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Principal Investigator: Huang Chiao Huang
Organization: UNIV OF MARYLAND, COLLEGE PARK
Fiscal Year: 2020
Award: $202,977
Funding agency: National Cancer Institute
DESCRIPTION (provided by applicant): It is increasingly evident that rationally designed combination therapies impacting multiple targets will most likely to improve outcomes in patients with glioblastoma (GBM). However, the selective delivery of multiple regimens to the right place, at the right time, and in the correct sequence with consideration of mechanistic interactions remains a major challenge. Light-activated approaches combined with nanotechnology provide a unique opportunity to deliver multiple agents targeted at several key molecular pathways. Photodynamic therapy (PDT) is a light-based cytotoxic modality that can synergize with chemo and biological agents. PDT is FDA-approved for several cancers and it is in phase III trial for GBM. The underlying hypothesis is that properly timed, nanotechnology-assisted combination therapies based on interactive mechanisms that target multiple non-overlapping tumor growth/survival pathways is key to improving treatment efficacy, and allows for non-overlapping toxicities and reduced dose. This proposal leverages image-guided approaches and polymer engineering to develop a photoimmunoconjugate-nanocarrier (PICNC) that integrates an FDA-approved PDT agent (verteporfin), a clinically promising chemodrug (SN-38), and a multi-receptor tyrosine kinase inhibitor (RTKi, cediranib). All the agents are compartmentalized for appropriate release kinetics to ensure the correct sequence of action that accounts for the mechanistic synergism of the combination treatment. During the K99 phase, SN-38-loaded nanocarriers will be decorated with cetuximab-verteporfin photoimmunoconjugates (PICs) for tumor targeting and image-guided combination therapy (PDT + SN-38). It is hypothesized that SN- 38 improves tumor tissue oxygenation to favor oxygen-dependent PDT, while PDT destroys efflux pumps to increase intracellular SN-38 levels, will improve the overall outcome. To prepare for R00 transition, Dr. Huang will leverage his chemical engineering background to develop a variety of modified polymer nanoparticles loaded with a third RTKi agent, engineered to modulate the RTKi release kinetics, which will be incorporated into the PICNC. The hypothesis is that the customized RTKi release kinetics will maximize the mitigation of the compensatory RTK survival pathways elicited by PDT and SN-38 to improve outcome. During the R00 phase, Dr. Huang will establish the molecular impact and the image-guided treatment planning of PICNCs, and then evaluate the therapeutic effects of PICNCs and customized PDT schedule. A strong mentoring committee has been assembled to guide Dr. Huang's research and facilitate his transition to independence. Dr. Tayyaba Hasan (primary mentor) will train Dr. Huang in photobiology, PIC-nanocarriers, and combination mechanism. Dr. David Boas (co-mentor) is an expert in optical and spectral imaging of tissue oxygen metabolism. Additional distinguished members are: Dr. Brian Pogue, a fluorescence imaging expert; Dr. Shiladitya Sengupta, an polymer nanoparticle expert; Drs. Robert Martuza, Xandra Breakefield, and Anat Stemmer-Rachamimov are experts in clinical management, animal models and molecular biology of GBM.
