Abstract
Cancer consists not only of tumor cells but also of tumor stroma. The latter has various components such as fibroblasts, mesenchymal cells, blood vessels or extracellular matrix proteins (e.g. collagen, fibronectin or fibrin). (See chapter by Tarin describing the pathogenesis of cancer and stromal changes during the process). Moreover, it also promotes tumor cell growth, survival, invasion and metastasis. It is thus increasingly important to understand the role of tumor stroma in tumorigenesis and tumor progression. In this chapter, stroma-mediated drug-resistance and methods to overcome it are described and evaluated.
Most recently, antibody-drug conjugates (ADCs), consisting of an antibody and a cytotoxic drug connected via a specialized linker have become available as a next generation of antibody therapeutics, intended to enhance focused delivery of anti-cancer agents into the internal tumor environment.
However, none of them has been proved to be effective in treating refractory cancers such as pancreatic cancer or scirrhous gastric cancer. These cancers are known to possess abundant stroma, which hinders the distribution of therapeutic antibodies and ADCs within the cancerous growth. This is the so-called tumor stromal barrier.
To overcome this drawback, we have developed a unique type of ADC, namely, cancer stromal targeting (CAST) therapy, in which stroma targeting mAbs (anti-collagen 4 or anti-insoluble fibrin (IF) mAbs) were conjugated with anticancer agents. Our results confirmed that ADCs bound to collagen 4 or IF in the stroma, from which effective sustained release of the drugs occurred. The released drug subsequently diffused through the tumor tissue, causing marked arrest of tumor growth associated with damage to tumor blood vessels and death of cancer cells.
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Diamantis N, Banerji U (2016) Antibody-drug conjugates–an emerging class of cancer treatment. Br J Cancer 114:362–367. https://doi.org/10.1038/bjc.2015.435
Mack F, Ritchie M, Sapra P (2014) The next generation of antibody drug conjugates. Semin Oncol 41:637–652. https://doi.org/10.1053/j.seminoncol.2014.08.001
Senter PD, Sievers EL (2012) The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat Biotechnol 30:631–637. https://doi.org/10.1038/nbt.2289
Thomas A, Teicher BA, Hassan R (2016) Antibody-drug conjugates for cancer therapy. Lancet Oncol 17:e254–e262. https://doi.org/10.1016/s1470-2045(16)30030-4
Pro B et al (2012) Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol Off J Am Soc Clin Oncol 30:2190–2196. https://doi.org/10.1200/jco.2011.38.0402
Sau S, Alsaab HO, Kashaw SK, Tatiparti K, Iyer AK (2017) Advances in antibody-drug conjugates: a new era of targeted cancer therapy. Drug Discov Today 22:1547–1556. https://doi.org/10.1016/j.drudis.2017.05.011
Younes A et al (2012) Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol Off J Am Soc Clin Oncol 30:2183–2189. https://doi.org/10.1200/jco.2011.38.0410
Verma S et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783–1791. https://doi.org/10.1056/NEJMoa1209124
Matsumura Y (2012) Cancer stromal targeting (CAST) therapy. Adv Drug Deliv Rev 64:710–719. https://doi.org/10.1016/j.addr.2011.12.010
Matsumura Y et al (2004) Phase I and pharmacokinetic study of MCC-465, a doxorubicin (DXR) encapsulated in PEG immunoliposome, in patients with metastatic stomach cancer. Ann Oncol Off J Eur Soc Med Oncol 15:517–525
Yasunaga M, Manabe S, Matsumura Y (2011a) New concept of cytotoxic immunoconjugate therapy targeting cancer-induced fibrin clots. Cancer Sci 102:1396–1402. https://doi.org/10.1111/j.1349-7006.2011.01954.x
Yasunaga M, Manabe S, Tarin D, Matsumura Y (2011b) Cancer-stroma targeting therapy by cytotoxic immunoconjugate bound to the collagen 4 network in the tumor tissue. Bioconjug Chem 22:1776–1783. https://doi.org/10.1021/bc200158j
Yasunaga M, Manabe S, Tarin D, Matsumura Y (2013) Tailored immunoconjugate therapy depending on a quantity of tumor stroma. Cancer Sci 104:231–237. https://doi.org/10.1111/cas.12062
Shimokawa M et al (2017) Visualization and targeting of LGR5(+) human colon cancer stem cells. Nature 545:187–192. https://doi.org/10.1038/nature22081
Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8:755–768. https://doi.org/10.1038/nrc2499
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983–3988. https://doi.org/10.1073/pnas.0530291100
