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A Perspective on the Development of TGF-? Inhibitors for Cancer Treatment.

ABSTRACT: Transforming growth factor (TGF)-? is a secreted multifunctional cytokine that signals via plasma membrane TGF-? type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-? signaling can contribute to cancer progression. In normal cells and early stages of cancer, TGF-? can stimulate epithelial growth arrest and elicit a tumor suppressor function. However, in late stages of cancer, when the cytostatic effects of TGF-? in cancer cells are blocked, TGF-? signaling can act as tumor promoter by its ability to stimulate epithelial-to-mesenchymal transition of cancer cells, by stimulating angiogenesis, and by promoting evasion of immune responses. In this review, we will discuss the rationale and challenges of targeting TGF-? signaling in cancer and summarize the clinical status of TGF-? signaling inhibitors that interfere with TGF?? bioavailability, TGF-??receptor interaction, or TGF-? receptor kinase function. Moreover, we will discuss targeting of TGF-? signaling modulators and downstream effectors as well as alternative approaches by using promising technologies that may lead to entirely new classes of drugs.

SUBMITTER: Huynh LK

PROVIDER: S-EPMC6921009 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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A Perspective on the Development of TGF-β Inhibitors for Cancer Treatment.

Huynh Linh Khanh LK Hipolito Christopher John CJ Ten Dijke Peter P

Biomolecules 20191117 11

Transforming growth factor (TGF)-β is a secreted multifunctional cytokine that signals via plasma membrane TGF-β type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-β signaling can contribute to cancer progression. In normal cells and early stages of cancer, TGF-β can stimulate epithelial growth arrest and elicit a tumor suppressor function. However, in late stages of cancer, when the cytostatic effects of TGF-β in cancer cells are ...[more]

PMID: 31744193

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Project description:BACKGROUNDCurrently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-β signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-β signaling in children with OI and conducted a phase I clinical trial of TGF-β inhibition in adults with OI.METHODSHistology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-β neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed.RESULTSOI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-β pathway as the top activated signaling pathway, and IPA showed that TGF-β1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD.CONCLUSIONIncreased TGF-β signaling is a driver pathogenic mechanism in OI. Anti-TGF-β therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover.TRIAL REGISTRATIONClinicalTrials.gov NCT03064074.FUNDINGBrittle Bone Disorders Consortium (U54AR068069), Clinical Translational Core of Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from National Institute of Child Health and Human Development, USDA/ARS (cooperative agreement 58-6250-6-001), and Sanofi Genzyme.

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A Perspective on the Development of TGF-? Inhibitors for Cancer Treatment.

Publications

A Perspective on the Development of TGF-β Inhibitors for Cancer Treatment.

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