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Targeting Malignant Reprogramming of Glioblastoma Stem Cells Through Dual Inhibition of S6K1 and BIRC3

Award Number: R01NS135220
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/19/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $621,135 )
2026	2026	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/11/2025	NON-COMPETING CONTINUATION	$559,022
2026	2026	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/5/2026	NON-COMPETING CONTINUATION	$62,113
														Subtotal = $621,135

Issue Date FY: 2025 ( Subtotal = $541,074 )
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/12/2024	NON-COMPETING CONTINUATION	$541,074
														Subtotal = $541,074

Issue Date FY: 2024 ( Subtotal = $549,937 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/19/2023	NEW	$549,937
														Subtotal = $549,937

Grand Total All Awards = $1,712,146

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Targeting Malignant Reprogramming of Glioblastoma Stem Cells Through Dual Inhibition of S6K1 and BIRC3

Award Number: R01NS135220

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/19/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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