Defining Bc12L12-driven resistance in malignant glioma

Glioblastoma (GBM), the most aggressive and prevalent manifestation of malignant glioma, are characterized by extreme resistance to all extant therapeutic modalities, including lategeneration targeted therapies, and a neurologically debilitating course culminating in death often within 14 months of diagnosis. With this dismal prognosis and a near 100% failure rate of GBM drug development, the critical challenges facing the glioma field are (a) to identify novel drug targets to overcome the notorious therapy (apoptosis) resistance of GBM, (b) to functionally characterize and preclinically validate these targets in physiologically relevant cell and animal models that recapitulate phenotypic and genotypic hallmarks of the human disease, and (c) to devise therapeutic strategies to target these aberrations. In our studies aimed at addressing these currently unmet needs in the development of effective glioma therapies, we identified Bcl2L12 (for Bcl2Like12) as a firstinclass glioma oncogene that is overexpressed in virtually all GBM samples, yet is low or absent in lowgrade disease and normal tissue. Extensive biochemical studies have established that Bcl2L12 functions as a mitogenic, antiapoptotic, and pronecrotic protein by inhibiting effector caspase and p53 function. These studies pointed to Bcl2L12 upregulation as a key progression event and molecular determinant for therapy refractoriness in GBM. The objective of this proposal is to validate Bcl2L12 as a target for drug development. In Aim 1, we will characterize the role of Bcl2L12 in GBM pathogenesis and therapy resistance in genetically engineered human and murine models harboring a conditional gainoffunction allele for Bcl2L12. We will determine the impact of Bcl2L12 on GBM tumor progression, and maintenance. Leveraging these model systems, we will determine the modes of action, by which Bcl2L12 drives tumor progression, emphasizing the impact of Bcl2L12 on p53dependent tumor surveillance programs in vivo. In Aim 2, we will preclincially characterize a novel nanotechnological platform, i.e., RNAibased, Bcl2L12targeting Hybrid Spherical Nucleic Acids (HSNAs). HSNAs contain gold nanoparticles (AuNPs, size 13 nm) functionalized with Bcl2L12specific siRNA oligonucleotides and chemotherapeutic agents, e.g., TMZ and EGFRinhibiting gefitinib. We propose a multileveled, proofofprinciple preclinical validation of SNAs in Bcl2L12driven mouse and cell culture models to drive the development of this nanomaterial as a potential antiglioma therapeutic toward pharmaceutical opportunity. The results of this proposal could pave the way to successfully implement Bcl2L12based therapies into neurooncological practice.