Glioblastoma (GBM) is the most common primary brain tumor in adults. Standard treatment involves surgery, followed by radiation and DNA alkylating agents like temozolomide. However, the tumors almost always recur, with median survival remaining in the range of 1-2 years. Current therapies depend on triggering cell suicide (apoptosis) by causing DNA damage, but genetic alterations in GBM cells make them relatively insensitive to apoptotic stimuli. Studies completed during the preceding project period led to the identification of a unique form of cell death termed 'methuosis', which is mechanistically distinct from apoptosis. It involves stimulation of macropinocytosis (cell drinking) together with changes in trafficking of endocytic vesicles, leading to massive cellular vacuolization and loss of membrane integrity. New compounds were discovered to induce methuosis in a broad spectrum of GBM cells, including those that are resistant temozolomide. Structure-activity studies have provided a lead compound referred to by the acronym MOMIPP. The Central Hypothesis underlying the continuation of this project is that a new type of localized therapy for GBM may be realized through the identification of the molecular targets of MOMIPP and the development of nanoparticle (NP) delivery vehicles and/or targeted prodrugs that can be used to direct the compound specifically to GBM. To test this hypothesis three Specific Aims are proposed:
Aim -1) Identify the relevant protein target(s) of MOMIPP. This will involve several complementary approaches, including the use of radiolabeled MOMIPP and inactive analogs for differential display analysis of protein arrays, and the use of MOMIPP photoaffinity probes combined with mass spectrometry to identify drug-binding proteins in intact GBM cells.
Aim -2) Develop strategies to optimize delivery of MOMIPP to GBM cells. The underlying premise is that MOMIPP might be most effective as an adjuvant therapy for GBM if delivered locally in a sustained release NP formulation. To minimize potential toxicity to normal cells, innovative strategies will be evaluated for selective delivery of the compound to GBM by decorating the NP with GBM-homing peptides or loading them with a MOMIPP prodrug containing a removable GBM-targeting peptide.
Aim -3) Evaluate the toxicity, pharmacokinetic properties and anti-tumor efficacy of MOMIPP in GBM xenograft models. Targeted NP and prodrug formulations with the greatest potential for selective delivery of MOMIPP to GBM will be tested in orthotopic xenografts derived from wt and temozolomide-resistant GBM cell lines or stem cells enriched from primary human GBM. These studies are expected to identify formulations that will inhibit tumor progression with minimal systemic toxicity or ill effects on normal neural cells. Impact: The results could have a substantial impact on GBM therapy by validating a new class of drugs that can kill GBM cells by a novel non-apoptotic mechanism. In addition, the development of tumor-homing NP or prodrugs that can be targeted to GBM would represent a technological advance that might be applied more generally for delivery of other therapeutic agents.
Glioblastomas are highly aggressive brain tumors that typically recur after surgery and therapy with radiation and conventional drugs, which kill tumor cells by a classical death pathway termed apoptosis. This project will explore the ability of a new class of chemical compounds to kill glioblastoma cells via a different cell death mechanism and test the effectiveness of innovative tumor-specific drug delivery strategies to avoid collateral damage to normal brain cells. The results could lead to a new approach for treatment of glioblastoma.
|Li, Zehui; Mbah, Nneka E; Maltese, William A (2017) Vacuole-inducing compounds that disrupt endolysosomal trafficking stimulate production of exosomes by glioblastoma cells. Mol Cell Biochem :|
|Mbah, Nneka E; Overmeyer, Jean H; Maltese, William A (2017) Disruption of endolysosomal trafficking pathways in glioma cells by methuosis-inducing indole-based chalcones. Cell Biol Toxicol 33:263-282|
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|Maltese, William A; Overmeyer, Jean H (2015) Non-apoptotic cell death associated with perturbations of macropinocytosis. Front Physiol 6:38|
|Trabbic, Christopher J; Overmeyer, Jean H; Alexander, Evan M et al. (2015) Synthesis and biological evaluation of indolyl-pyridinyl-propenones having either methuosis or microtubule disruption activity. J Med Chem 58:2489-512|
|Trabbic, Christopher J; Dietsch, Heather M; Alexander, Evan M et al. (2014) Differential Induction of Cytoplasmic Vacuolization and Methuosis by Novel 2-Indolyl-Substituted Pyridinylpropenones. ACS Med Chem Lett 5:73-77|
|Maltese, William A; Overmeyer, Jean H (2014) Methuosis: nonapoptotic cell death associated with vacuolization of macropinosome and endosome compartments. Am J Pathol 184:1630-42|
|Robinson, Michael W; Overmeyer, Jean H; Young, Ashley M et al. (2012) Synthesis and evaluation of indole-based chalcones as inducers of methuosis, a novel type of nonapoptotic cell death. J Med Chem 55:1940-56|
|Overmeyer, Jean H; Maltese, William A (2011) Death pathways triggered by activated Ras in cancer cells. Front Biosci (Landmark Ed) 16:1693-713|
|Wilson, Eden N; Bristol, Molly L; Di, Xu et al. (2011) A switch between cytoprotective and cytotoxic autophagy in the radiosensitization of breast tumor cells by chloroquine and vitamin D. Horm Cancer 2:272-85|
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