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Principal Investigator: Sherise Desiree Ferguson
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $202,500
Funding agency: National Institute of Neurological Disorders and Stroke
ABSTRACT/SUMMARY
Malignant gliomas, specifically glioblastoma (GBM), are highly aggressive, incurable brain tumors. Even with
maximal surgical resection, chemotherapy and radiation, tumor recurrence is absolute and median survival is
approximately 14 months. Immunotherapeutic strategies have had notable success in the management of
multiple solid malignancies. Unfortunately, immunotherapy, particularly checkpoint blockade, has had limited
success in the treatment of GBM due to its immunosuppressive microenvironment and multiple intrinsic immune
evasive mechanisms. Novel strategies to address local immunosuppression, augment the immune response
and enhance responsiveness to immunotherapies are warranted to improve patient outcome. The gut
microbiome is a well-established modulator of host immune responses. Microbiota-driven immunomodulation
has been demonstrated to impact responses to immunotherapy in multiple malignancies and interventions that
modulate the microbiome can enhance treatment response and improve patient outcome. In addition to the gut
microbiome, the intra-tumoral microbiome has also been demonstrated to impact patient response to
immunotherapy. The microbiome-gut-brain-axis is a known bidirectional pathway with extensive
immunomodulatory influence on the central nervous system (CNS) including a direct impact on the functionality
of microglia. Further the gut microbiome has also been implicated in the pathogenesis and progression of a
variety of neurological conditions. In addition to the gut microbiome, our own work and others have demonstrated
the presence of bacterial signatures in GBM patient samples, however the clinical impact of the GBM tumor
microbiome is unknown. Despite its pervasive influence, the role of the microbiome in CNS malignancies has
not been evaluated. We propose to address this gap in knowledge with a systematic, multi-platform evaluation
of the microbial composition GBM using prospectively collected clinical samples (tumor and gut/stool). We will
correlate these microbial signatures with both the immune composition of the GBM tumor microenvironment and
patient outcome measures. Further, we will compliment our clinical finding with preclinical, immunocompetent
GBM mouse model examining the impact of gut microbiome depletion on tumor growth and the tumor immune
microenvironment. Our hypothesis is that differential gut and tumor microbial signatures are present in GBM
patients, contribute to the tumor microenvironment composition and impact patient outcome. We will study this
via the following aims: AIM 1: Determine the gut and tumor microbiome signatures associated with improved
outcomes in patients with GBM. AIM 2: Determine the immunomodulatory role of the microbiome in GBM. If
successful, we will be the first to describe the role of the gut and tumor microbiome in malignant glioma. Our
long-term goal is to develop novel strategies to overcome therapeutic resistance and improve patient outcome.
Terms: <21+ years old><Abscission><Address><Adult><Adult Human><Architecture><Blood><Blood Reticuloendothelial System><Brain Cancer><Brain Neoplasia><Brain Neoplasms><Brain Tumors><CNS Nervous System><Cancer Center><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Central Nervous System><Chemotherapy and Radiation><Chemotherapy and/or radiation><Clinical><Data><Data Set><Dedications><Development><Disease><Disorder><Engineering / Architecture><Evaluation><Excision><Extirpation><Feces><GI microbiome><GI microbiota><Gastrointestinal microbiota><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Hortega cell><Immune><Immune Evasion><Immune mediated therapy><Immune response><Immunes><Immunocompetent><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunomodulators><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapeutic agent><Immunotherapy><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knowledge><Long-Term Survivors><Malignant Glial Neoplasm><Malignant Glial Tumor><Malignant Glioma><Malignant Neoplasms><Malignant Neuroglial Neoplasm><Malignant Neuroglial Tumor><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Mice><Mice Mammals><Microglia><Modeling><Murine><Mus><Neuraxis><Neuroglial Neoplasm><Neuroglial Tumor><Neurologic><Neurological><Operative Procedures><Operative Surgical Procedures><Outcome><Outcome Measure><Pathogenesis><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Property><RNA Seq><RNA sequencing><RNAseq><Recurrent Neoplasm><Recurrent tumor><Removal><Reporting><Resistance><Role><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Survivors><TCGA><The Cancer Genome Atlas><Treatment outcome><Viral><Work><adulthood><anti-tumor immune response><bio-informatics pipeline><bioinformatics pipeline><biological signal transduction><cancer care><cancer microenvironment><cancer type><candidate identification><check point blockade><checkpoint blockade><chemo/radiation therapy><chemotherapy and radiotherapy><clinical outcome measures><developmental><digestive tract microbiome><enteric microbial community><enteric microbiome><enteric microbiota><entire genome><fecal microbial transplantation><fecal microbiome transplantation><fecal microbiota transplant><fecal microbiota transplantation><fecal transplant><fecal transplantation><full genome><gastrointestinal microbial flora><gastrointestinal microbiome><genome sequencing><gitter cell><glial-derived tumor><glioblastoma multiforme><gut commensal><gut community><gut flora><gut microbe community><gut microbes><gut microbial community><gut microbial composition><gut microbial consortia><gut microbial species><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut to brain axis><gut-associated microbiome><gut-brain axis><gut-brain communication><gut-brain interactions><gut-brain relationship><gut-brain signaling><host response><immune check point blockade><immune checkpoint blockade><immune competent><immune drugs><immune evasive><immune microenvironment><immune modulation><immune modulators><immune regulation><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 therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive response><immunosuppressive tumor microenvironment><immunotherapeutics><immunotherapy agent><improved><improved outcome><insight><interventional strategy><intestinal biome><intestinal flora><intestinal microbes><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal tract microflora><longterm survivors><malignancy><measurable outcome><mesoglia><microbial><microbial composition><microbial consortia><microbial flora><microbial signature><microbiome><microbiome signature><microbiota><microflora><microglial cell><microgliocyte><mouse model><multispecies consortia><murine model><neoplasm recurrence><neoplasm/cancer><neural inflammation><neuroglia neoplasm><neuroglia tumor><neuroinflammation><neuroinflammatory><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><outcome measurement><pathway><patient oriented outcomes><patient response><patient specific response><perivascular glial cell><pre-clinical><preclinical><prospective><radiation or chemotherapy><resection><resistance to therapy><resistant><resistant to therapy><response><response to therapy><response to treatment><responsive patient><sample collection><social role><specimen collection><spongioblastoma multiforme><stool><success><surgery><therapeutic resistance><therapeutic response><therapy resistant><therapy response><transcriptome sequencing><transcriptomic sequencing><transplant model><treatment resistance><treatment response><treatment responsiveness><tumor><tumor growth><tumor immune microenvironment><tumor microbiome><tumor microenvironment><tumor-associated microbiome><tumor-immune system interactions><tumors in the brain><viral microbiome><virome><whole genome>