Anti-TGF-β1 aptamer enhances therapeutic effect of tyrosine kinase inhibitor, gefitinib, on non-small cell lung cancer in xenograft model

Abstract

Transforming growth factor β (TGF-β) is a multifunctional cytokine that plays crucial pathophysiological roles in various diseases, such as cancer and fibrosis. However, the disease modulation by targeting TGF-β1 isoform remains to be established, regardless of several studies employed with limited antibodies. Here, we developed an RNA aptamer to human active TGF-β1, named APT-β1, and characterized its properties in vitro and in vivo. APT-β1 bound to human and mouse active TGF-β1 proteins with high affinity and specificity and strongly inhibited TGF-β1-induced downstream signaling and cell morphology with 50% inhibition concentration (IC50) values at picomolar concentrations. In a xenograft mouse model of non-small cell lung cancer, APT-β1 alone showed no appreciable effect on tumor growth, while it greatly enhanced the anti-tumor effect of gefitinib, an approved tyrosine kinase inhibitor. These findings strongly suggest that the anti-TGF-β1 medication may be a promising cancer therapy to suppress repopulation of lung cancer in combination with certain anti-cancer drugs, such as gefitinib. Transforming growth factor β (TGF-β) is a multifunctional cytokine that plays crucial pathophysiological roles in various diseases, such as cancer and fibrosis. However, the disease modulation by targeting TGF-β1 isoform remains to be established, regardless of several studies employed with limited antibodies. Here, we developed an RNA aptamer to human active TGF-β1, named APT-β1, and characterized its properties in vitro and in vivo. APT-β1 bound to human and mouse active TGF-β1 proteins with high affinity and specificity and strongly inhibited TGF-β1-induced downstream signaling and cell morphology with 50% inhibition concentration (IC50) values at picomolar concentrations. In a xenograft mouse model of non-small cell lung cancer, APT-β1 alone showed no appreciable effect on tumor growth, while it greatly enhanced the anti-tumor effect of gefitinib, an approved tyrosine kinase inhibitor. These findings strongly suggest that the anti-TGF-β1 medication may be a promising cancer therapy to suppress repopulation of lung cancer in combination with certain anti-cancer drugs, such as gefitinib. IntroductionTransforming growth factor β (TGF-β) is a pleiotropic cytokine involved in diverse cellular events, including cell proliferation, differentiation, immune response, and apoptosis.1Morikawa M. Derynck R. Miyazono K. TGF-beta and the TGF-beta family: context-dependent roles in cell and tissue physiology.Cold Spring Harb. Perspect Biol. 2016; 8https://doi.org/10.1101/cshperspect.a021873Crossref PubMed Scopus (578) Google Scholar,2Derynck R. Budi E.H. Specificity, versatility, and control of TGF-beta family signaling.Sci. Signal. 2019; 12https://doi.org/10.1126/scisignal.aav5183Crossref Scopus (285) Google Scholar In mammals, there are three isoforms of TGF-β—TGF-β1, -β2, and -β3—encoded at distinct genomic loci,3Govinden R. Bhoola K.D. Genealogy, expression, and cellular function of transforming growth factor-beta.Pharmacol. Ther. 2003; 98: 257-265https://doi.org/10.1016/s0163-7258(03)00035-4Crossref PubMed Scopus (0) Google Scholar and TGF-β1 is the most abundant isoform in various tissues.4Flanders K.C. Yang Y.A. Herrmann M. Chen J. Mendoza N. Mirza A.M. Wakefield L.M. Quantitation of TGF-beta proteins in mouse tissues shows reciprocal changes in TGF-beta1 and TGF-beta3 in normal vs neoplastic mammary epithelium.Oncotarget. 2016; 7: 38164-38179https://doi.org/10.18632/oncotarget.9416Crossref PubMed Scopus (8) Google Scholar Although the isoforms largely overlap in their amino acid sequences and functions, in vivo studies using isoform-specific knockout mice showed distinct phenotypes,4Flanders K.C. Yang Y.A. Herrmann M. Chen J. Mendoza N. Mirza A.M. Wakefield L.M. Quantitation of TGF-beta proteins in mouse tissues shows reciprocal changes in TGF-beta1 and TGF-beta3 in normal vs neoplastic mammary epithelium.Oncotarget. 