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013
Lapidot T et al (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–648. https://doi.org/10.1038/367645a0
O’Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110. https://doi.org/10.1038/nature05372
Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–115. https://doi.org/10.1038/nature05384
Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111. https://doi.org/10.1038/35102167
Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science (New York, NY) 219:983–985
Matsumura Y, Kimura M, Yamamoto T, Maeda H (1988) Involvement of the kinin-generating cascade in enhanced vascular permeability in tumor tissue. Jpn J Cancer Res 79:1327–1334
Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF (2008) Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis 11:109–119. https://doi.org/10.1007/s10456-008-9099-z
Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46:6387–6392
Adams GP, Weiner LM (2005) Monoclonal antibody therapy of cancer. Nat Biotechnol 23:1147–1157. https://doi.org/10.1038/nbt1137
Damelin M, Zhong W, Myers J, Sapra P (2015) Evolving strategies for target selection for antibody-drug conjugates. Pharm Res 32:3494–3507. https://doi.org/10.1007/s11095-015-1624-3
Doronina SO et al (2003) Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol 21:778–784. https://doi.org/10.1038/nbt832
Lyon RP et al (2015) Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nat Biotechnol 33:733–735. https://doi.org/10.1038/nbt.3212
Yasunaga M et al (2017) Development of antibody-drug conjugates using DDS and molecular imaging. Bioengineering (Basel, Switzerland) 4(3):78. https://doi.org/10.3390/bioengineering4030078
Dan N, Setua S, Kashyap VK, Khan S, Jaggi M, Yallapu MM, Chauhan SC (2018) Antibody-drug conjugates for cancer therapy: chemistry to clinical implications. Pharmaceuticals (Basel, Switzerland) 11(2):32. https://doi.org/10.3390/ph11020032
Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659. https://doi.org/10.1056/nejm198612253152606
Hisada Y et al (2013) Discovery of an uncovered region in fibrin clots and its clinical significance. Sci Rep 3:2604. https://doi.org/10.1038/srep02604
Fuchigami H, Manabe S, Yasunaga M, Matsumura Y (2018) Chemotherapy payload of anti-insoluble fibrin antibody-drug conjugate is released specifically upon binding to fibrin. Sci Rep 8:14211. https://doi.org/10.1038/s41598-018-32601-0
Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM (2003) Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol 163:1801–1815. https://doi.org/10.1016/s0002-9440(10)63540-7
Hingorani SR et al (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7:469–483. https://doi.org/10.1016/j.ccr.2005.04.023
Obonai T, Fuchigami H, Furuya F, Kozuka N, Yasunaga M, Matsumura Y (2016) Tumour imaging by the detection of fibrin clots in tumour stroma using an anti-fibrin Fab fragment. Sci Rep 6:23613. https://doi.org/10.1038/srep23613
Catenacci DV et al (2015) Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol Off J Am Soc Clin Oncol 33:4284–4292. https://doi.org/10.1200/jco.2015.62.8719
Hurwitz H et al (2018) Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies. Investig New Drugs 36:683–695. https://doi.org/10.1007/s10637-018-0580-2
Hingorani SR et al (2016) Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clin Cancer Res 22:2848–2854. https://doi.org/10.1158/1078-0432.ccr-15-2010
Olive KP et al (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science (New York, NY) 324:1457–1461. https://doi.org/10.1126/science.1171362
Laing N et al (2013) Inhibition of platelet-derived growth factor receptor alpha by MEDI-575 reduces tumor growth and stromal fibroblast content in a model of non-small cell lung cancer. Mol Pharmacol 83:1247–1256. https://doi.org/10.1124/mol.112.084079
Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Ruttinger D (2017) Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer 5:53. https://doi.org/10.1186/s40425-017-0257-y
Ostermann E et al (2008) Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin Cancer Res 14:4584–4592. https://doi.org/10.1158/1078-0432.ccr-07-5211
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Yasunaga, M., Manabe, S., Matsumura, Y. (2019). CAST Therapy. In: Matsumura, Y., Tarin, D. (eds) Cancer Drug Delivery Systems Based on the Tumor Microenvironment. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56880-3_12
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