Development of Oncolytic Adenovirus Armed with a Fusion of Soluble Transforming Growth Factor-<i>?</i>Receptor II and Human Immunoglobulin Fc for Breast Cancer Therapy

Seth, Prem; Wang, Zhenguo; Pister, Amanda; Zafar, Maria; Kim, Sung Hoon; Guise, Theresa A.; Wakefield, Lalage M.

doi:10.1089/hum.2006.17.ft-252

Cited by 13 publications

(26 citation statements)

References 26 publications

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“…Seth et al [218] have recently proposed a novel approach to cancer gene therapy in which the oncolytic effects of an infectious adenoviral vector are combined with selective expression of a soluble fusion protein composed of the type II TGFβ receptor II extracellular domain and the Fc portion of IgG (Fc:TβRII) to antagonize active TGFβ in the tumor microenvironment. An oncolytic adenovirus expressing Fc:TβRII, was constructed by homologous recombination.…”

Section: Preclinical Therapeutic Studies Of Tgfβ Antagonists Against mentioning

confidence: 99%

Transforming growth factor-β signaling: emerging stem cell target in metastatic breast cancer?

Tan¹,

Alexe

Reiß³

2008

Breast Cancer Res Treat

120

123

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In most human breast cancers, lowering of TGFβ receptor-or Smad gene expression combined with increased levels of TGFβs in the tumor microenvironment is sufficient to abrogate TGFβs tumor suppressive effects and to induce a mesenchymal, motile and invasive phenotype. In genetic mouse models, TGFβ signaling suppresses de novo mammary cancer formation but promotes metastasis of tumors that have broken through TGFβ tumor suppression. In mouse models of "triple-negative" or basal-like breast cancer, treatment with TGFβ neutralizing anti-bodies or receptor kinase inhibitors strongly inhibits development of lung-and bone metastases. These TGFβ antagonists do not significantly affect tumor cell proliferation or apoptosis. Rather, they de-repress anti-tumor immunity, inhibit angiogenesis and reverse the mesenchymal, motile, invasive phenotype characteristic of basal-like and HER2-positive breast cancer cells. Patterns of TGFβ target genes upregulation in human breast cancers suggest that TGFβ may drive tumor progression in estrogenindependent cancer, while it mediates a suppressive host cell response in estrogen-dependent luminal cancers. In addition, TGFβ appears to play a key role in maintaining the mammary epithelial (cancer) stem cell pool, in part by inducing a mesenchymal phenotype, while differentiated, estrogen receptorpositive, luminal cells are unresponsive to TGFβ because the TGFBR2 receptor gene is transcriptionally silent. These same cells respond to estrogen by downregulating TGFβ, while antiestrogens act by upregulating TGFβ. This model predicts that inhibiting TGFβ signaling should drive the differentiation of mammary stem cells into ductal cells. Consequently, TGFβ antagonists may convert basal-like or HER2-positive cancers to a more epithelioid, non-proliferating (and, perhaps, non-metastatic) phenotype. Conversely, these agents might antagonize the therapeutic effects of anti-estrogens in estrogen-dependent luminal cancers. These predictions need to be addressed prospectively in clinical trials and should inform the selection of patient populations most likely to benefit from this novel anti-metastatic therapeutic approach.© Springer Science+Business Media, LLC. 2008 e-mail: E-mail: michael.reiss@umdnj.edu. NIH Public Access TGFβ in health and disease Physiological functions of TGFβThe TGFβ family of polypeptides comprises a group of highly conserved dimeric proteins with a molecular weight of approximately 25 kDa [1]. They are ubiquitously expressed in eukaryotes and typically secreted into the extracellular milieu in an inactive form, where they become locally activated in response to the appropriate stimuli [2][3][4]. As shown in Fig. 1A, the TGFβ signaling pathway is highly conserved from lower organisms, such as D. melanogaster, to man. TGFβ binds to the type II TGFβ receptor (TβR-II) kinase. The type I receptor (TβR-I) is then recruited into the ligand/TβR-II complex and phosphorylated and activated by the TβR-II kinase. The activated TβR-I receptor then phosphorylates receptor-ass...

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Section: Preclinical Therapeutic Studies Of Tgfβ Antagonists Against mentioning

confidence: 99%

Transforming growth factor-β signaling: emerging stem cell target in metastatic breast cancer?