2016; 7: 38164-38179https://doi.org/10.18632/oncotarget.9416Crossref PubMed Scopus (8) Google Scholar,5Kulkarni A.B. Thyagarajan T. Letterio J.J. Function of cytokines within the TGF-beta superfamily as determined from transgenic and gene knockout studies in mice.Curr. Mol. Med. 2002; 2: 303-327https://doi.org/10.2174/1566524024605699Crossref PubMed Scopus (65) Google Scholar indicating differential expression profiles and mechanisms of action of the isoforms.6Kane C.J. Hebda P.A. Mansbridge J.N. Hanawalt P.C. Direct evidence for spatial and temporal regulation of transforming growth factor beta 1 expression during cutaneous wound healing.J. Cell. Physiol. 1991; 148: 157-173https://doi.org/10.1002/jcp.1041480119Crossref PubMed Scopus (191) Google Scholar, 7Schmid P. Cox D. Bilbe G. McMaster G. Morrison C. Stahelin H. Luscher N. Seiler W. TGF-beta s and TGF-beta type II receptor in human epidermis: differential expression in acute and chronic skin wounds.J. Pathol. 1993; 171: 191-197https://doi.org/10.1002/path.1711710307Crossref PubMed Scopus (114) Google Scholar, 8Annes J.P. Rifkin D.B. Munger J.S. The integrin alphaVbeta6 binds and activates latent TGFbeta3.FEBS Lett. 2002; 511: 65-68https://doi.org/10.1016/s0014-5793(01)03280-xCrossref PubMed Scopus (0) Google Scholar, 9Dong X. Hudson N.E. Lu C. Springer T.A. Structural determinants of integrin beta-subunit specificity for latent TGF-beta.Nat. Struct. Mol. Biol. 2014; 21: 1091-1096https://doi.org/10.1038/nsmb.2905Crossref PubMed Scopus (85) Google Scholar Thus, when considering TGF-βs as therapeutic targets, their roles in physiological events should be considered carefully.Over the past decades, TGF-β has gained attention as a therapeutic target in various diseases, such as tissue fibrosis and tumorigenesis. In relation to cancer, TGF-β exhibits both anti-tumoral and oncogenic properties; however, many agents blocking the TGF-β signaling pathway have demonstrated promising anti-tumor activity in preclinical studies.10Huang C.Y. Chung C.L. Hu T.H. Chen J.J. Liu P.F. Chen C.L. Recent progress in TGF-beta inhibitors for cancer therapy.Biomed. Pharmacother. 2021; 134: 111046https://doi.org/10.1016/j.biopha.2020.111046Crossref PubMed Scopus (31) Google Scholar,11Liu S. Ren J. Ten Dijke P. Targeting for cancer Ther. 2021; PubMed Scopus Google Scholar agents targeting distinct of the TGF-β signaling pathway have developed and in C.Y. Chung C.L. Hu T.H. Chen J.J. Liu P.F. Chen C.L. Recent progress in TGF-beta inhibitors for cancer therapy.Biomed. Pharmacother. 2021; 134: 111046https://doi.org/10.1016/j.biopha.2020.111046Crossref PubMed Scopus (31) Google J.J. J.J. in to target the TGF-beta 2021; PubMed Scopus Google Scholar However, therapy that the TGF-β signaling pathway has therapeutic evidence in Ten Dijke P. are in cancer are Biol. PubMed Scopus Google Scholar of the to including J. N. Ten Dijke P. targeting of TGF-beta in a of immune 2021; PubMed Scopus Google Scholar, C. D. R. P. to a of a transforming growth in with J. 2014; PubMed Scopus Google Scholar, J. J. S. K. R. 1 of receptor in with PubMed Scopus Google Scholar and in the such events in the be to inhibition of TGF-β J. N. Ten Dijke P. targeting of TGF-beta in a of immune 2021; PubMed Scopus Google Wakefield L.M. S. TGF-beta3 and a PubMed Scopus Google Scholar, K. S. T. Transforming growth factor in disease and PubMed Scopus Google Scholar, M. S. M. C. P. and in with disease by in J. PubMed Scopus Google Scholar, A.M. H. G. H. in a TGF-beta and PubMed Scopus Google Scholar, G. G. C. G. G. in transforming growth gene type PubMed Scopus Google Scholar, K. in mice and PubMed Scopus Google Scholar considering the expression and of several inhibitors