT Research Center, 1650 boul. Lionel-Boulet, Varennes, J3X 1S2, Canada.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Canada</country><wicri:regionArea>Institut National de la Recherche Scientifique (INRS), EMT Research Center, 1650 boul. Lionel-Boulet, Varennes, J3X 1S2</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32042347</idno><idno type="pmc">6993244</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993244</idno><idno type="RBID">PMC:6993244</idno><idno type="doi">10.7150/thno.39995</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000B11</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B11</idno><idno type="wicri:Area/Pmc/Curation">000B11</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000B11</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Towards extracellular matrix normalization for improved treatment of solid tumors</title><author><name sortKey="Abyaneh, Hoda Soleymani" sort="Abyaneh, Hoda Soleymani" uniqKey="Abyaneh H" first="Hoda Soleymani" last="Abyaneh">Hoda Soleymani Abyaneh</name><affiliation wicri:level="1"><nlm:aff id="A1">Institut National de la Recherche Scientifique (INRS), EMT Research Center, 1650 boul. Lionel-Boulet, Varennes, J3X 1S2, Canada.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Canada</country><wicri:regionArea>Institut National de la Recherche Scientifique (INRS), EMT Research Center, 1650 boul. Lionel-Boulet, Varennes, J3X 1S2</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Canada</country><wicri:regionArea>Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2</wicri:regionArea></affiliation></author><author><name sortKey="Regenold, Maximilian" sort="Regenold, Maximilian" uniqKey="Regenold M" first="Maximilian" last="Regenold">Maximilian Regenold</name><affiliation wicri:level="1"><nlm:aff id="A2">Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Canada</country><wicri:regionArea>Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2</wicri:regionArea></affiliation></author><author><name sortKey="Mckee, Trevor D" sort="Mckee, Trevor D" uniqKey="Mckee T" first="Trevor D." last="Mckee">Trevor D. Mckee</name><affiliation wicri:level="1"><nlm:aff id="A3">STTARR Innovation Centre, University Health Network, 101 College Street Room 7-504, Toronto, Ontario M5G 1L7, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>STTARR Innovation Centre, University Health Network, 101 College Street Room 7-504, Toronto, Ontario M5G 1L7</wicri:regionArea></affiliation></author><author><name sortKey="Allen, Christine" sort="Allen, Christine" uniqKey="Allen C" first="Christine" last="Allen">Christine Allen</name><affiliation wicri:level="1"><nlm:aff id="A2">Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Canada</country><wicri:regionArea>Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2</wicri:regionArea></affiliation></author><author><name sortKey="Gauthier, Marc A" sort="Gauthier, Marc A" uniqKey="Gauthier M" first="Marc A." last="Gauthier">Marc A. Gauthier</name><affiliation wicri:level="1"><nlm:aff id="A1">Institut National de la Recherche Scientifique (INRS), EMT Research Center, 1650 boul. Lionel-Boulet, Varennes, J3X 1S2, Canada.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Canada</country><wicri:regionArea>Institut National de la Recherche Scientifique (INRS), EMT Research Center, 1650 boul. Lionel-Boulet, Varennes, J3X 1S2</wicri:regionArea></affiliation></author></analytic><series><title level="j">Theranostics</title><idno type="eISSN">1838-7640</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>It is currently challenging to eradicate cancer. In the case of solid tumors, the dense and aberrant extracellular matrix (ECM) is a major contributor to the heterogeneous distribution of small molecule drugs and nano-formulations, which makes certain areas of the tumor difficult to treat. As such, much research is devoted to characterizing this matrix and