TGF-β as a therapeutic target in high grade gliomas – Promises and challenges

• Published in: Biochemical pharmacology Vol. 85; no. 4; pp. 478 - 485
• Main Authors: Joseph, Justin V., Balasubramaniyan, Veerakumar, Walenkamp, Annemiek, Kruyt, Frank A.E.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 15.02.2013
• Subjects: anticarcinogenic activity; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; brain; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Cancer stem cells; cell proliferation; clinical trials; cytokines; drugs; Glioma; Glioma - drug therapy; homeostasis; Humans; hypoxia; Microenvironment; neoplasms; parenchyma; patients; phenotype; prognosis; relapse; Signal Transduction - physiology; stem cells; TGF-β; therapeutics; Therapy; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - metabolism; Therapy; TGF-β; Microenvironment; Glioma; Cancer stem cells
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2012.11.005

Transforming growth factor-β (TGF-β) is a cytokine with a key role in tissue homeostasis and cancer. TGF-β elicits both tumor suppressive and tumor promoting functions during cancer progression, in a wide range of cancers. Here, we review the tumor promoting function of TGF-β and its possible promise as a therapeutic target in high grade gliomas, including glioblastoma multiforme (GBM), a disease with very poor prognosis. TGF-β signaling is highly active in high grade gliomas and elevated TGF-β activity has been associated with poor clinical outcome in this deadly disease. Common features of GBMs include fast cell proliferation, invasion into normal brain parenchyma, hypoxia, high angiogenic – and immunosuppressive activity, characteristics that all have been linked to activation of the TGF-β pathway. TGF-β signaling has also been connected with the cancer stem cell (CSC) phenotype in GBM. CSCs represent a subset of GBM cells thought to be responsible for tumor initiation, progression and relapse of disease. Following the description of these different properties of TGF-β signaling and the underlying mechanisms identified thus far, the promise of TGF-β targeted therapy in malignant gliomas is discussed. Several drugs targeting TGF-β signaling have been developed that showed potent antitumor activity in preclinical models. A number of agents are currently evaluated in early clinical studies in glioma patients. Available results of these studies are highlighted and a perspective on the promise of TGF-β-targeted therapy is given.