to TGF-β1, such as and have developed and in preclinical and C. D. R. P. to a of a transforming growth in with J. 2014; PubMed Scopus Google M. M. H. K. M. P. targeting of in using the growth of 2019; PubMed Scopus Google Scholar The is a promising in of specificity to the of there are several and the have to be in C. D. R. P. to a of a transforming growth in with J. 2014; PubMed Scopus Google G. C. N. S. S. J. M. G. inhibition of TGF-beta1 by to in PubMed Scopus Google Scholar, C.J. C. C. S. inhibition of to therapy by tumor immune Med. Scopus Google Scholar, R. S. C.J. T. Chen D. S. J. of an for the of J. 2021; PubMed Scopus Google Scholar, P.A. D. P. N. J. J. human growth factor therapy in a of PubMed Scopus Google Scholar Thus, the of inhibition on various to be TGF-β1 to be developed and for therapeutic effect of inhibition diseases, including we developed an anti-TGF-β1 RNA APT-β1, and its effect on a xenograft cancer model using non-small cell lung cancer in TGF-β has a on in preclinical P.A. pathway inhibition in the of non-small cell lung Ther. PubMed Scopus Google Scholar acid to target of by to a and are by a as the of by in vitro of an RNA that PubMed Scopus Google C. of by RNA to PubMed Scopus Google Scholar These are to be a with of limited and tissue to the and as therapeutic PubMed Scopus Google and properties of APT-β1 TGF-β1 by and is of showed that APT-β1 binds to human TGF-β1, to and and latent TGF-β1 that is in the and APT-β1 binds to mouse TGF-β1 and inhibited to human APT-β1 by and at and to to M. for and of Scholar with and at to the The is to as and to the the of TGF-β1 at concentration to the receptor by with and at indicating the high of The of to be in the as by the and These showed the high affinity and specificity of of signaling of TGF-β with in sequences on genomic and the expression of various target a of physiological S. Ten Dijke P. Targeting TGF-beta signaling in PubMed Scopus Google Scholar Thus, we the effect of with and by using a in M. T. H. H. the and in Ther. PubMed Scopus Google Scholar In TGF-β1 expression with an 50% concentration of The expression by TGF-β1 by and at 50% inhibition concentration (IC50) values of and showed that to of in by TGF-β1 However, as a control a suppress of at W. D. transforming growth and transforming growth factor beta affinity Google Liu X. Chen J. S. W. Liu X. K. S. Chen J. tumor growth of tumor an anti-tumor in PubMed Scopus Google Scholar of the APT-β1 the activity TGF-β1 in the to of by and the specificity of to TGF-β1 and of and to TGF-β1-induced expression of the with the with various of In the TGF-β1 to with the in the of various of and The values as in to the TGF-β1 aptamer of in control the of APT-β1 on TGF-β1-induced gene of TGF-β1-induced expression of type 1 and N. and are with regulation in lung PubMed Scopus Google Scholar of in human lung that with TGF-β1 and by TGF-β1 by with of and while to a with of The with with of picomolar The with in a with of W. 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Chen J. tumor growth of tumor an anti-tumor in PubMed Scopus Google Scholar the effect of on TGF-β1-induced changes in expression of at the TGF-β1-induced changes in expression of and with at In and N. and are with regulation in lung PubMed Scopus Google Scholar by TGF-β1 and of Thus, is to TGF-β1-induced expression at both and in on using lung cancer we of TGF-β1-induced expression of in in and by Although in to its to TGF-β1, the in both cell inhibited TGF-β1-induced expression changes by effect of on the expression of TGF-β1-induced in and expression of TGF-β1-induced by with TGF-β1 in the of various of for and the expression of TGF-β and by The expression of by the expression of and the values of gene in the various as expression to in the control as is by a the The values of in the expression of TGF-β1-induced gene in the expression of TGF-β1-induced