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Current Pharmaceutical Design

Editor-in-Chief

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

Mini-Review Article

Therapeutic Potential of Targeting Transforming Growth Factor-beta in Colorectal Cancer: Rational and Progress

Author(s): Meysam Gachpazan, Hoda Kashani, Seyed M. Hassanian, Majid Khazaei, Shadi Khorrami, Gordon A. Ferns and Amir Avan*

Volume 25, Issue 38, 2019

Page: [4085 - 4089] Pages: 5

DOI: 10.2174/1381612825666191105114539

Price: $65

Abstract

Background: Colorectal cancer (CRC) is one of the most common types of cancer and is associated with an increasing rate of mortality. Transforming Growth Factor-Beta (TGF-β) is often upregulated in CRC, and appears to play an important role in regulating cell proliferation, migration, immune surveillance, apoptosis, cell differentiation, drug-resistance and many cellular processes that may be involved in CRC, and therefore underscores its potential value as a therapeutic target in the treatment of CRC. An increased expression of the TGF- β pathway has been associated with poor prognosis in several cancer types, including CRC.

Methods: Here, we describe the critical role of the TGF-β pathway in CRC as well as the preclinical and clinical investigations on TGF-β inhibitors, with particular emphasis on recent findings with small-molecule inhibitors in CRC. Several TGF-β inhibitors (e.g., Trabedersen, Galunisertib, Gradalis, PF-03446962, NIS793) have been generated over the past decade for targeting this pathway.

Results: There is accumulating evidence of the therapeutic potential of this and other TGF-β inhibitors for the treatment of other malignancies. These inhibitors might be used in combination with chemotherapy as well as with other biological agents, in order to overcome different resistance mechanisms. However, further studies are needed to identify determinants of the activity of TGF-β inhibitors, through the analysis of genetic and environmental alterations affecting TGF-β and parallel pro-cancer pathways.

Conclusion: These studies will be critical to improving the efficacy and selectivity of current and future anticancer strategies targeting TGF-β.

Keywords: Colorectal cancer, TGF-β pathway, TGF-β inhibitors, anticancer strategies, therapeutic target, pro-cancer pathways.

