RADIOSENSITIZING EFFECTS OF THROMBIN PEPTIDE TP508 ON MEDULLOBLASTOMA CANCER STEM CELLS
Moya, Stephanie Michelle
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Brain cancer is the second leading cause of cancer-related deaths in children in the United States, with medulloblastoma leading all pediatric cases. With intensive treatments, including surgery, radiation, and/or chemotherapy, the average 5-year survival rate is approximately 60-80 percent. Unfortunately, nearly all survivors experience hindered quality of life due to radiation therapy induced cognitive dysfunctions. Additionally, current therapies are unsuccessful in completely eradicating the disease due to their inability to target a subpopulation of resistant cancer stem cells (CSCs) known to be responsible for tumor recurrence. Therefore, it is important to develop novel non-toxic therapeutics capable of sparing normal cells/tissues to prevent cognitive dysfunctions, while also sensitizing CSCs to radiation therapy in order to prevent tumor relapse. Recently our laboratory showed that thrombin peptide TP508, a novel 23-amino acid investigational drug, protects normal neural stem cells from ionizing radiation damage. To determine whether the peptide would also protect brain CSCs from radiation damage, I examined the effects of TP508 on the stemness and tumor relapse potential of medulloblastoma and glioblastoma CSCs, post-RT. In both tumor types, I concluded that TP508 did not protect CSCs from RT. More specifically, in medulloblastoma, I found that TP508 decreased CSC viability and stemness potential in vitro and delayed tumor growth in vivo post-RT. Therefore, I concluded that TP508 acts as a radiosensitizer of CSCs, making them more susceptible to RT damage and cellular death. Based on these findings, my goal was to identify the mechanisms by which the peptide exerts its radiosensitizing effects on CSCs. Specifically, my studies focused on investigating the effects of TP508 on DNA double-strand break repair mechanisms. Results showed that TP508 significantly sensitizes medulloblastoma CSCs to RT by inhibiting activation of DNA repair molecule, BRCA1, involved in homologous recombination, and by downregulating the activation of checkpoint kinases necessary for cell cycle arrest and repair. A strong understanding of the mechanisms by which TP508 exerts its effects on CSCs will allow for the development of this peptide as a novel therapeutic to target brain cancers, improve clinical outcome, and prevent tumor relapse.