by in are and with TGF-β1 in the of for and the expression of by as a The expression of by the expression of and the values of gene in the various as expression to of control in as is by a by and by the in cell with and TGF-β1 in cell no in by cellular growth factor of Med. PubMed Scopus Google R. K. R. G. N. G. to both in and of the cell to an of in the cell PubMed Scopus Google Scholar in the of with TGF-β1 in the of TGF-β1 at for of as growth factor of Med. PubMed Scopus Google R. K. R. G. N. G. to both in and of the cell to an of in the cell PubMed Scopus Google Scholar and changes by at and showed no changes in cell TGF-β1 showed no in cell and Thus, a of in vitro showed a activity of the anti-TGF-β1 effect of in xenograft cancer model the in vivo effect of TGF-β1 inhibition by a xenograft cancer model to the anti-tumor effect of alone in combination with the tyrosine kinase gefitinib, and the in is a of of cancer, such as and in of the growth factor receptor C. M. D. T. as for with lung cancer with for and PubMed Scopus Google Scholar The xenograft model with is cancer a human cell in and and both of of oncogenic in of the M. T. T. 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PubMed Scopus Google Scholar xenograft tumor in the gene and in and a we to effect of the aptamer in several the effect of TGF-β1 by with and combination with and in and and and and The a inhibition of tumor growth by gefitinib, by in the in combination therapy for xenograft inhibited tumor growth with with there no appreciable and combination with as by the from xenograft and the of from of mice in effect of in xenograft cancer of xenograft cancer with and cancer with their as a control during in and In vivo of in are the gene in by an at the at the in vivo in mice in the the in the mice of in is at and in in xenograft and at and in in xenograft and their by and by the for at in at in of on in and is anti-cancer effect of on and the of and of in by the of and and in xenograft and and and in xenograft in by and by the for at in at in of at in and at in the of in combination during the to in and to in in in with the and and Thus, the repopulation of both and in be as indicating a action of with at and growth inhibited The of during in and in with the with that TGF-β1 inhibition has no effect on with anti-cancer and and The findings suggest that inhibition may as an for combination cancer therapy with certain of drugs, such as gefitinib, to has attention as a therapeutic target in cancer, the effect of inhibition remains to the limited of In the we developed anti-TGF-β1 and that inhibition in xenograft model enhanced anti-tumor effect of on cancer repopulation in combination binds to human and mouse TGF-β1 proteins with high affinity and specificity and TGF-β1 to its blocking the downstream signaling in vitro and in vivo and The that alone tumor growth in the mouse xenograft model with and human cell However, in combination with gefitinib, enhanced the effect of on cancer repopulation In xenograft at xenograft at the may on cell type and of gefitinib, may be high that aptamer effect Thus, that inhibition of TGF-β1 may be an in combination therapy for we the of the aptamer in combination the remains that may be by TGF-β1 inhibition the expression of such as from by TGF-β and M. in PubMed Scopus Google Scholar, H. J. H. plays a in the of and to to in PubMed Scopus Google Scholar, R. K. K. and of human non-small cell lung cancer J. PubMed Scopus Google Scholar, M. H. that to by 2: PubMed Scopus Google Scholar and effect of in tumor Recent studies have demonstrated the function of tumor in the oncogenic of TGF-β and its of during mammary of TGF-beta and the tumor during mammary PubMed Scopus (0) Google Scholar there are to for the action as considering of it has that anti-cancer of cell and its therapy enhanced by the inhibition of TGF-β1 signaling using such as and