Inhibitors of HGF or c MET have berberine shown preclinical activity against glioblastoma cell lines.79 The anti HGF antibody AMG102 enhanced TMZ induced inhibition of glioblastoma cell line growth in vitro and in xenografts, 81 and in an ongoing phase II trial in patients with recurrent glioblastoma, AMG102 was well tolerated, with initial evidence of response seen in a small proportion of patients.26 PF02341066, an orally available ATP competitive small molecule inhibitor of c MET that inhibited glioblastoma growth and cMET phosphorylation in preclinical studies,82 is under clinical investigation in patients with advanced cancers. Glutamate Receptor Inhibition Alpha amino 3 hydroxy 5 methyl 4 isoxazolepropionate glutamate receptor antagonists have been used to prevent neurotoxicity in several nontumor research chemicals library neurologic disorders. Because glioblastomas secrete glutamate, and because preclinical evidence suggests a role of the glutamate/ AMPA system in proliferation and migration, talampanel, an orally available BBB permeable AMPA inhibitor, has been assessed in clinical trials.
Initial phase I/II data for first line rhein talampanel combined with the standard of care have suggested improved efficacy compared with recent historical controls, the median OS duration was 18.3 months.25 However, a phase II trial of talampanel monotherapy in patients with recurrent disease found no significant activity.44 Histone Deacetylase Inhibition Histone deacetylases are involved in multiple processes shaping the malignant phenotype of glioma, including maintanance of stemness, angiogenesis, and resistance to DNA damage. Vorinostat is an orally available inhibitor of class I and II HDAC approved for advance cutaneous T cell lymphoma. In a phase II study of recurrent glioblastoma, vorinostat monotherapy was well tolerated and had modest clinical activity.45 Vorinostat is currently being evaluated for use in newly diagnosed and recurrent glioblastoma as a combination therapy. Death receptor targeting has been an experimental approach for malignant glioma for.1 decade.83 Death receptor ligand activation can also have TSA hdac inhibitor nonapoptotic effects, as demonstrated using anti CD95 antibody treatment of mouse glioblastoma models.84 APG101 is an inhibitor of CD95 ligand consisting of the CD95 receptor extracellular domain fused to the Fc domain of IgG.
A randomized phase II trial of APG101 plus radiotherapy versus radiotherapy has recently been initiated in patients with recurrent glioblastoma. Future research will determine whether inducing apoptosis or relying on the nonapoptotic properties of death ligands will be advantageous for glioblastoma treatment. Poly polymerase is a DNA repair enzyme implicated in the resistance tumor of tumors to DNA damaging anticancer agents and radiotherapy.85 Iniparib, which has recently demonstrated clinical efficacy in triple negative breast cancer,86 iscurrently being explored in a phase I/II study in patients with newly diagnosed glioblastoma. Discussion Targeted therapies have revolutionized oncology, causing a shift from systemic and/or slow release implants of cytotoxic drugs towards highly specific agents that are more selective at targeting tumor cells. Clinical studies of EGFR and PDGFR inhibitors as monotherapy.