Compensatory proliferation in post-therapeutic glioblastoma (NIH/R01)

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Glioblastoma multiforme (GBM) is a devastating form of primary brain cancer with poor prognosis. GBM cells are heterogeneous containing a subpopulation of glioma stem cells (GSCs)-, chemo- and radiotherapy resistant cells with prominent tumorigenic ability, and non- GSCs. Here, we propose a novel concept for the significance of non-GSCs for GBM stemness – irradiation triggers paradoxical signals from apoptotic signals in non-GSCs to induce an inter-cellular proliferative signal in the neighboring GSCs, rendering them hyper-proliferative and therapy-resistant GSCs in GBM. This hypothesis is based on the elegant studies in Drosophila eye cancer models demonstrating that inter-clonal cooperation and signaling from apoptotic clones provoke aggressive growth of neighboring tumorigenic clones. These aggressive tumors show up-regulation of JNK (upstream of c-JUN), Dronc (Drosophila Casp9) and Wg (Drosophila Wnt). Our preliminary data suggests that, even in human cancers, c-JUN (and its binding partner MELK), Caspase 9, and Wnt likely contribute to the hyper-proliferation in aggressive tumors. Given the importance of Wnt in the CNS development and self-renewal of stem cells, we hypothesize that, similar to the Drosophila cancer models, induction of apoptosis in non-GSCs drives compensatory proliferation of GSCs through Wnt activation in humans. We propose to study the inter-cellular interactions between the apoptosis-prone non-GSC cells and the hyper-proliferative GSCs using the in vitro tumor sphere cultures and xenograft based mammalian models. As the proof-of-principal and for the clinical development, we will then test the efficacy of the MELK inhibitor and the WNT inhibitor, both of which were currently tested by Phase I Clinical Trial for advanced non-CNS cancers. We believe that this “co-clinical trial” approach will guide us to design successful Phase II/III trials for clinical use of novel anti-cancer drugs. Overall, our research is novel because the conceptual idea that the dying non-GSCs secrete signals that induce proliferation of GSCs is promising and untested. Our approaches and investigation will yield insights about molecular signaling interactions in the context of post-irradiation management of GBM, and is likely to revise our understanding of changes in gene expression and cell-cell interactions post-irradiation, which is a vital area of cancer biology with wide-applications to many cancer types.

High Grade Glioma (HGG) is a devastating cancer in the brain with few therapeutic options, and therefore, more effective treatment is urgently needed. This proposal will build on our recent discovery of tumor repopulation after therapeutic failure. Specifically, our proposed studies will determine whether inter-cellular signaling between therapy-induced dying tumor cells and surviving cells leads to creation of recurrent tumors with even more therapy resistant phenotype. This study will ultimately facilitate the rational development of novel therapeutic strategies with significant potential for early translation to the clinic.