Even with aggressive treatments, high?risk neuroblastoma often recurs. The prognosis is usually poor despite additional therapies. One of the features of high?risk neuroblastomas is their high S?phase fraction. Several lines of evidence suggest that in the aggressive cases, proliferative activities are predictive of poor outcomes. The hypothesis tested in these studies states that the second generation MIBG analogs radiolabeled with Auger?electron emitters can be developed into a nontoxic curative molecular radiotherapy for high?risk and aggressive neuroblastoma. Drugs developed in this application, because of their design and their mode of actions, have the potential to treat high?risk neuroblastoma. They mimic MIBG in their mechanism of neuroblastoma targeting, however, unlike MIBG they subsequently undergo intracellular processing and their metabolites are efficiently incorporated into the DNA of neuroblastoma cells, which have high proliferation activities, i.e., these of the high?risk and aggressive disease. Moreover, the structure of these drugs include groups allowing for the lock?in mechanism, which traps the metabolites within the cancer cells assuring their sustained availability throughout the cell cycle. Proposed studies are designed to follow two parallel lines of inquiry: (1) to define the mechanism(s) by which these drugs are taken up and processed by neuroblastoma cells in vivo and in vitro; and (2) the evaluation of these drugs and correlation of their properties with neuroblastoma cell proliferative activities. Seven new drugs will be initially screened in six neuroblastoma cells lines. When the correlative studies between the stability, uptake and intracellular processing are completed, the decision will be made to either select drugs suitable for in vivo testing or to continue to refine he structure of new drugs to improve their uptake and human serum stability. This information will be used to select four candidate drugs for the in vivo evaluation. In vivo studies have three objectives: (1) to determine biodistribution, pharmacokinetics, and dosimetry in tumor?bearing mice; (2) to measure subcellular distribution of radioactivity in extirpated tumors; (3) to evaluat the therapeutic potential of these drugs in transgenic mice. The characterization of new drugs will provide important stability and uptake information needed for further drug development and the chemical structure refinement studies. The long?term impact will be in providing safe and effective novel theranostic approach to the treatment of high?risk neuroblastoma.
Children with high?risk neuroblastoma have a 3?year event?free survival rate of <20%. Proposed studies develop and characterize new theranostics for high?risk neuroblastoma. These drugs have the potential to provide a treatment option significantly more effective and less toxic than 131IMIBG.
|Kortylewicz, Zbigniew P; Baranowska-Kortylewicz, Janina (2018) Radiosynthesis of microtubule-targeted theranostic methyl N-[5-(3'-radiohalobenzoyl)-1H-benzimidazol-2-yl]carbamates. J Labelled Comp Radiopharm :|