| Autor: |
Eustace NJ; Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA., Anderson JC; Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA., Warram JM; Department of Otolaryngology, The University of Alabama at Birmingham, Birmingham, AL, USA., Widden HN; Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA., Pedersen RT; ChemoMetec, DK-3450, Allerod, Denmark., Alrefai H; Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA., Patel Z; Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA., Hicks PH; Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA., Placzek WJ; Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA., Gillespie GY; Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA., Hjelmeland AB; Department of Cell, Developmental and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL, USA., Willey CD; Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA. cwilley@uabmc.edu. |
| Abstrakt: |
Glioblastoma (GBM) is an aggressive malignancy with limited effectiveness of standard of care therapies including surgery, radiation, and temozolomide chemotherapy necessitating novel therapeutics. Unfortunately, GBMs also harbor several signaling alterations that protect them from traditional therapies that rely on apoptotic programmed cell death. Because almost all GBM tumors have dysregulated phosphoinositide signaling as part of that process, we hypothesized that peptide mimetics derived from the phospholipid binding domain of Myristoylated alanine-rich C-kinase substrate (MARCKS) could serve as a novel GBM therapeutic. Using molecularly classified patient-derived xenograft (PDX) lines, cultured in stem-cell conditions, we demonstrate that cell permeable MARCKS effector domain (ED) peptides potently target all GBM molecular classes while sparing normal human astrocytes. Cell death mechanistic testing revealed that these peptides produce rapid cytotoxicity in GBM that overcomes caspase inhibition. Moreover, we identify a GBM-selective cytolytic death mechanism involving plasma membrane targeting and intracellular calcium accumulation. Despite limited relative partitioning to the brain, tail-vein peptide injection revealed tumor targeting in intracranially implanted GBM PDX. These results indicate that MARCKS ED peptide therapeutics may overcome traditional GBM resistance mechanisms, supporting further development of similar agents. |
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