TGF-β1 G. C. N. S. S. J. M. G. inhibition of TGF-beta1 by to in PubMed Scopus Google Scholar, C.J. C. C. S. inhibition of to therapy by tumor immune Med. Scopus Google Scholar, R. S. C.J. T. Chen D. S. J. of an for the of J. 2021; PubMed Scopus Google Scholar aptamer targeting TGF-β X. X. G. H. aptamer targeting TGF-beta receptor II of human PubMed Scopus Google T. of RNA transforming growth type receptor on cell PubMed Scopus Google Scholar to be and no in vivo it to its therapeutic at showed that TGF-β1 of at the of and Thus, and activity is for agents targeting active TGF-β1, and may have and we to various such as of to TGF-β1 in cell of active and of TGF-β1 in and of and and in the in J. N. Ten Dijke P. targeting of TGF-beta in a of immune 2021; PubMed Scopus Google Scholar, C. D. R. P. to a of a transforming growth in with J. 2014; PubMed Scopus Google Scholar, J. J. S. K. R. 1 of receptor in with PubMed Scopus Google Scholar with no and there is a that the inhibition may have with These may a of the aptamer has high specificity to TGF-β1, limited and to cellular may be a promising for combination cancer therapy with that TGF-β1 is involved in and to studies are to the effect of inhibition on various events of using to of immune such as with and control for Although may be a in cancer the that active TGF-β1 the isoforms and its latent may as of TGF-β1-induced expression of and in certain of combination for with findings the that inhibition of TGF-β1 the and of in may as a for anti-cancer in combination The and affinity of to TGF-β1 should to in both neoplastic and and and of RNA from and its is as sequences for and in vitro as is in using the and The to using and in aptamer RNA in M. The using cell for and to RNA to cell 2016; PubMed Scopus Google aptamer human TGF-β1 as T. H. J. of of signaling and of in mouse PubMed Scopus Google Scholar RNA to a aptamer affinity TGF-β1 to In for to a sequences on the and cell using M. for and of for of the aptamer to activity and with to the to and sequences on and M. for and of Scholar The aptamer is in and at at and at The aptamer and by several for the aptamer by and at M. for and of Scholar The is as and and as using T. H. J. of of signaling and of in mouse PubMed Scopus Google R. T. H. K. M. in RNA aptamer from on and PubMed Scopus Google of to of aptamer with at and with of the proteins at concentration of for human TGF-β1 mouse TGF-β1 human human human latent TGF-β1 and human as a of and for s in inhibition effect of on of by amino the as in a of a at a concentration of in of the receptor of the receptor of TGF-β1 and at In of of of human TGF-β1 by amino the as in a of TGF-β1, of the aptamer by the aptamer at in of in the to of of using by using and of and of the aptamer by The using and model by and from the and and in with and and at in a human cell and from and and both cell in with and at in a with in and at a cell of The the with and with at a concentration of for at to the with and at a cell of 1 1 the with of TGF-β1 and aptamer at for with The with and the expression of by The with R. Bhoola K.D. Genealogy, expression, and cellular function of transforming growth factor-beta.Pharmacol. Ther. 2003; 98: 257-265https://doi.org/10.1016/s0163-7258(03)00035-4Crossref PubMed Scopus (0) Google Scholar and with in and at a cell of 1 with of TGF-β1 and aptamer at and for and with in and at a cell of and for of and and for expression of with of TGF-β1 and aptamer at for to in and for to expression of proteins and in and The with 1 1 and a with for and by on The proteins of using and The and in as mouse and mouse in vivo with a and in as in the using cell expression with in and at a cell of 1 with The with of TGF-β1 and aptamer at for with The with and to using a for to The by using an and a for human and from model and of and tumor growth by the gene and using a by of of the gene a of using an The the gene