Targeting transforming growth factor-β signaling in liver metastasis of colon cancer

Zhang, Bixiang; Halder, Sunil K.; Zhang, Sanguo; Datta, Pran K.

doi:10.1016/j.canlet.2008.11.035

Cited by 112 publications

(21 citation statements)

References 14 publications

(21 reference statements)

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“…CT-26 tumour cells harbour an activating mutation in K-Ras, 18 which commonly confers resistance to PI3K/mTORC1/2 inhibition. 19,20 We confirmed this prediction, observing that CT-26 tumours were insensitive to vistusertib when delivered with a regimen that promotes anti-tumour efficacy in sensitive tumour cell lines.…”

Section: Resultsmentioning

confidence: 99%

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

et al. 2018

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ABSTRACTmTOR inhibition can promote or inhibit immune responses in a context dependent manner, but whether this will represent a net benefit or be contraindicated in the context of immunooncology therapies is less understood. Here, we report that the mTORC1/2 dual kinase inhibitor vistusertib (AZD2014) potentiates anti-tumour immunity in combination with anti-CTLA-4 (αCTLA-4), αPD-1 or αPD-L1 immune checkpoint blockade. Combination of vistusertib and immune checkpoint blocking antibodies led to tumour growth inhibition and improved survival of MC-38 or CT-26 pre-clinical syngeneic tumour models, whereas monotherapies were less effective. Underlying these combinatorial effects, vistusertib/immune checkpoint combinations reduced the occurrence of exhausted phenotype tumour infiltrating lymphocytes (TILs), whilst increasing frequencies of activated Th1 polarized T-cells in tumours. Vistusertib alone was shown to promote a Th1 polarizing proinflammatory cytokine profile by innate primary immune cells. Moreover, vistusertib directly enhanced activation of effector T-cell and survival, an effect that was critically dependent on inhibitor dose. Therefore, these data highlight direct, tumour-relevant immune potentiating benefits of mTOR inhibition that complement immune checkpoint blockade. Together, these data provide a clear rationale to investigate such combinations in the clinic.

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Section: Resultsmentioning

confidence: 99%

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

et al. 2018

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“…For these experiments, we used the colon carcinoma cell lines MC-38 and CT26-wt (19,20), which secrete high levels of IL-10 and TGF-b (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

c-Src Suppresses Dendritic Cell Antitumor Activity via T Cell Ig and Mucin Protein-3 Receptor

Gujar

Maurya

Yadav

et al. 2016

The Journal of Immunology

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The enhanced expression of T cell Ig and mucin protein-3 (TIM-3) on tumor-associated dendritic cells (DCs) attenuates antitumor effects of DNA vaccines. To identify a potential target (or targets) for reducing TIM-3 expression on tumor-associated DCs, we explored the molecular mechanisms regulating TIM-3 expression. In this study, we have identified a novel signaling pathway (c-Src→Bruton’s tyrosine kinase→transcription factors Ets1, Ets2, USF1, and USF2) necessary for TIM-3 upregulation on DCs. Both IL-10 and TGF-β, which are produced in the tumor microenvironment, upregulated TIM-3 expression on DCs via this pathway. Suppressed expression of c-Src or downstream Bruton’s tyrosine kinase, Ets1, Ets2, USF1, or USF2 blocked IL-10– and TGF-β–induced TIM-3 upregulation on DCs. Notably, in vivo knockdown of c-Src in mice reduced TIM-3 expression on tumor-associated DCs. Furthermore, adoptive transfer of c-Src–silenced DCs in mouse tumors enhanced the in vivo antitumor effects of immunostimulatory CpG DNA; however, TIM-3 overexpression in c-Src–silenced DCs blocked this effect. Collectively, our data reveal the molecular mechanism regulating TIM-3 expression in DCs and identify c-Src as a target for improving the efficacy of nucleic acid–mediated anticancer therapy.

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“…These multiple roles of TGF-b in glioma initiation and progression have promoted the development of therapeutic agents based on the inhibition of the TGF-b pathway (13,15). LY2109761, a novel TGFbR-I kinase inhibitor, has shown a SMAD2-selective inhibitory profile with antitumor activity in various tumor models such as colorectal cancer (16), pancreatic cancer (17), and hepatocellular carcinoma (18).…”

Section: Introductionmentioning

confidence: 99%

Blockade of TGF-β Signaling by the TGFβR-I Kinase Inhibitor LY2109761 Enhances Radiation Response and Prolongs Survival in Glioblastoma

Kleber²,

et al. 2011

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Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that tends to be resistant to the ionizing radiotherapy used to treat it. Because TGF-b is a modifier of radiation responses, we conducted a preclinical study of the antitumor effects of the TGF-b receptor (TGFbR) I kinase inhibitor LY2109761 in combination with radiotherapy. LY2109761 reduced clonogenicity and increased radiosensitivity in GBM cell lines and cancer stem-like cells, augmenting the tumor growth delay produced by fractionated radiotherapy in a supra-additive manner in vivo. In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival, and extended the prolongation of survival induced by radiation treatment. Histologic analyses showed that LY2109761 inhibited tumor invasion promoted by radiation, reduced tumor microvessel density, and attenuated mesenchymal transition. Microarray-based gene expression analysis revealed signaling effects of the combinatorial treatments that supported an interpretation of their basis. Together, these results show that a selective inhibitor of the TGFbR-I kinase can potentiate radiation responses in glioblastoma by coordinately increasing apoptosis and cancer stem-like cells targeting while blocking DNA damage repair, invasion, mesenchymal transition, and angiogenesis. Our findings offer a sound rationale for positioning TGFbR kinase inhibitors as radiosensitizers to improve the treatment of glioblastoma. Cancer Res; 71(23); 7155-67. Ó2011 AACR.

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Targeting transforming growth factor-β signaling in liver metastasis of colon cancer

Cited by 112 publications

References 14 publications

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

c-Src Suppresses Dendritic Cell Antitumor Activity via T Cell Ig and Mucin Protein-3 Receptor

Blockade of TGF-β Signaling by the TGFβR-I Kinase Inhibitor LY2109761 Enhances Radiation Response and Prolongs Survival in Glioblastoma

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