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Decoding and Targeting the PI3K-mTOR Signaling Network in Cancer

Award Number: R35CA197459
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Decoding and Targeting the PI3K-mTOR Signaling Network in Cancer - ABSTRACT The major growth factor signaling pathways in normal cells (e.g., PI3K and RAS) are also the ones that are most frequently genetically activated in cancer cells, leading to cell autonomous growth and proliferation. mTOR complex 1 (mTORC1) is a shared downstream effector of these pathways and a central driver of cell growth and is aberrantly activated in the majority of human cancers. This activation occurs through a network of upstream oncogenes and tumor suppressors that converge on a small G protein switch directly upstream of mTORC1. This switch involves the tuberous sclerosis complex (TSC) tumor suppressors, which form a protein complex (the TSC complex) that regulates a member of the Ras family of GTPases, called Rheb, an essential direct activator of mTORC1. Our previous studies have found that the TSC complex and Rheb serve as the key molecular link between the PI3K pathway and mTORC1 signaling and that this regulation promotes changes in key metabolic pathways underlying cell growth in both normal and cancer cells. Supported by the last 6 years of funding from this R35, we have greatly advanced and expanded this area of research, opening up several previously unforeseen new avenues of investigation through both published and ongoing work. Taking advantage of the long-term, stable funding afforded by this mechanism, we have also developed innovative new genetic mouse models and methodologies that set us up for new breakthrough discoveries over the next cycle of this grant, especially related to PI3K-mTOR signaling within the poorly understood nutrient and metabolic niche of the tumor microenvironment, which is a major focus of this renewal. Four major areas of research will include defining A) the biochemical and pathophysiological mechanisms underlying the regulation and function of the TSC complex, B) the capacity of mTORC1 to properly integrate oncogenic and nutrient signals within the tumor microenvironment, C) the metabolic consequences of PI3K- mTOR activation and inhibition in tumors of different origins, stages, and niches, and D) targetable metabolic vulnerabilities accompanying its aberrant regulation in tumors. While key mechanistic questions regarding this ubiquitous signaling network will continue to be answered through rigorous biochemical and cell biological studies, much of our efforts will combine novel genetic models with state-of-the-art analytical tools to define the salient in vivo features of the PI3K-mTOR network as they apply to tumor metabolism, growth, and progression. The overarching goals of our research are to define the precise roles of this signaling network in cancer and how best to therapeutically target the high percentage of tumors with uncontrolled mTORC1 signaling, beyond the single-agent use of mTOR inhibitors. I am confident that, if given the resources, we will continue to gain a deeper understanding of cancer cell biology, the tumor microenvironment, and therapeutic vulnerabilities, while also making leaps into new, currently unpredictable domains of cancer research.


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 = $959,712 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Biology Research	000	12	6/23/2026	NON-COMPETING CONTINUATION	$959,712
														Subtotal = $959,712

Issue Date FY: 2025 ( Subtotal = $959,712 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Biology Research	000	11	9/12/2025	NON-COMPETING CONTINUATION	$959,712
														Subtotal = $959,712

Issue Date FY: 2024 ( Subtotal = $911,728 )
2024	2024	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	002	10	7/9/2024	NON-COMPETING CONTINUATION	$53,511
2024	2024	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	10	5/30/2024	NON-COMPETING CONTINUATION	$858,217
2024	2023	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	9	7/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $911,728

Issue Date FY: 2023 ( Subtotal = $932,003 )
2023	2023	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	002	9	6/12/2023	NON-COMPETING CONTINUATION	$932,003
2023	2022	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	8	5/24/2023	COMPETING CONTINUATION	$8,516
2023	2021	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	7	5/24/2023	NON-COMPETING CONTINUATION	-$8,516
														Subtotal = $932,003

Issue Date FY: 2022 ( Subtotal = $974,587 )
2022	2022	HARVARD COLLEGE PRESIDENT & FELLOWS OF	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	8	8/1/2022	COMPETING CONTINUATION	$974,587
														Subtotal = $974,587

Issue Date FY: 2021 ( Subtotal = $834,405 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	7	7/15/2021	NON-COMPETING CONTINUATION	$834,405
														Subtotal = $834,405

Issue Date FY: 2020 ( Subtotal = $904,904 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	6	7/31/2020	NON-COMPETING CONTINUATION	$904,904
														Subtotal = $904,904

Issue Date FY: 2019 ( Subtotal = $877,757 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	5	6/27/2019	NON-COMPETING CONTINUATION	$877,757
														Subtotal = $877,757

Issue Date FY: 2018 ( Subtotal = $924,904 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	4	7/3/2018	NON-COMPETING CONTINUATION	$924,904
														Subtotal = $924,904

Issue Date FY: 2017 ( Subtotal = $924,904 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	677 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	3	7/12/2017	NON-COMPETING CONTINUATION	$924,904
														Subtotal = $924,904

Issue Date FY: 2016 ( Subtotal = $924,904 )
2016	2016	HARVARD UNIVERSITY, SCHOOL OF PUBLIC HEALTH	55 SHATTUCK STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	7/12/2016	NON-COMPETING CONTINUATION	$924,904
														Subtotal = $924,904

Issue Date FY: 2015 ( Subtotal = $655,619 )
2015	2015	HARVARD UNIVERSITY, SCHOOL OF PUBLIC HEALTH	55 SHATTUCK STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	1	8/14/2015	NEW	$655,619
														Subtotal = $655,619

Grand Total All Awards = $10,785,139

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Decoding and Targeting the PI3K-mTOR Signaling Network in Cancer

Award Number: R35CA197459

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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