Project 3 has developed new approaches for targeting brain tumors using lipidic nanoparticle-based drugs, ncluding novel liposomes and immunoliposomes. These advances include: new and extremely robust technologies for drug loading and stabilization, resulting in novel nanoliposomal drugs that can deliver a number of anticancer compounds to brain tumors;antibody-targeted constructs (immunoliposomes) against EGFR and/or EGFRvlll;the first successful demonstration of convection-enhanced delivery (CED) of lipidic nanoparticles in the CMS;and imaging of drug delivery using CED of liposomal gadolinium (Gd). One of these novel agents, nanoliposomal CPT-11, has shown highly promising preclinical efficacy and has entered clinical trials as a systemic treatment. Using a clinically validated liposome-based scaffold, we can engineer additional capabilities to generate innovative and multifunctional nanoparticles for targeted delivery of anticancer drugs, either by systemic or CED routes. We now hypothesize that CED of lipidic nanoparticle- based agents combining drug delivery with imaging capability can provide targeted therapy of brain tumors. Our ongoing studies infusing lipidic nanoparticles into the brain via CED have exceeded our expectations as a robust and clinically applicable approach for the treatment of brain tumors, including the potential for targeting via MRI guidance. Accordingly, we will develop multifunctional nanoparticle-based systems for integrated image-guided therapy, combining encapsulated drugs and MRI probes and optimized for CED infusion to brain tumors.
Our Aims i nclude: 1) Develop lipidic nanoparticle/CED imaging strategy via co- infusion system or multifunctional nanoparticles co-encapsulating Gd + drug;2) Evaluate other lipidic nanoparticle agents in conjunction with image-guided CED, including other cytotoxic drugs and siRNA;3) Evaluate immunoliposome targeting combined with CED;and 4) Translate """"""""best"""""""" multifunctional lipidic nanoparticle agent/strategy to clinical trial. Lay summary: We are studying new approaches to deliver drugs more efficiently to brain tumors using nanoparticle agents (sub-microscopic carriers of drugs). We propose to infuse these particles directly into the brain to target brain tumors, and will use MRI to guide this treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
3P50CA097257-10S1
Application #
8540601
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2011-05-01
Budget End
2013-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$59,989
Indirect Cost
$21,441
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Griveau, Amelie; Seano, Giorgio; Shelton, Samuel J et al. (2018) A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment. Cancer Cell 33:874-889.e7
Disney-Hogg, Linden; Cornish, Alex J; Sud, Amit et al. (2018) Impact of atopy on risk of glioma: a Mendelian randomisation study. BMC Med 16:42
Wang, Qianghu; Hu, Baoli; Hu, Xin et al. (2018) Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell 33:152
Salas, Lucas A; Wiencke, John K; Koestler, Devin C et al. (2018) Tracing human stem cell lineage during development using DNA methylation. Genome Res 28:1285-1295
Ostrom, Quinn T; Kinnersley, Ben; Wrensch, Margaret R et al. (2018) Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21. Sci Rep 8:7352
Salas, Lucas A; Koestler, Devin C; Butler, Rondi A et al. (2018) An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray. Genome Biol 19:64
Choi, Serah; Yu, Yao; Grimmer, Matthew R et al. (2018) Temozolomide-associated hypermutation in gliomas. Neuro Oncol 20:1300-1309
Jacobs, Daniel I; Liu, Yanhong; Gabrusiewicz, Konrad et al. (2018) Germline polymorphisms in myeloid-associated genes are not associated with survival in glioma patients. J Neurooncol 136:33-39
Berntsson, Shala G; Merrell, Ryan T; Amirian, E Susan et al. (2018) Glioma-related seizures in relation to histopathological subtypes: a report from the glioma international case-control study. J Neurol 265:1432-1442
Goode, Benjamin; Joseph, Nancy M; Stevers, Meredith et al. (2018) Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation. Mod Pathol 31:660-673

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