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Principal Investigator: DEBABRATA MUKHOPADHYAY
Organization: MAYO CLINIC JACKSONVILLE
Fiscal Year: 2024
Award: $599,828
Funding agency: National Institute of Neurological Disorders and Stroke
Glioblastoma multiforme (GBM) is associated with poor prognosis due to its highly invasive and drug-resistant
phenotype. Recurrence is a common phenomenon in GBM patients due to the presence of chemo- and radio-
resistant Brain Tumor-Initiating Cells (BTICs). Consequently, current therapies including surgery followed by
radiation or chemotherapy with Temozolomide (TMZ) failed to improve patient median overall survival
emphasizing the necessity of novel treatment strategies for drug-resistant GBM. Interestingly, Neuroplin-1
(NRP1) has been shown to be implicated in the drug-resistance and stemness in multiple types of cancer.
Recently, we showed that depletion of NRP1 improved survival compared to that of vascular endothelial growth
factor (VEGF-A) depletion in mice bearing patient-derived GBM xenografts. NRP1 depletion also improved
sensitivity to TMZ and enhanced the overall survival when combined with TMZ. Our preliminary data further
showed that a proprietary tumor-targeted liposomal (TTL) formulation combining a first generation small-
molecule NRP1 inhibitor (EG00229; G in short) with Everolimus (E) provided significant survival advantage in
TMZ resistant glioma cells as compared to that of TMZ alone. However, EG00229 is poorly water soluble, and
its liposomal formulation is not stable for long term storage. Hence, we developed a new generation of small-
molecule NRP1 inhibitors (NRP1i, Ni in short) with better solubility in order to create a stable liposomal
formulation. The central hypothesis of our proposal is that NRP1i combined with everolimus in a single payload
using TTL, either as a systemic therapy or delivered locally in a hydrogel-based system, will reduce drug-
resistance and stemness and augment radiation sensitivity in GBM, leading to better therapeutic outcomes. To
validate our hypothesis, we propose three major aims. In Aim 1, we will combine the most effective NRP1i with
everolimus as a single payload in TTL formulation (TTL-ENi) for evaluating in vitro efficacy in inhibiting stemness
and drug-resistance signaling pathways and in vivo studies using multiple therapy resistance BTICs animal
models including immune-competent mice models. Further, the additive effect of radiotherapy and chemotherapy
(e.g. TMZ) in combination with the TTL-ENi will be evaluated. We will also analyze the effect of our proposed
therapy on the tumor immune microenvironment using two state-of-the-art techniques namely mass cytometry
(CyTOF) and digital spatial profiling (DSP). In Aim 2, we will assess the efficacy of the local administration of
TTL-ENi-hydrogel in a resection and recurrence model of GBM. Moreover, the additive effect of radiotherapy
and chemotherapy (e.g. TMZ) in combination with the TTL-ENi-hydrogel will be evaluated. Aim 3 will focus on
the comparative pharmacokinetics, pharmacodynamics, and preliminary toxicity studies of the most potent
formulation for future clinical trials. We expect that a successful execution of our proposed research will lead to
clinical trial in near future for a better therapeutic strategy to override the drug-resistance in GBM patients as
well as patients suffering from other drug-resistant cancers.
