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Principal Investigator: Gary E Schiltz
Organization: LOYOLA UNIVERSITY CHICAGO
Fiscal Year: 2024
Award: $487,318
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
This R01 renewal proposal intends to extend the PI's past productivity that includes 35 publications since the
year, 2016, including 3 senior-authored manuscripts in Clinical Cancer Research and 2 additional bodies of work
that are under review in Neuro-Oncology and Nature. The scientific premise of the PI's renewal application is an
extension of continuous NIH/NINDS F32 (Postdoctoral NRSA), NIH/NINDS K99/R00 (Pathway To
Independence) and NIH/NINDS R01 support that have collectively focused on the investigation of indoleamine
2,3 dioxygenase 1 (IDO; IDO1) in glioblastoma (GBM). IDO is expressed in >90% of all patient-resected GBM
and potently suppresses the anti-GBM immune response. IDO expression is increased by GBM-infiltrating T
cells and therefore represents a key mechanism of resistance to immune-based therapies, since targeted
approaches that aim to enhance T cell infiltration into GBM, will in-turn, result in a compensatory increase of IDO
expression and suppression of the anti-GBM immune response. Importantly, the high intratumoral IDO
expression is associated with significantly decreased GBM patient survival and increased immunosuppressive
regulatory T cells (CD4+CD25+FoxP3+). Since IDO is canonically characterized as a rate-limiting enzyme that
metabolizes the essential amino acid, tryptophan (Trp), into the downstream metabolite, kynurenine (Kyn), the
depletion of Trp and/or accumulation of Kyn has been the presumed mechanism of how IDO suppresses the
anti-GBM immune response. However, our work has challenged this hypothesis, supported in-part through the
creation of IDO-deficient murine GBM cells reconstituted with either (i) empty expression vector, (ii) a vector
expressing wild-type IDO, (iii) or a vector expressing enzyme-inactive IDO. When intracranially-engrafted into
the syngeneic mouse brain, GBM cell IDO expression increases Tregs and decreases survival independent of
tryptophan metabolism. Our collective results indicate that GBM cell IDO represents a complex mechanism of
immune resistance that has motivated our development of IDO-proteolysis targeting chimeras (IDO-PROTACs)
- compounds that bind to IDO protein and recruit an E3 ubiquitin ligase to facilitate proteasome degradation.
IDO-PROTACs enable experiments to address IDO immunosuppressive effects that are enzyme independent.
The aims of our proposal are therefore to (i) investigate the mechanism responsible for GBM cell IDO enzyme
independent immunosuppression and (ii) design, create and optimize novel IDO-PROTACs that mediate IDO
protein degradation in human GBM cells. Determination of how IDO suppresses the immune response combined
with the generation of potent IDO-PROTACs will address knowledge gaps about GBM immunobiology while also
improving treatment outcomes of GBM patients that are co-treated with immunotherapy and IDO-PROTACs.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><21+ years old><Active Follow-up><Address><Adult><Adult Human><Affect><Amino Acids><Autologous><Binding><Biodistribution><Brain><Brain Cancer><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><CD25><Cell Body><Cells><Characteristics><Clinical><Complement Factor H><Complex><Data><Development><E3 Ligase><E3 Ubiquitin Ligase><Encephalon><Engraftment><Enhancers><Enzyme Antagonist><Enzyme Gene><Enzyme Inhibitor><Enzyme Inhibitor Agent><Enzyme Inhibitor Drugs><Enzymes><Essential Amino Acids><FOXP3><FOXP3 gene><Factor H><Forkhead Box P3><Future><Generations><Glioblastoma><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Heterograft><Heterologous Transplantation><Human><IDOase><IL2R><IL2RA><IL2RA gene><Immune><Immune mediated therapy><Immune response><Immunes><Immunobiology><Immunological response><Immunologically Directed Therapy><Immunophysiology><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Indoleamine 2,3-Dioxygenase><Intracranial Central Nervous System Neoplasms><Intracranial Central Nervous System Tumors><Intracranial Neoplasms><Intracranial Tumor><Investigation><JM2><Knowledge><Kynurenine><L-Tryptophan><Lead><Levotryptophan><Macropain><Macroxyproteinase><Malignant Tumor of the Brain><Malignant neoplasm of brain><Manuscripts><Mediating><Metabolic><Metabolic Protein Degradation><Mice><Mice Mammals><Microarray Analysis><Microarray-Based Analysis><Modern Man><Molecular><Molecular Interaction><Multicatalytic Proteinase><Murine><Mus><NIH><NINDS><NRSA><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><National Institutes of Health><National Research Service Awards><Nature><Newly Diagnosed><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pb element><Phase 3 Clinical Trials><Phase III Clinical Trials><Postdoc><Postdoctoral Fellow><Productivity><Property><Prosome><Protac><Proteasome><Proteasome Endopeptidase Complex><Protein Turnover><Proteins><Proteolysis targeting chimeric><Proteosome><Publications><Recurrence><Recurrent><Regulation><Regulatory Protein Degradation><Regulatory T-Lymphocyte><Research><Research Associate><Resected><SCURFIN><Scientific Publication><Short interfering RNA><Small Interfering RNA><Structure-Activity Relationship><T cell infiltration><TCGFR><Testing><Therapeutic><Treatment outcome><Treg><Tryptophan><Tryptophan 2,3 Dioxygenase><Tryptophan Metabolism><Tryptophan Metabolism Pathway><Tumor Immunity><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><United States National Institutes of Health><Up-Regulation><Upregulation><Work><Xenograft><Xenograft procedure><Xenotransplantation><active followup><adulthood><aminoacid><anti-cancer research><anti-tumor immune response><anti-tumor immunity><antitumor immunity><cancer immunity><cancer research><cancer type><check point blockade><checkpoint blockade><chemical structure function><design><designing><developmental><experiment><experimental research><experimental study><experiments><expression vector><follow up><follow-up><followed up><followup><glioblastoma multiforme><heavy metal Pb><heavy metal lead><host response><humanized mice><humanized mouse><immune check point blockade><immune checkpoint blockade><immune resistance><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immune-resistant><immuno therapy><immunoresistance><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><in vivo><interest><microarray analyses><microarray technology><mouse model><multicatalytic endopeptidase complex><murine model><neuro-oncology><neurooncology><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><pathway><patient oriented outcomes><pharmacologic><phase III protocol><post-doc><post-doctoral><post-doctoral trainee><protein degradation><proteolysis targeting chimera><reconstitute><reconstitution><recruit><regulatory T-cells><research associates><resistance mechanism><resistant mechanism><siRNA><spongioblastoma multiforme><structure function relationship><success><tool><tryptamine 2,3 dioxygenase><tumors in the brain><ubiquitin-protein ligase><vector><xeno-transplant><xeno-transplantation>