[1]
Jones PA, Issa J-PJ, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet 2016; 17(10): 630-41.
[http://dx.doi.org/10.1038/nrg.2016.93] [PMID: 27629931]
[2]
van de Wetering M, Francies HE, Francis JM, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 2015; 161(4): 933-45.
[http://dx.doi.org/10.1016/j.cell.2015.03.053] [PMID: 25957691]
[3]
Linnekamp JF, Wang X, Medema JP, Vermeulen L. Colorectal cancer heterogeneity and targeted therapy: a case for molecular disease subtypes. Cancer Res 2015; 75(2): 245-9.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-2240] [PMID: 25593032]
[4]
Bauer J, Ozden O, Akagi N, et al. Activin and TGFβ use diverging mitogenic signaling in advanced colon cancer. Mol Cancer 2015; 14(1): 182.
[http://dx.doi.org/10.1186/s12943-015-0456-4] [PMID: 26497569]
[5]
Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med 2016; 14(1): 73.
[http://dx.doi.org/10.1186/s12916-016-0623-5] [PMID: 27151159]
[6]
Huang S, Hölzel M, Knijnenburg T, et al. MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. Cell 2012; 151(5): 937-50.
[http://dx.doi.org/10.1016/j.cell.2012.10.035] [PMID: 23178117]
[7]
Zhao S, Sun H, Jiang W, et al. miR-4775 promotes colorectal cancer invasion and metastasis via the Smad7/TGFβ-mediated epithelial to mesenchymal transition. Mol Cancer 2017; 16(1): 12.
[http://dx.doi.org/10.1186/s12943-017-0585-z] [PMID: 28095858]
[8]
Tauriello DVF, Palomo-Ponce S, Stork D, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018; 554(7693): 538-43.
[http://dx.doi.org/10.1038/nature25492] [PMID: 29443964]
[9]
Wang J-L, Qi Z, Li Y-H, Zhao H-M, Chen Y-G, Fu W. TGFβ induced factor homeobox 1 promotes colorectal cancer development through activating Wnt/β-catenin signaling. Oncotarget 2017; 8(41): 70214-25.
[http://dx.doi.org/10.18632/oncotarget.19603] [PMID: 29050273]
[10]
Ikushima H, Miyazono K. TGF beta signalling: a complex web in cancer progression. Nat Rev Cancer 2010; 10(6): 415-24.
[http://dx.doi.org/10.1038/nrc2853] [PMID: 20495575]
[11]
Friedman E, Gold LI, Klimstra D, Zeng ZS, Winawer S, Cohen A. High levels of transforming growth factor beta 1 correlate with disease progression in human colon cancer. Cancer Epidemiol Biomarkers Prev 1995; 4(5): 549-54.
[PMID: 7549813]
[12]
Tsushima H, Kawata S, Tamura S, et al. High levels of transforming growth factor beta 1 in patients with colorectal cancer: association with disease progression. Gastroenterology 1996; 110(2): 375-82.
[http://dx.doi.org/10.1053/gast.1996.v110.pm8566583] [PMID: 8566583]
[13]
Wakefield LM, Hill CS. Beyond TGFβ: roles of other TGFβ superfamily members in cancer. Nat Rev Cancer 2013; 13(5): 328-41.
[http://dx.doi.org/10.1038/nrc3500] [PMID: 23612460]
[14]
Feng J, Song D, Jiang S, Yang X, Ding T, Zhang H, et al. Quercetin restrains TGF-β1-induced epithelial-mesenchymal transition by inhibiting Twist1 and regulating E-cadherin expression. Biochem Biophys Res Commun 2018; 498(1): 132-8.
[http://dx.doi.org/10.1016/j.bbrc.2018.02.044]
[15]
Ji Q, Liu X, Han Z, et al. Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-β1/Smads signaling pathway mediated Snail/E-cadherin expression. BMC Cancer 2015; 15(1): 97.
[http://dx.doi.org/10.1186/s12885-015-1119-y] [PMID: 25884904]
[16]
Tang B, Vu M, Booker T, et al. TGF-β switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J Clin Invest 2003; 112(7): 1116-24.
[http://dx.doi.org/10.1172/JCI200318899] [PMID: 14523048]
[17]
Zhang YE. Non-Smad pathways in TGF-β signaling. Cell Res 2009; 19(1): 128-39.
[http://dx.doi.org/10.1038/cr.2008.328] [PMID: 19114990]
[18]
Wrana JL, Attisano L, Wieser R, Ventura F, Massagué J. Mechanism of activation of the TGF-β receptor. Nature 1994; 370(6488): 341-7.
[http://dx.doi.org/10.1038/370341a0] [PMID: 8047140]
[19]
Lebrin F, Goumans MJ, Jonker L, et al. Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transduction. EMBO J 2004; 23(20): 4018-28.
[http://dx.doi.org/10.1038/sj.emboj.7600386] [PMID: 15385967]
[20]
Nakao A, Imamura T, Souchelnytskyi S, et al. TGF-β receptor-mediated signalling through Smad2, Smad3 and Smad4. EMBO J 1997; 16(17): 5353-62.
[http://dx.doi.org/10.1093/emboj/16.17.5353] [PMID: 9311995]
[21]
