LonP1 as a Key Driver of Tumor Progression and a Therapeutic Target in IDH Mutant Astrocytoma
Abstract
Diffuse glioma is designated as grade III-IV and has poor overall survival with inevitable recurrence. The IDH1 mutation co-occurring with 1p/19q codeletion classifies a distinct clinical glioma designated as IDH-mutant astrocytoma. While grade IV IDH-mutant astrocytoma also displays microvascular proliferation and/or necrosis, it is distinguished from IDH-wildtype grade IV glioblastoma. The presence of the IDH mutation usually changes underlying features of the hypoxic and treatment responses that entail improved overall survival and distinct pathways of resistance. More recent work has highlighted the importance of epithelial mesenchymal transition and more specifically local foci of Wnt signaling as being a mode for tumor progression in the latter. Understanding and ultimately targeting genetic drivers of epithelial mesenchymal transition in diffuse glioma may limit recurrence and improve clinical outcomes.In this thesis, evidence is provided for the role of LonP1 in driving and maintaining treatment resistance and features of epithelial mesenchymal transition in high grade IDH1 mutant astrocytoma. As part of this aim, we (1) explored the role of LonP1 in driving enhanced features of tumor progression in various types of diffuse glioma and (2) validating the use of a novel dual LonP1 and chymotrypsin-like proteasome inhibitor for supplementing the standard-of-care, Temolozomide in improving survival in an intracranial orthotopic xenograft model. We then (3) expanded upon the former aim to investigate the importance of LonP1 in different cell populations within the tumor microenvironment.