Reference Detail

Ref Type

Journal Article

PMID

(27863384)

Authors

Qin T, Barron L, Xia L, Huang H, Villarreal MM, Zwaagstra J, Collins C, Yang J, Zwieb C, Kodali R, Hinck CS, Kim SK, Reddick RL, Shu C, O'Connor-McCourt MD, Hinck AP, Sun LZ

Title

A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	7	52	2016 Dec 27	86087-86102	Oncotarget

URL

Abstract Text

The effects of transforming growth factor beta (TGF-β) signaling on prostate tumorigenesis has been shown to be strongly dependent on the stage of development, with TGF-β functioning as a tumor suppressor in early stages of disease and as a promoter in later stages. To study in further detail the paradoxical tumor-suppressive and tumor-promoting roles of the TGF-β pathway, we investigated the effect of systemic treatment with a TGF-β inhibitor on early stages of prostate tumorigenesis. To ensure effective inhibition, we developed and employed a novel trivalent TGF-β receptor trap, RER, comprised of domains derived from the TGF-β type II and type III receptors. This trap was shown to completely block TβRII binding, to antagonize TGF-β1 and TGF-β3 signaling in cultured epithelial cells at low picomolar concentrations, and it showed equal or better anti-TGF-β activities than a pan TGF-β neutralizing antibody and a TGF-β receptor I kinase inhibitor in various prostate cancer cell lines. Systemic administration of RER inhibited prostate tumor cell proliferation as indicated by reduced Ki67 positive cells and invasion potential of tumor cells in high grade prostatic intraepithelial neoplasia (PIN) lesions in the prostate glands of Pten conditional null mice. These results provide evidence that TGF-β acts as a promoter rather than a suppressor in the relatively early stages of this spontaneous prostate tumorigenesis model. Thus, inhibition of TGF-β signaling in early stages of prostate cancer may be a novel therapeutic strategy to inhibit the progression as well as the metastatic potential in patients with prostate cancer.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
RER	RER	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
RER		RII-BGE-RII	TGFB inhibitor 5	RER is a TGF-beta trivalent trap with avidity to TGF-beta1 and TGF-beta3, potentially inhibiting downstream TGF-beta signaling, cell migration, and cell proliferation (PMID: 27863384).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN del	prostate cancer	sensitive	RER	Preclinical	Actionable	In a preclinical study, RER treatment inhibited Tgf-beta and Akt pathways signaling, led to inhibition of tumor cell proliferation and tumorigenesis in a PTEN knock-out mouse model of prostate cancer (PMID: 27863384).	27863384