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.