Massagué J, Seoane J, Wotton D. Smad transcription factors. Genes Dev 2005; 19(23): 2783-810.
[http://dx.doi.org/10.1101/gad.1350705] [PMID: 16322555]
[22]
Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P. Balancing the activation state of the endothelium via two distinct TGF‐β type I receptors. The EMBO J 2002; 21(7): 1743-53.
[http://dx.doi.org/10.1093/emboj/21.7.1743] [PMID: 11927558]
[23]
Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL. SARA, a FYVE domain protein that recruits Smad2 to the TGF beta receptor. Cell 1998; 95(6): 779-91.
[http://dx.doi.org/10.1016/S0092-8674(00)81701-8] [PMID: 9865696]
[24]
Nakao A, Afrakhte M, Morén A, et al. Identification of Smad7, a TGF beta-inducible antagonist of TGF-β signalling. Nature 1997; 389(6651): 631-5.
[http://dx.doi.org/10.1038/39369] [PMID: 9335507]
[25]
Hayashi H, Abdollah S, Qiu Y, et al. The MAD-related protein Smad7 associates with the TGF beta receptor and functions as an antagonist of TGF beta signaling. Cell 1997; 89(7): 1165-73.
[http://dx.doi.org/10.1016/S0092-8674(00)80303-7] [PMID: 9215638]
[26]
Schlingensiepen R, Goldbrunner M, Szyrach MN, et al. Intracerebral and intrathecal infusion of the TGF-β 2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: toxicology and safety. Oligonucleotides 2005; 15(2): 94-104.
[http://dx.doi.org/10.1089/oli.2005.15.94] [PMID: 15989424]
[27]
Bogdahn U, Hau P, Stockhammer G, et al. Targeted therapy for high-grade glioma with the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol 2011; 13(1): 132-42.
[http://dx.doi.org/10.1093/neuonc/noq142] [PMID: 20980335]
[28]
Hilbig A, Seufferlein T, Schmid R, et al. Preliminary results of a phase I/II study in patients with pancreatic carcinoma, malignant melanoma, or colorectal carcinoma using systemic iv administration of AP 12009. J Clin Oncol 2008; 26(15 Suppl.): 4621.
[http://dx.doi.org/10.1200/jco.2008.26.15_suppl.4621]
[29]
Jaschinski F, Rothhammer T, Jachimczak P, Seitz C, Schneider A, Schlingensiepen K-H. The antisense oligonucleotide trabedersen (AP 12009) for the targeted inhibition of TGF-β2. Curr Pharm Biotechnol 2011; 12(12): 2203-13.
[http://dx.doi.org/10.2174/138920111798808266] [PMID: 21619536]
[30]
Herbertz S, Sawyer JS, Stauber AJ, et al. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des Devel Ther 2015; 9: 4479-99.
[PMID: 26309397]
[31]
Senzer N, Barve M, Kuhn J, et al. Phase I trial of “bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell” vaccine (FANG) in advanced cancer. Mol Ther 2012; 20(3): 679-86.
[http://dx.doi.org/10.1038/mt.2011.269] [PMID: 22186789]
[32]
van Meeteren LA, Thorikay M, Bergqvist S, et al. Anti-human activin receptor-like kinase 1 (ALK1) antibody attenuates bone morphogenetic protein 9 (BMP9)-induced ALK1 signaling and interferes with endothelial cell sprouting. J Biol Chem 2012; 287(22): 18551-61.
[http://dx.doi.org/10.1074/jbc.M111.338103] [PMID: 22493445]
[33]
Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 2011; 129(1): 245-55.
[http://dx.doi.org/10.1002/ijc.25864] [PMID: 21170960]
[34]
Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381(9863): 303-12.
[http://dx.doi.org/10.1016/S0140-6736(12)61900-X] [PMID: 23177514]
[35]
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366(26): 2443-54.
[http://dx.doi.org/10.1056/NEJMoa1200690] [PMID: 22658127]
[36]
Villalba M, Evans SR, Vidal-Vanaclocha F, Calvo A. Role of TGF-β in metastatic colon cancer: it is finally time for targeted therapy. Cell Tissue Res 2017; 370(1): 29-39.
[http://dx.doi.org/10.1007/s00441-017-2633-9] [PMID: 28560691]
[37]
Slattery ML, Herrick JS, Lundgreen A, Wolff RK. Genetic variation in the TGF-β signaling pathway and colon and rectal cancer risk. Cancer Epidemiol Biomarkers Prev 2011; 20(1): 57-69.
[http://dx.doi.org/10.1158/1055-9965.EPI-10-0843] [PMID: 21068203]
[38]
Gotovac JR, Fujihara KM, Phillips WA, Clemons NJ. TGF-beta signaling and its targeted therapy in gastrointestinal cancers. Discov Med 2018; 26(142): 103-12.
[PMID: 30399328]
[39]
Neuzillet C, Tijeras-Raballand A, Cohen R, et al. Targeting the TGFβ pathway for cancer therapy. Pharmacol Ther 2015; 147: 22-31.
[http://dx.doi.org/10.1016/j.pharmthera.2014.11.001] [PMID: 25444759]

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