by a cell on the of that with the gene for cell by cell and of and cell the and with and in 50% at a concentration of 1 and of cell for and for the of mice by with an to the at of the of and the using a for to xenograft cancer the mice by aptamer as combination therapy from to and to of and as control of to as in xenograft and in for of repopulation of cancer for and in and to from to in xenograft and from to in for anti-cancer effect of on cancer in mice from and to the of the of The of approved by the on the of of the and in with the for of the for of to of the aptamer at a of as a control to the mice the aptamer of the aptamer in several and and tumor by to the K. H. S. S. M. S. K. J. J. for inhibition of by a Struct. Mol. Biol. 2016; PubMed Scopus Google Scholar concentration in and several tissues and with a using with and with amino with concentration of with by with and the of and by the and and the by of by for and the by by the by by the at IntroductionTransforming growth factor β (TGF-β) is a pleiotropic cytokine involved in diverse cellular events, including cell proliferation, differentiation, immune response, and apoptosis.1Morikawa M. Derynck R. Miyazono K. TGF-beta and the TGF-beta family: context-dependent roles in cell and tissue physiology.Cold Spring Harb. Perspect Biol. 2016; 8https://doi.org/10.1101/cshperspect.a021873Crossref PubMed Scopus (578) Google Scholar,2Derynck R. Budi E.H. Specificity, versatility, and control of TGF-beta family signaling.Sci. Signal. 2019; 12https://doi.org/10.1126/scisignal.aav5183Crossref Scopus (285) Google Scholar In mammals, there are three isoforms of TGF-β—TGF-β1, -β2, and -β3—encoded at distinct genomic loci,3Govinden R. Bhoola K.D. Genealogy, expression, and cellular function of transforming growth factor-beta.Pharmacol. Ther. 2003; 98: 257-265https://doi.org/10.1016/s0163-7258(03)00035-4Crossref PubMed Scopus (0) Google Scholar and TGF-β1 is the most abundant isoform in various tissues.4Flanders K.C. Yang Y.A. Herrmann M. Chen J. Mendoza N. Mirza A.M. Wakefield L.M. Quantitation of TGF-beta proteins in mouse tissues shows reciprocal changes in TGF-beta1 and TGF-beta3 in normal vs neoplastic mammary epithelium.Oncotarget. 2016; 7: 38164-38179https://doi.org/10.18632/oncotarget.9416Crossref PubMed Scopus (8) Google Scholar Although the isoforms largely overlap in their amino acid sequences and functions, in vivo studies using isoform-specific knockout mice showed distinct phenotypes,4Flanders K.C. Yang Y.A. Herrmann M. Chen J. Mendoza N. Mirza A.M. Wakefield L.M. Quantitation of TGF-beta proteins in mouse tissues shows reciprocal changes in TGF-beta1 and TGF-beta3 in normal vs neoplastic mammary epithelium.Oncotarget. 2016; 7: 38164-38179https://doi.org/10.18632/oncotarget.9416Crossref PubMed Scopus (8) Google Scholar,5Kulkarni A.B. Thyagarajan T. Letterio J.J. Function of cytokines within the TGF-beta superfamily as determined from transgenic and gene knockout studies in mice.Curr. Mol. Med. 2002; 2: 303-327https://doi.org/10.2174/1566524024605699Crossref PubMed Scopus (65) Google Scholar indicating differential expression profiles and mechanisms of action of the isoforms.6Kane C.J. Hebda P.A. Mansbridge J.N. Hanawalt P.C. Direct evidence for spatial and temporal regulation of transforming growth factor beta 1 expression during cutaneous wound healing.J. Cell. Physiol. 1991; 148: 157-173https://doi.org/10.1002/jcp.1041480119Crossref PubMed Scopus (191) Google Scholar, 7Schmid P. Cox D. Bilbe G. McMaster G. Morrison C. Stahelin H. Luscher N. Seiler W. TGF-beta s and TGF-beta type II receptor in human epidermis: differential expression in acute and chronic skin wounds.J. Pathol. 