Glioblastoma (GBM) is a deadly, malignant brain tumor with a poor long-term prognosis. The current median survival is approximately fifteen to seventeen months with the standard of care therapy which includes surgery, radiation, and chemotherapy. An important factor contributing to recurrence of GBM is high resistance of GBM cancer stem cells (CSCs), for which a systematically delivered single drug approach will be unlikely to produce a viable cure. Therefore, multi-drug therapies are needed. Currently, only temozolomide (TMZ), which is a DNA alkylator, affects overall survival in GBM patients. CSCs regenerate rapidly and over-express a methyl transferase which overrides the DNA-alkylating mechanism of TMZ, leading to drug resistance. Idasanutlin (RG7388, R05503781) is a potent, selective MDM2 antagonist that additively kills GBM CSCs when combined with diagnostics in a truly theranostic manner for enhancing personalized medicine against GBM. The goal of this thesis was to develop a multi-drug therapy using mutli-functional nanoparticles (NPs) that preferentially target the GBM CSC subpopulation and provide in vivo preclinical imaging capability. Polymer-micellar NPs composed of poly(styrene-<i>b</i>-ethylene oxide) (PS-<i>b</i>-PEO) and poly(lactic-<i>co</i>-glycolic) acid (PLGA) were developed investigating both single and double emulsion fabrication techniques as well as combinatinos of TMZ and RG7388. The NPs were covalently bound to a 15 base-pair CD133 aptamer in order to target a specific epitope on the CD133 antigen expressed on the surface of GBM CSC subpopulation. For theranostic functionality, the NPs were also labelled with a positron emission tomography (PET) radiotracer, zirconium-89 (⁸⁹Zr). The NPs maintained a small size of less than 100 nm, a relatively neutral charge and exhibited the ability to produce a cytotoxic effect on CSCs. There was a slight increase in killing with the aptamer-bound NPs compared to those without a targeting agent. This work has provided a potentially therapeutic option for GBM specific for CSC targeting and future in vivo biodistribution

<p>Liposarcoma (LPS) arises from adipocytes and is a rare malignancy among all cancer types, but represents the most common form of soft tissue sarcoma, with approximately 2,000 new cases reported annually. Clinically, liposarcomas are classified into four subtypes based on histological analysis: well-differentiated liposarcoma (WDLPS), dedifferentiated liposarcoma (DDLPS), myxoid/round cell liposarcoma, and pleomorphic liposarcoma. Although histological analysis provides useful information for identifying various liposarcoma subtypes, treatment options rely on a fundamental understanding of driver mutations and molecular mechanisms underlying tumorigenesis. This thesis focuses on elucidating important driver mutations and therapeutic targets to eradicate DDLPS. Notch signaling is an evolutionarily conserved signaling pathway essential for organ development and stem cell function. Aberrant Notch signaling underlies the tumorigenesis of many cancers including LPS. However, the specific role of Notch signaling in development of LPS remains elusive. In Chapter 2, I provide evidence demonstrating that Notch signaling plays a key role in cancer stem cells (CSCs), also referred to as tumor-initiating cells (TICs), that drive aggressive DDLPS. I used serial transplantation to enrich and generate a murine DDLPS cell line with constitutively activated Notch signaling (NICDOE). My analyses revealed that NICDOE DDLPS cells are heterogeneous and contain TICs that express cancer stem cell markers. Chapter 3 elucidates how Notch signaling regulates CSCs of LPS. I analyzed human LPS samples to establish a strong correlation between Notch signaling activation and tumor marker expression and prognosis. I further performed gene expression and metabolic analyses of NICDOE DDLPS cells. These assays revealed that NICDOE reduced mitochondrial respiration in DDLPS cells, which was associated with diminished expression of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis. CRISPR/CAS9-mediated deletion of the NICDOE cassette rescued the expression of PGC-1α and mitochondrial respiration in DDLPS cells. Similarly, overexpression of PGC-1α was sufficient to rescue mitochondrial biogenesis in DDLPS cells. Together, these data demonstrate that Notch signaling regulates CSCs, at least partially by controlling PGC-1α mediated mitochondria biogenesis.</p>