Glioblastoma (GBM) is a uniformly lethal cancer with a dismal median survival following surgery, Temozolomide (TMZ) and Radiotherapy (RT). Futile attempts with second-line therapies for GBM as well as recent failures in GBM immunotherapy trials further underscore the strong need for new paradigms in GBM. One hypothesis of treatment resistance in GBMs is that Brain Tumor Initiating Cells (BTIC) retain molecular- subtype plasticity such that treatment drives GBMs away from the proneural (PN) subtype towards a treatment resistant mesenchymal (MES) phenotype. PN is associated with a significantly increased long-term survival compared to the highly resistant MES subtype. Hence, devising GBM therapies that either prevent PN-MES transition or promote transition back from MES-PN would constitute innovation and a paradigm-shift solution, since such therapies do not currently exist and all current efforts have been futile. This proposal provides an innovative and paradigm-shifting solution to the GBM quagmire in that we have identified a novel mechanism of PN-MES reprogramming that we can target and drive GBM molecular subtype plasticity towards a ?long- term survival? phenotype. Developing therapies that modulate GBM plasticity towards a ?long-term survival? phenotype is our long-term goal. The objective in this application is to understand how BIRC3 and impacted pathways mediate PN-MES reprogramming in GBM. BIRC3 is an inhibitor of apoptosis protein, and we have demonstrated its role in: (i) GBM resistance; (ii) GBM patient outcome/survival, and (iii) upregulation by PI3K and STAT3 signaling. Furthermore, we have identified BIRC3 as a biomarker for the MES subtype in GBM patients and driver of hypoxia-mediated survival in GBM. We now provide new and novel preliminary evidence that BIRC3 promotes PN-MES reprogramming in GBM cell lines and BTIC models. We further provide novel mechanistic evidence that BIRC3 interacts with STAT3 through the BIR1 domain; and that STAT3 phosphorylation enables nuclear translocation of BIRC3 and subsequent downstream activation of MES target genes as a co-transcriptional factor. Hence, there is a strong rationale to examine how BIRC3 influences PN- MES reprogramming in GBM. We submit that BIRC3 and STAT3 heterodimerize and translocate into the nucleus to initiate a transcriptional program that mediates PN-MES reprogramming in GBM; and we hypothesize that inhibition of BIRC3/STAT3 signaling will reverse PN-MES reprogramming in GBM.
In Aim 1, we will determine how BIRC3-STAT3 signaling impacts PN-MES reprogramming in GBM.
In Aim 2, we will determine if disruption of BIRC-STAT3 signaling in vivo prevents treatment-induced PN-MES reprogramming, sensitizes tumors to therapy and promotes a long-term survival phenotype in GBM. Mechanistic knowledge attained from this proposal could lead to the development of innovative GBM treatment strategies directed against PN-MES reprogramming.
Treatment failures in glioblastoma are often the rule as opposed to the exception. Mechanisms that promote tumor survival despite aggressive therapy are largely responsible for dismal prognosis of GBM patients. These studies are design to examine and target such mechanisms with novel strategies.
