Addressing pharmacological challenges to the treatment of pediatric brain tumors using modern technology
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Clark, Amanda Renee
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CitationClark, Amanda Renee. 2021. Addressing pharmacological challenges to the treatment of pediatric brain tumors using modern technology. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.
AbstractDespite decades of research, several obstacles remain a challenge to effectively treat and manage pediatric brain tumors. Tumor type, drug delivery, and drug distribution are three factors that contribute to the obstacles limiting effective treatment of these diseases. The following work establishes a foundation for the ways that modern technology can be applied to address unmet needs of pediatric brain tumors. With regard to tumor type, matrix assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) was applied to characterize the metabolomic profile of medulloblastomas and pineoblastoma. This work demonstrated that MALDI MSI is capable of distinguishing these two histopathologically similar tumor types and could be a useful method to aid in rapid diagnosis of medulloblastomas from pineoblastoma during surgical procedures. In terms of drug delivery, the blood-brain barrier (BBB) represents a considerable challenge to treating pediatric brain tumors. Transcytosis, a novel mechanism of BBB regulation suggested to be controlled by an omega-3 enriched lipid profile, may have potential to be harnessed for drug delivery purposes. To begin to understand whether transcytosis could be modulated for drug delivery purposes, the distributions of transcytosis lipids in mouse brains from an omega-3 deficient diet model were spatially resolved using a combination of high spatial resolution and high spectral resolution MALDI MSI platforms. Transcytosis lipids displayed regional patterns throughout the brain and the omega-3 containing transcytosis lipid species exhibited significantly decreased signal intensity in the mouse brains from the omega-3 deficient diet group. Lastly, after a drug traverses the BBB to reach its therapeutic target for pediatric brain tumors, another challenge remains: ensuring that an appropriate drug response occurs. Following a first-in-human study of a novel pre-clinical ACVR1 inhibitor, TP-0184, in a diffuse intrinsic pontine glioma patient which showed high drug penetrance without matching response, we applied an untargeted “-omics” approach to investigate drug response mechanisms in the patient’s treatment naïve cell line. The integrated use of RNA-sequencing and phosphoproteomics demonstrated that adaptive response mechanisms in the cell signaling network could arise in response to drug exposure, suggesting that TP-0184 may be more effective if used in combination with additional targeted receptor tyrosine kinase inhibitors. Collectively, the findings discussed in this thesis advance our understanding of childhood brain cancers and showcases some of the ways in which modern technology can be applied to address pharmacological barriers in disease states.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37368311
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