trabedersen and Glioma

High-grade gliomas are the most common primary tumors in the central nervous system (CNS) in adults. Despite efforts to improve treatment by combination therapies (neurosurgery, radio- and chemotherapy), high-grade glioma patients still have a grim prognosis, indicating an urgent need for new therapeutic approaches. The molecular processes of gliomagenesis are being unraveled, and novel targeted therapeutic strategies to defy high-grade gliomas are emerging. Transforming growth factor-beta (TGF-β), in particular the TGF-β2 isoform, has been identified as a key factor in the progression of malignant gliomas. TGF-β2, originally described as "glioblastoma-derived T-cell suppressor factor", is associated with the immuno-suppressed status of patients with glioblastoma, and is therefore responsible for loss of tumor immune surveillance. Elevated TGF-β2 levels in tumors and in the plasma of patients have been associated with advanced disease stage and poor prognosis. Consequently, a targeted strategy to modulate TGF-β2 signaling is highly promising. The antisense oligonucleotide trabedersen (AP 12009) that specifically blocks TGF-β2 mRNA will be the main focus of this review. In three phase I/II studies and a randomized, active-controlled dose-finding phase IIb study, trabedersen treatment of high-grade glioma patients with recurrent or refractory tumor disease led to long-lasting tumor responses and so far promising survival data. On the basis of these data the currently ongoing phase III study SAPHIRRE was initiated.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Glioma; Humans; Oligodeoxyribonucleotides; Thionucleotides; Transforming Growth Factor beta2

Antisense oligodeoxynucleotides (AS-ODNs) have been widely used to determine gene function, validate drug targets and as novel therapeutics for human diseases. In this review, we describe the development of AS-ODNs, including their modifications, pharmacokinetics and toxicity in animal models and humans, and their preclinical and clinical development in the therapy of human high-grade gliomas. The most advanced AS-ODN for the therapy of high-grade gliomas is a phosphorothioate-modified AS-ODN, AP 12009 (trabedersen), which targets mRNA encoding TGF-beta2. AP 12009 is administered intratumorally using convection-enhanced delivery. A series of Phase I and II clinical trials have evaluated the toxicity profile and optimal dose of the substance. A randomized, controlled international Phase III study was initiated in March 2009 and will compare trabedersen 10 microM versus conventional alkylating chemotherapy in patients with recurrent or refractory anaplastic astrocytoma after standard radio- and chemotherapy.

Topics: Animals; Brain Neoplasms; Clinical Trials as Topic; Glioma; Humans; Injections, Intralesional; Oligodeoxyribonucleotides; Oligonucleotides, Antisense; Thionucleotides; Transforming Growth Factor beta2

Topics: Antineoplastic Agents; Brain Neoplasms; Clinical Trials, Phase II as Topic; Drug Delivery Systems; Glioma; Humans; Neoplasm Recurrence, Local; Oligodeoxyribonucleotides; Randomized Controlled Trials as Topic; Survival Rate; Thionucleotides; Transforming Growth Factor beta2; Treatment Outcome

Topics: Antineoplastic Agents; Brain Neoplasms; Clinical Trials, Phase II as Topic; Drug Delivery Systems; Glioma; Humans; Neoplasm Recurrence, Local; Oligodeoxyribonucleotides; Randomized Controlled Trials as Topic; Survival Rate; Thionucleotides; Transforming Growth Factor beta2; Treatment Outcome

Trabedersen (AP-12009), which is being developed by Antisense Pharma GmbH, is a synthetic antisense oligodeoxynucleotide designed to block the production of TGFbeta2, a secreted protein that can exert protumor effects. Trabedersen is indicated for the treatment of malignant brain tumors and other solid tumors overexpressing TGFbeta2, such as those of the skin, pancreas and colon. Preclinical studies demonstrated that trabedersen reduced the secretion of TGFbeta2 in cultured tumor cells and exhibited antitumor activity ex vivo. It was also demonstrated that chronic intracerebral or intravascular administration of trabedersen did not cause life-threatening side effects in animals. This observation was confirmed in early clinical trials in patients with advanced cancer. In a phase IIb trial, improved survival was observed in patients with brain tumors who were intratumorally administered trabedersen, compared with patients receiving standard chemotherapy. However, this observation requires validation by an ongoing large-scale, phase III, randomized, controlled trial. Meanwhile, continued research on trabedersen should help to determine the roles of TGFbeta2 in cancer and also further the development of antisense technology.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Clinical Trials as Topic; Drug Evaluation, Preclinical; Glioma; Humans; Neoplasms; Oligodeoxyribonucleotides; Oligonucleotides, Antisense; Thionucleotides; Transforming Growth Factor beta2