devising strategies to modify its properties as a means to facilitate the improved penetration of drugs and their nano-formulations. This contribution presents the current state of knowledge on the composition of normal ECM and changes to ECM that occur during the pathological progression of cancer. It also includes discussion of strategies designed to modify the composition/properties of the ECM as a means to enhance the penetration and transport of drugs and nano-formulations within solid tumors. Moreover, a discussion of approaches to image the ECM, as well as ways to monitor changes in the ECM as a function of time are presented, as these are important for the implementation of ECM-modifying strategies within therapeutic interventions. Overall, considering the complexity of the ECM, its variability within different tissues, and the multiple pathways by which homeostasis is maintained (both in normal and malignant tissues), the available literature - while promising - suggests that improved monitoring of ECM remodeling <italic>in vivo</italic> is needed to harness the described strategies to their full potential, and match them with an appropriate chemotherapy regimen.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Perry, Jl" uniqKey="Perry J">JL Perry</name></author><author><name sortKey="Reuter, Kg" uniqKey="Reuter K">KG Reuter</name></author><author><name sortKey="Luft, Jc" uniqKey="Luft J">JC Luft</name></author><author><name sortKey="Pecot, Cv" uniqKey="Pecot C">CV Pecot</name></author><author><name sortKey="Zamboni, W" uniqKey="Zamboni W">W Zamboni</name></author><author><name sortKey="Desimone, Jm" uniqKey="Desimone J">JM 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Theranostics</journal-id><journal-id journal-id-type="iso-abbrev">Theranostics</journal-id><journal-id journal-id-type="publisher-id">thno</journal-id><journal-title-group><journal-title>Theranostics</journal-title></journal-title-group><issn pub-type="epub">1838-7640</issn><publisher><publisher-name>Ivyspring International Publisher</publisher-name><publisher-loc>Sydney</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32042347</article-id><article-id pub-id-type="pmc">6993244</article-id><article-id pub-id-type="doi">10.7150/thno.39995</article-id><article-id pub-id-type="publisher-id">thnov10p1960</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Towards extracellular matrix normalization for improved treatment of solid tumors</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Abyaneh</surname><given-names>Hoda Soleymani</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Regenold</surname><given-names>Maximilian</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>McKee</surname><given-names>Trevor D.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Allen</surname><given-names>Christine</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib><contrib contrib-type="author"><name><surname>Gauthier</surname><given-names>Marc A.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="corresp" rid="FNA_envelop">✉</xref></contrib></contrib-group><aff id="A1"><label>1</label>Institut National de la Recherche Scientifique (INRS), EMT Research Center, 1650 boul. Lionel-Boulet, Varennes, J3X 1S2, Canada.</aff><aff id="A2"><label>2</label>Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada.</aff><aff id="A3"><label>3</label>STTARR Innovation Centre, University Health Network, 101 College Street Room 7-504, Toronto, Ontario M5G 1L7, Canada</aff><author-notes><corresp id="FNA_envelop">✉ Corresponding authors: <email>cj.allen@utoronto.ca</email> (CA); <email>gauthier@emt.inrs.ca</email> (MAG)</corresp><fn fn-type="COI-statement"><p>Competing Interests: The authors have declared that no competing interest exists.