Terms: <ABC15><ABCG2><ABCG2 gene><ABCP><ATP-Binding Cassette, Sub-Family G (WHITE), Member 2 Gene><ATP-Binding Cassette, Sub-Family G, Member 2><ATP-Binding Cassette, Subfamily G, Member 2><Acute><Animal Model><Animal Models and Related Studies><Anti-EGFR Monoclonal Antibody><Anti-Epidermal Growth Factor Receptor Monoclonal Antibody><BCRP><BCRP1><BPD verteporfin><BPD-MA><Benzoporphyrin Derivative Monoacid Ring A><Binding><Biodegradation><Biodistribution><Biologic Products><Biological><Biological Agent><Biological Markers><Biological Products><Boa><Breast Cancer Resistance Protein><C-KIT Gene><CD117><CD117 Antigens><CD140B><CD31><Cancers><Cell Body><Cell Survival><Cell Viability><Cells><Cessation of life><Cetuximab><Chemical Engineering><Clinical><Clinical Management><Clinical Trials><Combined Modality Therapy><Common Rat Strains><Custom><DNA Molecular Biology><Death><Disease><Disorder><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drugs><EGF Receptor><EGFR><ERBB Protein><EST157481><Encapsulated><Engineering><Ensure><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Evaluation><FDA approved><FLK1><Glioblastoma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><HER1><In Vitro><Intermediary Metabolism><JTK12><KDR gene><Kinetics><Light><Lipid A><Lipid Bilayers><MRX><MXR1><Malignant Neoplasms><Malignant Tumor><Mast Cell Growth Factor Receptor><Medication><Mentors><Metabolic Processes><Metabolism><Mitoxantrone Resistance Protein><Modality><Modeling><Molecular><Molecular Biology><Molecular Interaction><Multimodal Therapy><Multimodal Treatment><Nano platform><Nano-technological platform><Nano-technology platform><Nanoplatform><Nanotechnological platform><Nanotechnology><O element><O2 element><Outcome><Oxygen><PDGF-R-Beta><PDGFR><PDGFR1><PDGFRB><PDGFRB gene><PECAM1><PECAM1 gene><PTK Inhibitors><PTK Receptors><PUVA><PUVA Photochemotherapy><Pathway interactions><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Phase><Photobiology><Photobiology Radiation Biology><Photochemotherapy><Photodynamic Therapy><Photoradiation><Placenta-Specific ATP-Binding Cassette Transporter><Polymers><Prognosis><Protein Tyrosine Kinase Inhibitors><Proto-Oncogene Protein c-kit><Rat><Rats Mammals><Rattus><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Regimen><Research><SCF Receptor><SCF Receptor Gene><SCFR><SN-38><Schedule><Solid><Stem Cell Factor Receptor><Stem Cell Factor Receptor Gene><Surface><TGF-alpha Receptor><TK Inhibitors><Therapeutic><Therapeutic Effect><Time><Tissue imaging><Toxic effect><Toxicities><Training><Transforming Growth Factor alpha Receptor><Transmembrane Receptor Protein Tyrosine Kinase><Treatment Efficacy><Tumor Tissue><Tumor Volume><Tyrosine Kinase Inhibitor><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Urogastrone Receptor><VEGF Receptors><VEGFR><VEGFR-2><VEGFR2><VPF Receptor><Vascular Endothelial Cell Growth Factor Receptor><Vascular Endothelial Growth Factor Receptor 2><Vascular Permeability Factor Receptor><Verteporfin><Visudyne><Western Blotting><Western Immunoblotting><base><benzoporphyrin D><bio-markers><biologic marker><biomarker><biopharmaceutical><biotherapeutic agent><brain health><c kit><c-erbB-1><c-erbB-1 Protein><c-kit Protein><c-kit Receptor><clinical relevance><clinically relevant><combination therapy><combined modality treatment><combined treatment><customized therapy><customized treatment><cytotoxic><density><design><designing><drug/agent><efflux pump><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><fluorescence imaging><fluorescent imaging><glioblastoma multiforme><image guidance><image guided><improved><improved outcome><individualized medicine><individualized patient treatment><individualized therapy><individualized treatment><intervention efficacy><kit Proto-Oncogene Protein><lipid bilayer membrane><malignancy><member><model of animal><model organism><multi-modal therapy><multi-modal treatment><nano carrier><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanocarrier><nanoparticle><nanosized particle><nanotech><nanotechnological><nanotechnology platform><neoplasm/cancer><neoplasm/cancer photoradiation therapy><optic imaging><optical imaging><outcome forecast><p145(c-kit)><p145c-kit><pathway><patient specific therapies><patient specific treatment><phase 3 trial><phase III trial><primary end point><primary endpoint><protein blotting><proto-oncogene protein c-erbB-1><public health relevance><quantitative imaging><response to treatment><secondary end point><secondary endpoint><spectral image><spectral imagery><spectrograph><spectrum image><spectrum imagery><spongioblastoma multiforme><synergism><tailored medical treatment><tailored therapy><tailored treatment><targeted agent><targeted imaging><therapeutic efficacy><therapeutic outcome><therapeutic response><therapeutically effective><therapy efficacy><therapy outcome><tissue oxygen saturation><tissue oxygenation><treatment planning><treatment response><tumor><tumor growth><unique treatment><uptake><verteporphin>