1993; 171: 191-197https://doi.org/10.1002/path.1711710307Crossref PubMed Scopus (114) Google Scholar, 8Annes J.P. Rifkin D.B. Munger J.S. The integrin alphaVbeta6 binds and activates latent TGFbeta3.FEBS Lett. 2002; 511: 65-68https://doi.org/10.1016/s0014-5793(01)03280-xCrossref PubMed Scopus (0) Google Scholar, 9Dong X. Hudson N.E. Lu C. Springer T.A. Structural determinants of integrin beta-subunit specificity for latent TGF-beta.Nat. Struct. Mol. Biol. 2014; 21: 1091-1096https://doi.org/10.1038/nsmb.2905Crossref PubMed Scopus (85) Google Scholar Thus, when considering TGF-βs as therapeutic targets, their roles in physiological events should be considered carefully.Over the past decades, TGF-β has gained attention as a therapeutic target in various diseases, such as tissue fibrosis and tumorigenesis. In relation to cancer, TGF-β exhibits both anti-tumoral and oncogenic properties; however, many agents blocking the TGF-β signaling pathway have demonstrated promising anti-tumor activity in preclinical studies.10Huang C.Y. Chung C.L. Hu T.H. Chen J.J. Liu P.F. Chen C.L. Recent progress in TGF-beta inhibitors for cancer therapy.Biomed. Pharmacother. 2021; 134: 111046https://doi.org/10.1016/j.biopha.2020.111046Crossref PubMed Scopus (31) Google Scholar,11Liu S. Ren J. Ten Dijke P. Targeting for cancer Ther. 2021; PubMed Scopus Google Scholar agents targeting distinct of the TGF-β signaling pathway have developed and in C.Y. Chung C.L. Hu T.H. Chen J.J. Liu P.F. Chen C.L. Recent progress in TGF-beta inhibitors for cancer therapy.Biomed. Pharmacother. 2021; 134: 111046https://doi.org/10.1016/j.biopha.2020.111046Crossref PubMed Scopus (31) Google J.J. J.J. in to target the TGF-beta 2021; PubMed Scopus Google Scholar However, therapy that the TGF-β signaling pathway has therapeutic evidence in Ten Dijke P. are in cancer are Biol. PubMed Scopus Google Scholar of the to including J. N. Ten Dijke P. targeting of TGF-beta in a of immune 2021; PubMed Scopus Google Scholar, C. D. R. P. to a of a transforming growth in with J. 2014; PubMed Scopus Google Scholar, J. J. S. K. R. 1 of receptor in with PubMed Scopus Google Scholar and in the such events in the be to inhibition of TGF-β J. N. Ten Dijke P. targeting of TGF-beta in a of immune 2021; PubMed Scopus Google Wakefield L.M. S. TGF-beta3 and a PubMed Scopus Google Scholar, K. S. T. Transforming growth factor in disease and PubMed Scopus Google Scholar, M. S. M. C. P. and in with disease by in J. PubMed Scopus Google Scholar, A.M. H. G. H. in a TGF-beta and PubMed Scopus Google Scholar, G. G. C. G. G. in transforming growth gene type PubMed Scopus Google Scholar, K. in mice and PubMed Scopus Google Scholar considering the expression and of several inhibitors to TGF-β1, such as and have developed and in preclinical and C. D. R. P. to a of a transforming growth in with J. 2014; PubMed Scopus Google M. M. H. K. M. P. targeting of in using the growth of 2019; PubMed Scopus Google Scholar The is a promising in of specificity to the of there are several and the have to be in C. D. R. P. to a of a transforming growth in with J. 2014; PubMed Scopus Google G. C. N. S. S. J. M. G. inhibition of TGF-beta1 by to in PubMed Scopus Google Scholar, C.J. C. C. S. inhibition of to therapy by tumor immune Med. Scopus Google Scholar, R. S. C.J. T. Chen D. S. J. of an for the of J. 2021; PubMed Scopus Google Scholar, P.A. D. P. N. J. J. human growth factor therapy in a of PubMed Scopus Google Scholar Thus, the of inhibition on various to be TGF-β1 to be developed and for therapeutic effect of inhibition diseases, including we developed an anti-TGF-β1 RNA APT-β1, and its effect on a xenograft cancer model using non-small cell lung cancer in TGF-β has a on in preclinical P.A. pathway inhibition in the of non-small cell lung Ther. PubMed Scopus Google Scholar acid to target of by to a and are by a as the of by in vitro of an RNA that PubMed Scopus Google C. of by RNA to PubMed Scopus Google Scholar These are to be a with of limited and tissue to the and as therapeutic PubMed Scopus Google Scholar

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