I. SPECIFIC AIMS – OVERALL The proposed Northwestern University (NU) CCNE will feature three projects (one discovery-based and two translational), one core facility, and two for-profit partners united to provide novel nanotechnology-based solutions to daunting and complex issues in cancer research and treatment. Much still remains to be learned about the genetic basis of this highly heterogeneous disease class and how it can be analyzed and treated using genetic approaches. Current treatment methodologies fall short of providing efficacious, targeted, precision therapies geared towards the individual patient. Due to their novel size-, shape-, and composition-dependent chemical, biological, and physical properties nucleic-acid based nanomaterials can be used to gain access to privileged intracellular environments, discover new aspects of cancer biology and genetics, and exploit nanostructure-biomolecular interactions to create effective treatment options. Nanostructures made out of genetic materials offer the potential for fundamental learning and treatment solutions beyond what is possible with traditional therapies. The new NU CCNE (Nanostructure Genetic Constructs for the Treatment of Cancer) will explore these vast possibilities by applying a novel class of nanostructure genetic constructs – the spherical nucleic acid (SNA) and variants of it – for the study and treatment of brain (glioblastoma multiforme (GBM)) and prostate cancer (pCa) through the following specific aims: Specific Aim 1: Determine the “design rules” for the synthesis of a novel class of nanostructure genetic constructs – spherical nucleic acids (SNAs) – for use in nanotherapeutics. This specific aim will be primarily accomplished by Project 1 and the core facility and the “design rules” will be implemented in the context of brain and prostate cancer treatment in Projects 2 and 3, respectively. The modularity of SNAs and the ease of their synthesis, as well as the availability of novel nanotechnology-based analytical tools, such as NanoFlare technology and matrix-assisted laser desorption/ionization mass spectrometry (SAMDI-MS) technology, will allow for the systematic creation of a large library of SNAs consisting of tens of thousands of structures and their high-throughput cellular testing on the bulk and single-cell level. Those architectural features that lead to the desired gene regulatory or immunostimulatory effect will be honed in on, and SNAs possessing those features will be mass produced in an economical manner according to rigorous quality control standards set out by the core facility. These structures will then be used in translational work in Project 2 and Project 3. Specific Aim 2: Develop a first-in-class SNA that can be utilized in neuro-oncology as an agent for the treatment of GBM via metabolic disruption and drug sensitization. This aim will be primarily accomplished by Project 2. Project 1 and the core will feed this aim by providing large quantities of highly uniform and optimized SNA structures proven to have the desired functionality. Work in this aim will build off the known ability of SNAs to cross the blood-brain and blood-tumor-barriers (BBB, BTB). A well-known metabolic pathway involving isocitrate dehydrogenases (IDHs; that promote tumor function and growth) also will be exploited. The knockdown of IDH by SNAs, which will be targeted to gliomal cells using peptides, will not only compromise tumor cell function, but also sensitize tumor cells to known therapies, namely receptor tyrosine kinase inhibitors (RTKIs). By accompli
|Effective start/end date||9/1/15 → 7/31/21|
- National Cancer Institute (1U54CA199091-01)
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