Tan¹,

Alexe

Reiß³

2008

Breast Cancer Res Treat

120

123

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“…17 Furthermore, it had been reported that systemic administration of an oncolytic adenovirus expressing a soluble form of TGF-b receptor II fused with human Fc IgG1 (sRIIFc) resulted in significant inhibition of tumor growth of established bone metastases in a human xenograft mouse model. [18][19][20] In this study, we evaluated the strategies to deliver modified TGF-b receptors to the tumor environment by antigen-specific T cells. We constructed three g-retroviral vectors, one that expressed mouse TGF-b-dominant-negative receptor II (MSGV1.DNRII), a second that secreted a soluble TGF-b-RII containing the extracellular domain of TGF-b-RII (MSGV1.sRII) and third a soluble TGFb-RIIFc, in which the extracellular domain was fused to the mouse immunoglobulin (IgG 2a ) Fc fragment (MSGV1.sRIIFc) (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of TGF-β signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy

Zhang

Muranski

et al. 2012

Gene Ther

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Transforming growth factor β (TGF-β) is a cytokine with complex biological functions that may involve tumor promotion or tumor suppression. It has been reported that multiple types of tumors secrete TGF-β, which can inhibit tumor-specific cellular immunity and may represent a major obstacle to the success of tumor immunotherapy. In this study, we sought to enhance tumor immunotherapy using genetically modified antigen-specific T cells by interfering with TGF-β signaling. We constructed three γ-retroviral vectors, one that expressed TGF-β-dominant-negative receptor II (DNRII) or two that secreted soluble TGF-β receptors: soluble TGF-β receptor II (sRII) and the sRII fused with mouse IgG Fc domain (sRIIFc). We demonstrated that T cells genetically modified with these viral vectors were resistant to exogenous TGF-β-induced smad-2 phosphorylation in vitro. The functionality of antigen-specific T cells engineered to resist TGF-β signaling was further evaluated in vivo using the B16 melanoma tumor model. Antigen-specific CD8+ T cells (pmel-1) or CD4+ T cells (tyrosinase-related protein-1) expressing DNRII dramatically improved tumor treatment efficacy. There was no enhancement in the B16 tumor treatment using cells secreting soluble receptors. Our data support the potential application of the blockade of TGF-β signaling in tumor-specific T cells for cancer immunotherapy.

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“…TGFb inhibitors are being developed as antimetastatic agents for treating patients with cancer because TGFb has a variety of antitumorigenic effects (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)31). Although ligand traps, such as 1D11 (17), and antisense-specific oligos (ASO), such as AP12009 (32), limit the bioavailability of active TGFb ligands, they fail to directly block signaling through the receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Thus far, the following three approaches have been used to inhibit TGFb signaling: (i) inhibition of TGFb signaling at a translational level using antisense oligonucleotides (15,16); (ii) inhibition of the ligandreceptor interaction using monoclonal antibodies (mAb; refs. [17][18][19][20]; and (iii) inhibition of the receptor-mediated signaling cascade using inhibitors of TGFb receptor kinases (21). Small-molecule inhibitors of TGFb/ALK5 kinase activity, such as SD-208 (22), SB-431542 (23), Ki26894 (24), LY-215799 (14), and LY-2109761 (25), which compete for the ATP-binding site of ALK5, have been successfully used to suppress tumor development and metastasis in animal models.…”

Section: Introductionmentioning

confidence: 99%

EW-7197, a Novel ALK-5 Kinase Inhibitor, Potently Inhibits Breast to Lung Metastasis

Son

Park

Kim

et al. 2014

Molecular Cancer Therapeutics

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Advanced tumors produce an excessive amount of transforming growth factor b (TGFb), which promotes tumor progression at late stages of malignancy. The purpose of this study was to develop anti-TGFb therapeutics for cancer. We synthesized a novel small-molecule TGFb receptor I kinase (activin receptorlike kinase 5) inhibitor termed N- [[4-([1,2,4], and we investigated its potential antimetastatic efficacy in mouse mammary tumor virus (MMTV)/c-Neu mice and 4T1 orthotopic-grafted mice. EW-7197 inhibited Smad/ TGFb signaling, cell migration, invasion, and lung metastasis in MMTV/c-Neu mice and 4T1 orthotopicgrafted mice. EW-7197 also inhibited the epithelial-to-mesenchymal transition (EMT) in both TGFb-treated breast cancer cells and 4T1 orthotopic-grafted mice. Furthermore, EW-7197 enhanced cytotoxic T lymphocyte activity in 4T1 orthotopic-grafted mice and increased the survival time of 4T1-Luc and 4T1 breast tumorbearing mice. In summary, EW-7197 showed potent in vivo antimetastatic activity, indicating its potential for use as an anticancer therapy.

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Development of Oncolytic Adenovirus Armed with a Fusion of Soluble Transforming Growth Factor-?Receptor II and Human Immunoglobulin Fc for Breast Cancer Therapy

Cited by 13 publications

References 26 publications

Transforming growth factor-β signaling: emerging stem cell target in metastatic breast cancer?

Transforming growth factor-β signaling: emerging stem cell target in metastatic breast cancer?

Inhibition of TGF-β signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy

EW-7197, a Novel ALK-5 Kinase Inhibitor, Potently Inhibits Breast to Lung Metastasis

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