Targeting Malignant Reprogramming of Glioblastoma Stem Cells Through Dual Inhibition of S6K1 and BIRC3 - Glioblastoma (GBM) is highly resistant and uniformly fatal despite current therapeutic efforts. Intra-tumoral malignant reprogramming evolution of GBM stem cells (GSCs) towards a highly resistant and invasive mesenchymal-like (MES) phenotype has emerged as a leading hypothesis for GBM lethality. Unfortunately, there are currently no therapeutic strategies that address malignant reprogramming in GBM. Our long-term goal is to develop such therapies. The current proposal is significant in that it presents a potential therapeutic approach that targets malignant reprogramming of GSCs to improve GBM survival. It builds upon our validation of the mechanistic underpinnings of BIRC3/STAT3 signaling in malignant reprogramming of GSCs; and also, from our published works that have uncovered novel functions of BIRC3 in GBM resistance; GBM survival; GBM stemness reprogramming; GBM regional MES phenotype; and hypoxia survival adaptation. A notable and novel preliminary mechanistic finding was that interaction between BIRC3 and STAT3 was essential for nuclear translocation of this complex, and activation of downstream MES target genes. Using two distinct BIRC3-centered proteomic profiling approaches, we identified P70S6K1 (S6K1) as the critical upstream kinase regulator of BIRC3/STAT3 mediated MES reprogramming in GSCs. Further, we have demonstrated the preliminary efficacy of targeting S6K1/BIRC3/STAT3 signaling axis to preventing MES reprogramming and improving survival in PDX models through a combination of genetic and pharmacological approaches. Utilizing a combination of patient-derived GSCs models, patient tissues, and state-of-the-art techniques, our objective is to further understand and optimally target S6K1/BIRC3/STAT3 signaling axis in GBM. Our central premise is that S6K1/BIRC3/STAT3 axis is a critical regulator of malignant reprogramming in GBM; and we hypothesize that combinatorial targeting this axis will improve GBM outcomes. In Aim 1, we will examine the cooperative roles of S6K1 and BIRC3/STAT3 complex in propagating malignant reprogramming in GBM. In Aim 2, we will investigate the feasibility of combinatorial pharmacologic targeting of S6K1/BIRC3 in GBM. In Aim 3, We will evaluate synergy between S6K1/BIRC3 axis inhibition and current GBM therapies-Temozolomide (TMZ)/Radiotherapy (RT). Collectively, these proposed studies will provide further insights into novel clonal evolution reprogramming mechanisms in cancer stem cells that would permit development of therapies that effectively target malignant clonal divergence in GBM and other cancers.
