echinomycin and Brain-Neoplasms

The objective of this trial was to determine the efficacy of echinomycin (1.2 mg/m2) administered on a weekly times four schedule in the treatment of patients with recurrent or progressive central nervous malignancies despite adequate radiotherapy. Thirty-five patients were registered on study. The majority of patients (20) had glioblastoma multiforme. Ten had anaplastic astrocytoma. Eight patients had received prior nitrosoureas. SWOG performance status was 1 in 11 patients and 2 in 22. The median age was 51 years (25-75 years). One patient had a partial remission (3%:95% confidence interval: 1%-16%). Twenty two patients had progressive disease. The median survival was 5.9 months. Toxicity was primarily gastrointestinal with nausea and vomiting in 13 patients and nausea only in 11 patients. Hepatotoxicity occurred in 10 patients. Echinomycin given at this dose and schedule is not effective in treating patients with recurrent or progressive glioblastoma multiforme or anaplastic astrocytomas.

Topics: Adult; Aged; Brain Neoplasms; Drug Administration Schedule; Echinomycin; Female; Glioma; Humans; Male; Middle Aged; Survival Rate

Glioblastoma multiforme (GBM), a lethal brain tumor, remains the most daunting challenge in cancer therapy. Overexpression and constitutive activation of PDGFs and PDGFRα are observed in most GBM; however, available inhibitors targeting isolated signaling pathways are minimally effective. Therefore, better understanding of crucial mechanisms underlying GBM is needed for developing more effective targeted therapies.. Target genes controlled by HIF1α in GBM were identified by analysis of TCGA database and by RNA-sequencing of GBM cells with HIF1α knockout by sgRNA-Cas9 method. Functional roles of HIF1α, PDGFs and PDGFRs were elucidated by loss- or gain-of-function assays or chemical inhibitors, and compared in response to oxygen tension. Pharmacological efficacy and gene expression in mice with intracranial xenografts of primary GBM were analyzed by bioluminescence imaging and immunofluorescence.. HIF1α binds the PDGFD proximal promoter and PDGFRA intron enhancers in GBM cells under normoxia or mild-hypoxia to induce their expression and maintain constitutive activation of AKT signaling, which in turn increases HIF1α protein level and activity. Paradoxically, severe hypoxia abrogates PDGFRα expression despite enhancing HIF1α accumulation and corresponding PDGF-D expression. Knockout of HIF1A, PDGFD or PDGFRA in U251 cells inhibits cell growth and invasion in vitro and eradicates tumor growth in vivo. HIF1A knockdown in primary GBM extends survival of xenograft mice, whereas PDGFD overexpression in GL261 shortens survival. HIF1α inhibitor Echinomycin induces GBM cell apoptosis and effectively inhibits growth of GBM in vivo by simultaneously targeting HIF1α-PDGFD/PDGFRα-AKT feedforward pathway.. HIF1α orchestrates expression of PDGF-D and PDGFRα for constitutive activation of AKT pathway and is crucial for GBM malignancy. Therefore, therapies targeting HIF1α should provide an effective treatment for GBM.

Topics: Animals; Antibiotics, Antineoplastic; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Echinomycin; Enzyme Activation; Glioblastoma; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lymphokines; Mice; Mice, Inbred NOD; Neoplasm Invasiveness; Oxygen; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-akt; Receptor, Platelet-Derived Growth Factor alpha