Terms: <A5 Antigen><Abscission><Address><Animal Model><Animal Models and Related Studies><Animals><BBB crossing><Biodistribution><Brain Cancer><Brain Neoplasia><Brain Neoplasms><Brain Tumors><Cancers><Cell Body><Cell Line><CellLine><Cells><Chemoresistance><Chemotherapy and Radiation><Chemotherapy and/or radiation><Clinical><Clinical Trials><Cytometry><Data><Delayed-Action Preparations><Disease><Disorder><Drug Delivery><Drug Delivery Systems><Drug Formulations><Drug Kinetics><Drug Targeting><Drug resistance><Drugs><Evaluation><Excision><Extirpation><Formulation><Future><Generalized Growth><Generations><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Growth><Heterograft><Heterologous Transplantation><Human><Hydrogels><Hydrogen Oxide><Immunocompetent><In Situ><In Vitro><Injections><Intrasurgical Resection Cavity><Invaded><Laboratories><Lead><Liposomal><Liposomes><Local Therapy><Localized Therapy><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Mediating><Medication><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><NIH><NRP1 Protein><Nanoplatform><Nanotechnological platform><Nanotechnology><National Institutes of Health><Neuroglial Neoplasm><Neuroglial Tumor><Neuropilin-1><Npn-1 Protein><Operative Procedures><Operative Surgical Procedures><Outcome><Patients><Pb element><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Phenotype><Pre-Clinical Model><Preclinical Models><Primary Neoplasm><Primary Tumor><Process><Prognosis><Radiation><Radiation Sensitivity><Radiation Tolerance><Radiation therapy><Radioresistance><Radiosensitivity><Radiotherapeutics><Radiotherapy><Recurrence><Recurrent><Recurrent Neoplasm><Recurrent tumor><Regimen><Removal><Reporting><Research><Resection Cavity><Resistance><Role><SDZ RAD><SYS-TX><Sema III Receptor><Semaphorin III Receptor><Signal Pathway><Solubility><Stem Cell like><Strains Cell Lines><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Surgically-Created Cystic Resection Cavity><Surgically-Created Resection Cavity><System><Systemic Therapy><Techniques><Temodal><Temodar><Testing><Therapeutic><Tissue Growth><Toxic effect><Toxicities><Toxicology><United States National Institutes of Health><VEGF><VEGFs><Validation><Vascular Endothelial Cell Growth Factor 165 Receptor><Vascular Endothelial Growth Factors><Water><Work><Xenograft><Xenograft procedure><Xenotransplantation><blood-brain barrier crossing><bloodbrain barrier crossing><cancer type><chemo-/radio-therapy><chemo-radio-therapy><chemo-radiotherapy><chemo/radiation therapy><chemoradiation><chemoradiation therapy><chemoradiation treatment><chemoradiotherapy><chemoresistant><chemotherapy and radiotherapy><chemotherapy resistance><chemotherapy resistant><clinical relevance><clinically relevant><comparative><cultured cell line><determine efficacy><digital><drug release kinetics><drug release rate><drug resistant><drug/agent><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy testing><evaluate efficacy><everolimus><examine efficacy><glial-derived tumor><glioblastoma multiforme><heavy metal Pb><heavy metal lead><immune competent><immune microenvironment><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><improved><in vivo><in vivo Model><inhibitor><liposomal formulation><liposomal preparation><mTOR Inhibitor><malignancy><methazolastone><model of animal><mouse model><murine model><nano formulation><nano tech><nano technology><nano-technological><nanoformulation><nanotech><nanotechnological><nanotechnology platform><neoplasm recurrence><neoplasm/cancer><neuroglia neoplasm><neuroglia tumor><novel><ontogeny><pre-clinical evaluation><preclinical evaluation><prevent><preventing><radiation or chemotherapy><radiation resistance><radiation resistant><radiation treatment><radio resistance><radio-chemo-therapy><radio-chemotherapy><radio-sensitivity><radiochemotherapy><radioresistant><radiosensitive><refractory cancer><resection><resistance to Drug><resistance to therapy><resistant><resistant cancer><resistant to Drug><resistant to radiation><resistant to therapy><side effect><site targeted delivery><slow release drug><small molecule><social role><spongioblastoma multiforme><standard care><standard treatment><stem cell characteristics><stemness><surgery><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><temozolomide><therapeutic outcome><therapeutic resistance><therapeutically effective><therapy outcome><therapy resistant><time release medication><translational opportunities><translational potential><treatment resistance><treatment strategy><treatment with radiation><tumor><tumor growth><tumor immune microenvironment><tumor initiation><tumor-immune system interactions><tumors in the brain><validations><xeno-transplant><xeno-transplantation>