</p></fn></author-notes><pub-date pub-type="collection"><year>2020</year></pub-date><pub-date pub-type="epub"><day>12</day><month>1</month><year>2020</year></pub-date><volume>10</volume><issue>4</issue><fpage>1960</fpage><lpage>1980</lpage><history><date date-type="received"><day>4</day><month>9</month><year>2019</year></date><date date-type="accepted"><day>9</day><month>12</month><year>2019</year></date></history><permissions><copyright-statement>© The author(s)</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access"><license-p>This is an open access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">https://creativecommons.org/licenses/by/4.0/</ext-link>). See <ext-link ext-link-type="uri" xlink:href="http://ivyspring.com/terms">http://ivyspring.com/terms</ext-link> for full terms and conditions.</license-p></license></permissions><abstract><p>It is currently challenging to eradicate cancer. In the case of solid tumors, the dense and aberrant extracellular matrix (ECM) is a major contributor to the heterogeneous distribution of small molecule drugs and nano-formulations, which makes certain areas of the tumor difficult to treat. As such, much research is devoted to characterizing this matrix and devising strategies to modify its properties as a means to facilitate the improved penetration of drugs and their nano-formulations. This contribution presents the current state of knowledge on the composition of normal ECM and changes to ECM that occur during the pathological progression of cancer. It also includes discussion of strategies designed to modify the composition/properties of the ECM as a means to enhance the penetration and transport of drugs and nano-formulations within solid tumors. Moreover, a discussion of approaches to image the ECM, as well as ways to monitor changes in the ECM as a function of time are presented, as these are important for the implementation of ECM-modifying strategies within therapeutic interventions. Overall, considering the complexity of the ECM, its variability within different tissues, and the multiple pathways by which homeostasis is maintained (both in normal and malignant tissues), the available literature - while promising - suggests that improved monitoring of ECM remodeling <italic>in vivo</italic> is needed to harness the described strategies to their full potential, and match them with an appropriate chemotherapy regimen.</p></abstract><kwd-group><kwd>tumor extracellular matrix</kwd><kwd>collagen</kwd><kwd>hyaluronic acid</kwd><kwd>fibrosis</kwd><kwd>nano-formulations</kwd></kwd-group></article-meta></front><floats-group><fig id="F1" position="float"><label>Figure 1</label><caption><p><bold> Towards extracellular matrix (ECM) normalization for improved treatment of solid tumors.</bold> Healthy ECM versus aberrant tumor ECM (left and right panels, respectively). Healthy ECM is characterized by the presence of an intact basement membrane, non-activated fibroblasts and random arrangement of collagen fibers (left panel). Aberrant tumor ECM features the tumor vessel basement membrane with a heterogeneous thickness that allows the dissemination of tumor cells as well as accumulation of nano-formulations. The presence of collagen fibers which are aligned in an ordered fashion and activated fibroblasts are other characteristics of tumor ECM.</p></caption><graphic xlink:href="thnov10p1960g001"></graphic></fig><fig id="F2" position="float"><label>Figure 2</label><caption><p><bold> Fibroblasts are highly plastic and exhibit multi-potency.</bold> Activated fibroblasts readily differentiate into adipocytes, chondrocytes and endothelial cells, among others. Adapted with permission from <xref rid="B49" ref-type="bibr">49</xref>, Copyright 2016 Springer Nature. Of note, there are conflicting reports on the differentiation of activated fibroblasts into adipocytes <xref rid="B197" ref-type="bibr">197</xref>.