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|Ref Type||Journal Article|
|Authors||Huber-Ruano I, Raventós C, Cuartas I, Sánchez-Jaro C, Arias A, Parra JL, Wosikowski K, Janicot M, Seoane J|
|Title||An antisense oligonucleotide targeting TGF-β2 inhibits lung metastasis and induces CD86 expression in tumor-associated macrophages.|
|Journal||Annals of oncology : official journal of the European Society for Medical Oncology|
|Date||2017 Sep 01|
|Abstract Text||The transforming growth factor (TGF)-β pathway is a well-described inducer of immunosuppression and can act as an oncogenic factor in advanced tumors. Several preclinical and clinical studies show that the TGF-β pathway can be considered a promising molecular target for cancer therapy. The human genome has three TGF-β isoforms and not much is known about the oncogenic response to each of the isoforms. Here, we studied the antitumor response to ISTH0047, a recently developed locked nucleic acid-modified antisense oligonucleotide targeting TGF-β2.We have studied the anticancer response to ISTH0047 using gymnotic delivery in tumor cell cultures and in in vivo preclinical orthotopic mouse models for primary tumors (breast and kidney tumors) and lung metastasis.We observed that ISTH0047 is able to significantly reduce TGF-β2 mRNA and protein levels without altering the levels of TGF-β1 and TGF-β3. ISTH0047 prevented lung metastasis in syngeneic orthotopic renal cell carcinoma (RENCA) and breast cancer (4T1) tumor models. In addition, using an orthotopic xenograft model of a lung cancer cell line (CRL5807) that mainly expresses TGF-β2, we observed that ISTH0047 had an important effect on the lung microenvironment inhibiting the growth of lung lesions. ISTH0047 treatment re-educated macrophages in the lung parenchyma to express the tumor-suppressive factor, CD86.Overall, our data point to TGF-β2 as a therapeutic target and ISTH0047 as a novel anticancer drug to prevent lung metastasis by impacting on the tumor niche, in part, through the induction of CD86 in tumor-associated macrophages.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|ISTH0047||ISTH0047 is a locked nucleic acid antisense oligonucleotide that targets TGF-beta2, which may result in decreased stromal TGF-beta2 expression and reduced tumor metastasis (PMID: 28911087).|
|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|
|Unknown unknown||breast cancer||not applicable||ISTH0047||Preclinical||Actionable||In a preclinical study, ISTH0047 reduced lung metastasis, but not primary tumor growth, in a mouse model of metastatic breast cancer (PMID: 28911087).||28911087|
|Unknown unknown||kidney cancer||not applicable||ISTH0047||Preclinical||Actionable||In a preclinical study, ISTH0047 reduced lung metastasis, but not primary tumor growth, in a mouse model of metastatic kidney cancer (PMID: 28911087).||28911087|