</p></caption><graphic xlink:href="thnov10p1960g002"></graphic></fig><fig id="F3" position="float"><label>Figure 3</label><caption><p><bold> Molecular processes involved in wound repair and fibrosis</bold>. LOX: lysyl oxidase, LOXL2: lysyl oxidase like 2, MMP: matrix metalloproteinase, PDGF: platelet-derived growth factor, and TGF-β: transforming growth factor beta. Adapted with permission from <xref rid="B198" ref-type="bibr">198</xref>, Copyright 2007 American Society for Clinical Investigation.</p></caption><graphic xlink:href="thnov10p1960g003"></graphic></fig><fig id="F4" position="float"><label>Figure 4</label><caption><p><bold> Interactions of tumor-associated fibroblasts and collagen.</bold> Daily multiphoton laser scanning microscopy images were acquired in a tumor growing in a dorsal skinfold window chamber. Two channels were acquired: Second harmonic generation (SHG) signal arising from collagen (shown in red), and green fluorescent protein (GFP) present in cancer associated fibroblasts (shown in green). Image montage presents a maximum intensity projection of a few images each, acquired 24 hours apart for four consecutive days. Fibroblasts are seen to migrate within the tumor to varying degrees, and occasionally interact with collagen fibers. Figure is generated from data provided by Dr. Trevor D. McKee which was originally captured and analyzed in <xref rid="B181" ref-type="bibr">181</xref>. With permission from <xref rid="B181" ref-type="bibr">181</xref>, Copyright 2009 Springer Nature.</p></caption><graphic xlink:href="thnov10p1960g004"></graphic></fig><fig id="F5" position="float"><label>Figure 5</label><caption><p><bold> Fibrosis in cancer.</bold> Representative trichrome (blue) staining for collagen in normal pancreas and different cancerous tissues. Magnification ×20. Reprinted with permission from <xref rid="B34" ref-type="bibr">34</xref>, Copyright 2017 Springer Nature.</p></caption><graphic xlink:href="thnov10p1960g005"></graphic></fig><fig id="F6" position="float"><label>Figure 6</label><caption><p><bold> Heat-triggered intravascular drug release from thermosensitive liposomes.</bold> Localized mild hyperthermia is employed to heat the tumor area by a few degrees (39-43°C) which can trigger rapid drug release within the tumor microvasculature. The released drug enters the tumor interstitium via diffusion along the existing concentration gradient.</p></caption><graphic xlink:href="thnov10p1960g006"></graphic></fig><fig id="F7" position="float"><label>Figure 7</label><caption><p>Schematic model of therapeutic interventions for normalization of the extracellular matrix (ECM) in solid tumors.</p></caption><graphic xlink:href="thnov10p1960g007"></graphic></fig><table-wrap id="T1" position="float"><label>Table 1</label><caption><p>Overview of clinical trials investigating drugs with ECM remodeling properties in combination with nano-formulations for cancer therapy, as of July 17 2019</p></caption><table frame="hsides" rules="groups"><thead valign="top"><tr><th rowspan="1" colspan="1">ECM remodeling drug</th><th rowspan="1" colspan="1">Design</th><th rowspan="1" colspan="1">Cancer type</th><th rowspan="1" colspan="1"></th><th rowspan="1" colspan="1">Clinical Phase</th><th rowspan="1" colspan="1">Clinicaltrials.gov identifier</th></tr></thead><tbody valign="top"><tr><td colspan="6" align="center" rowspan="1"><bold>Liposomal Irinotecan, Onivyde<sup> ®</sup></bold></td></tr><tr><td rowspan="1" colspan="1">Paricalcitol</td><td rowspan="1" colspan="1">Liposomal Irinotecan + 5-FU + Leucovorin + Paricalcitol</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1</td><td rowspan="1" colspan="1">NCT03883919</td></tr><tr><td colspan="6" align="center" rowspan="1"><bold>Protein-bound paclitaxel, Nab-Paclitaxel (nanoparticle albumin-bound paclitaxel), Abraxane<sup>®</sup></bold></td></tr><tr><td rowspan="3" colspan="1">PEGPH20<break></break>(PEGylated hyaluronidase)</td><td rowspan="1" colspan="1">PEGPH20 + Nab-paclitaxel + Gemcitabine VS Nab-paclitaxel + Gemcitabine</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">2</td><td rowspan="1" colspan="1">NCT01839487</td></tr><tr><td rowspan="1" colspan="1">PEGPH20 + Nab-paclitaxel + Gemcitabine + Rivaroxaban</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">N/A</td><td rowspan="1" colspan="1">NCT02921022</td></tr><tr><td rowspan="1" colspan="1">PEGPH20 + Nab-Paclitaxel + Gemcitabine VS Placebo + Nab-Paclitaxel + Gemcitabine</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">3</td><td rowspan="1" colspan="1">NCT02715804</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">PEGPH20 monotherapy followed by combination therapy of PEGPH20 + Nab-Paclitaxel + Gemcitabine</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">2</td><td rowspan="1" colspan="1">NCT02487277</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1">Paricalcitol</td><td rowspan="1" colspan="1">Paricalcitol IV + Nab-paclitaxel + Gemcitabine VS Paricalcitol oral + Nab-paclitaxel + Gemcitabine VS Placebo + Nab-paclitaxel + Gemcitabine</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1/2</td><td rowspan="1" colspan="1">NCT03520790</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">Paricalcitol + Nab-paclitaxel + Gemcitabine + Nivolumab VS Nab-paclitaxel + Gemcitabine + Nivolumab</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">Early 1</td><td rowspan="1" colspan="1">NCT03519308</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">Paricalcitol + Nab-paclitaxel + Gemcitabine + Cisplatin</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">2</td><td rowspan="1" colspan="1">NCT03138720</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">Paricalcitol IV + Nab-paclitaxel + Gemcitabine</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">N/A</td><td rowspan="1" colspan="1">NCT02030860</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">Paricalcitol + Nab-paclitaxel + Cisplatin + Gemcitabine</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">2</td><td rowspan="1" colspan="1">NCT03415854</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">Paricalcitol IV + Nab-paclitaxel + Cisplatin + Gemcitabine + Nivolumab</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">2</td><td rowspan="1" colspan="1">NCT02754726</td></tr><tr><td rowspan="1" colspan="1">Nintedanib</td><td rowspan="1" colspan="1">Nintedanib monotherapy followed by combination therapy of Nintedanib + Gemcitabine + Nab-Paclitaxel</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1/2</td><td rowspan="1" colspan="1">NCT02902484</td></tr><tr><td rowspan="1" colspan="1">Nintedanib</td><td rowspan="1" colspan="1">Nintedanib + Nab-Paclitaxel VS Placebo + Nab-paclitaxel</td><td rowspan="1" colspan="1">Non-small cell lung cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1/2</td><td rowspan="1" colspan="1">NCT03361319</td></tr><tr><td rowspan="1" colspan="1">Metformin</td><td rowspan="1" colspan="1">Metformin + Nab-Paclitaxel + Gemcitabine + Dietary supplement</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1</td><td rowspan="1" colspan="1">NCT02336087</td></tr><tr><td rowspan="1" colspan="1">Hyaluronidase</td><td rowspan="1" colspan="1">VCN-01 (genetically modified human adenovirus encoding human PH20 hyaluronidase) + Gemcitabine + Nab-Paclitaxel</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1</td><td rowspan="1" colspan="1">NCT02045589</td></tr><tr><td rowspan="1" colspan="1">Hyaluronidase</td><td rowspan="1" colspan="1">VCN-01+ Nab-Paclitaxel + Gemcitabine VS VCN-01</td><td rowspan="1" colspan="1">Pancreatic cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1</td><td rowspan="1" colspan="1">NCT02045602</td></tr><tr><td colspan="6" align="center" rowspan="1"><bold>PEGylated Liposomal Doxorubicin (PLD), Doxil<sup>®</sup>, Caelyx<sup>®</sup></bold></td></tr><tr><td rowspan="1" colspan="1">Nintedanib (BIBF 1120)</td><td rowspan="1" colspan="1">Nintedanib + PLD + Carboplatin</td><td rowspan="1" colspan="1">Ovarian cancer, or peritoneal cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">1</td><td rowspan="1" colspan="1">NCT01314105</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">Nintedanib + PLD</td><td rowspan="1" colspan="1">Ovarian cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">Terminated (funding withdrawn due to drug unavailability)</td><td rowspan="1" colspan="1">NCT01485874</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">Nintedanib + PLD + Carboplatin</td><td rowspan="1" colspan="1">Ovarian cancer</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1">Terminated</td><td rowspan="1" colspan="1">NCT01329549</td></tr></tbody></table><table-wrap-foot><fn><p>ECM, extracellular matrix; 5-FU, 5-fluorouracil.</p></fn></table-wrap-foot></table-wrap><table-wrap id="T2" position="float"><label>Table 2</label><caption><p>Summary of ECM targeting strategies</p></caption><table frame="hsides" rules="groups"><thead valign="top"><tr><th rowspan="1" colspan="1">Mechanism</th><th rowspan="1" colspan="1">Agent</th><th rowspan="1" colspan="1">Treatment objective</th><th rowspan="1" colspan="1">Pathological conditions</th></tr></thead><tbody valign="top"><tr><td colspan="4" align="center" rowspan="1"><bold>Collagen</bold></td></tr><tr><td rowspan="3" colspan="1">Inhibition of collagen synthesis via TGF-β signaling</td><td rowspan="1" colspan="1">Intraperitoneal injection <xref rid="B109" ref-type="bibr">109</xref> or oral administration <xref rid="B110" ref-type="bibr">110</xref> of Halofuginone</td><td rowspan="1" colspan="1">Reduce fibrosis</td><td rowspan="1" colspan="1">Murine models of pancreas <xref rid="B109" ref-type="bibr">109</xref> and liver fibrosis <xref rid="B110" ref-type="bibr">110</xref></td></tr><tr><td rowspan="1" colspan="1">Intraperitoneal injection of Halofuginone</td><td rowspan="1" colspan="1">Inhibit the establishment and progression of melanoma bone metastases</td><td rowspan="1" colspan="1">Murine melanoma <xref rid="B111" ref-type="bibr">111</xref></td></tr><tr><td rowspan="1" colspan="1">Oral administration of Losartan</td><td rowspan="1" colspan="1">Enhance the efficacy of FOLFIRINOX chemotherapy</td><td rowspan="1" colspan="1">Human pancreatic cancer (NCT01821729) <xref rid="B114" ref-type="bibr">114</xref></td></tr><tr><td rowspan="3" colspan="1">Degradation of stromal collagen</td><td rowspan="1" colspan="1">Intratumoral injection of collagenase</td><td rowspan="1" colspan="1">Enhance the distribution of a herpes simplex virus vector</td><td rowspan="1" colspan="1">Human melanoma xenograft <xref rid="B124" ref-type="bibr">124</xref></td></tr><tr><td rowspan="1" colspan="1">Intravenous injection of collagenase</td><td rowspan="1" colspan="1">Improve the accumulation of a liposome/plasmid DNA complex</td><td rowspan="1" colspan="1">Murine lung tumor model <xref rid="B125" ref-type="bibr">125</xref></td></tr><tr><td rowspan="1" colspan="1">Collagenase-functionalized polystyrene nanoparticles</td><td rowspan="1" colspan="1">Enhance the penetration of the nanoparticles in multicellular spheroids</td><td rowspan="1" colspan="1">Human cervical carcinoma multicellular tumor spheroids <xref rid="B126" ref-type="bibr">126</xref></td></tr><tr><td rowspan="1" colspan="1">Stimulation of collagenase synthesis and downregulation of collagen production</td><td rowspan="1" colspan="1">Relaxin</td><td rowspan="1" colspan="1">Enhance the penetration of fluorescent-labeled dextran</td><td rowspan="1" colspan="1">Human osteosarcoma spheroids <xref rid="B131" ref-type="bibr">131</xref></td></tr><tr><td rowspan="1" colspan="1">Binding to denatured collagen</td><td rowspan="1" colspan="1">Collagen mimetic peptides</td><td rowspan="1" colspan="1">Monitor ECM-remodeling</td><td rowspan="1" colspan="1">Human prostate cancer xenograft <xref rid="B138" ref-type="bibr">138</xref></td></tr><tr><td rowspan="1" colspan="1">Binding to intact collagen</td><td rowspan="1" colspan="1">High density lipoprotein nanoparticles decorated with collagen binding molecules</td><td rowspan="1" colspan="1">Imaging of exposed collagen network</td><td rowspan="1" colspan="1">Murine model of atherosclerosis regression <xref rid="B182" ref-type="bibr">182</xref></td></tr><tr><td rowspan="1" colspan="1">Inhibition of collagen cross-linking</td><td rowspan="1" colspan="1">Simtuzumab (anti-LOXL2)</td><td rowspan="1" colspan="1">Enhance the efficacy of combination therapy with gemcitabine</td><td rowspan="1" colspan="1">Pancreatic cancer (NCT01472198) <xref rid="B145" ref-type="bibr">145</xref></td></tr><tr><td rowspan="1" colspan="1">Inhibition of collagen cross-linking</td><td rowspan="1" colspan="1">Poly(lactide-co-glycolide) nanoparticles decorated with LOX inhibitory antibody</td><td rowspan="1" colspan="1">Reduce tumor growth</td><td rowspan="1" colspan="1">Breast cancer xenograft mouse model <xref rid="B144" ref-type="bibr">144</xref></td></tr><tr><td rowspan="1" colspan="1">Imaging MMP-overexpressing cells</td><td rowspan="1" colspan="1">Nanoprobe system with a MMP-labile linker</td><td rowspan="1" colspan="1">Image MMP-2-overexpressing tumors</td><td rowspan="1" colspan="1">Human fibrosarcoma and glioma xenografts <xref rid="B183" ref-type="bibr">183</xref></td></tr><tr><td rowspan="1" colspan="1">Binding to integrins</td><td rowspan="1" colspan="1">Nanoparticles decorated with integrin binding molecules</td><td rowspan="1" colspan="1">Enhance tumor treatment and imaging</td><td rowspan="1" colspan="1">Multiple models <xref rid="B78" ref-type="bibr">78</xref></td></tr><tr><td colspan="4" align="center" rowspan="1"><bold>Hyaluronic acid</bold></td></tr><tr><td rowspan="1" colspan="1">Degradation of hyaluronic acid</td><td rowspan="1" colspan="1">Intravenous infusion of PEGylated human hyaluronidase (PEGPH20)</td><td rowspan="1" colspan="1">Enhance the efficacy of combination therapy with gemcitabine and nab-paclitaxel</td><td rowspan="1" colspan="1">Human pancreatic cancer (NCT02715804) <xref rid="B158" ref-type="bibr">158</xref></td></tr><tr><td rowspan="1" colspan="1">Hyaluronidase substrate</td><td rowspan="1" colspan="1">Hyaluronic acid tagged-gold nanoparticles</td><td rowspan="1" colspan="1">Detect hyaluronidase-overexpressing tumors</td><td rowspan="1" colspan="1">Ovarian tumor xenograft <xref rid="B186" ref-type="bibr">186</xref></td></tr><tr><td rowspan="1" colspan="1">Hyaluronidase substrate</td><td rowspan="1" colspan="1">Complexation of hyaluronic acid and cationic agent</td><td rowspan="1" colspan="1">Enhanced tumor penetration of polycationic agents</td><td rowspan="1" colspan="1">Multiple models <xref rid="B161" ref-type="bibr">161</xref></td></tr><tr><td rowspan="1" colspan="1">Inhibition of hyaluronic acid synthesis</td><td rowspan="1" colspan="1">4-methylumbelliferone</td><td rowspan="1" colspan="1">Reduce tumor progression</td><td rowspan="1" colspan="1">Multiple cell lines (<italic>in vitro</italic>) <xref rid="B163" ref-type="bibr">163</xref>, <xref rid="B164" ref-type="bibr">164</xref></td></tr><tr><td rowspan="1" colspan="1">Inhibition of hyaluronic acid synthesis</td><td rowspan="1" colspan="1">Liposome-encapsulated 4-methylumbelliferone</td><td rowspan="1" colspan="1">Enhance the efficacy of combination therapy with liposomal doxorubicin</td><td rowspan="1" colspan="1">4T1 murine breast tumor model <xref rid="B165" ref-type="bibr">165</xref></td></tr></tbody></table><table-wrap-foot><fn><p>ECM, extracellular matrix; FOLFIRINOX, the FOLFIRINOX chemotherapy regimen is a combination of the drugs 5-fluorouracil, leucovorin and oxaliplatin; LOXL2, Lysyl oxidase‐like 2; MMPs, matrix metalloproteinases; TGF-β, transforming growth factor beta.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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