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Role of Phosphoinositides and Protein Kinases in the control of Cancer Metabolism

Award Number: R35CA197588
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/05/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Role of Phosphoinositides and Protein Kinases in the control of Cancer Metabolism - Project Summary/Abstract Previous work funded by this R35 grant led to the discovery that oncogenic viruses stimulate the production of a set of lipids that were not previously known to exist: phosphatidylinositol-3-phosphate, phosphatidylinositol- 3,4-bisphosphate and phosphatidylinositol-3,4,5-trisphosphate. This led to the discovery of the family of enzymes that generate these lipids, the phosphoinositide 3-kinases (encoded by the PIK3C family of genes). Subsequently, the PTEN tumor suppressor gene was shown to dephosphorylate the 3 position of these lipids. It is now clear that activating mutations in the PIK3CA gene and loss of function mutations in the PTEN gene are among the most common events driving the growth of cancers. Research funded by this grant revealed that the lipid products of PI3K directly activate a subset of protein Ser/Thr kinases, most notably the AKT family, and thereby initiate a set of protein kinase cascades, including activation of the mTOR protein kinase that coordinates a set of anabolic networks necessary for cell growth. Importantly, this research ultimately revealed that PI3Kalpha mediates the ability of insulin and IGF1, as well as other growth factors and oncogenic mutations, to stimulate glucose uptake into tissues. In order to identify the downstream protein substrates of AKT, mTOR and the host of other protein-Ser/Thr kinases and protein-Tyr kinases that regulate cell metabolism and cell growth, the funds from this grant were used to generate a set of oriented synthetic peptide mixtures, 10 residues in length, in which specific amino acids were locked-in at a specific position and all other positions had a mixture of all 20 amino acids. This allowed, for each human protein Ser/Thr or Tyr kinase, the identification of the optimal amino acid at each position, up to 5 residues N-terminal and up to 4 residues C-terminal of the Ser/Thr or Tyr that is phosphorylated. A manuscript describing the substrate specificity of all the Ser/Thr kinases was published in Nature this year and a paper describing the substrate specificity of all human Tyr kinases got a favorable review at Nature and is in revision. During the next granting period we will utilize the software described in the two Nature papers to determine what protein kinases are responsible for directly phosphorylating the hundreds of Ser, Thr and Tyr residues observed on enzymes that mediate anabolic metabolism. By comparing mass spec phosphoproteomics in cancers to normal tissues this approach will reveal the protein kinase cascades that drive anabolic metabolism in cancers and reveal new targets for pharmaceutical intervention to prevent survival of tumor cells.


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 = $1,064,242 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	10	7/21/2026	NON-COMPETING CONTINUATION	$1,064,242
														Subtotal = $1,064,242

Issue Date FY: 2025 ( Subtotal = $1,062,381 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	9	9/3/2025	NON-COMPETING CONTINUATION	$1,062,381
2025	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	7	3/5/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $1,062,381

Issue Date FY: 2024 ( Subtotal = $1,052,496 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	8	8/6/2024	COMPETING CONTINUATION	$1,052,496
														Subtotal = $1,052,496

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	7	5/12/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$13,607
2023	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	6	5/12/2023	NON-COMPETING CONTINUATION	-$13,607
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $993,256 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	7	8/1/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$993,256
2022	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	6	7/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $993,256

Issue Date FY: 2021 ( Subtotal = $1,017,000 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	6	7/21/2021	NON-COMPETING CONTINUATION	$1,017,000
														Subtotal = $1,017,000

Issue Date FY: 2020 ( Subtotal = $1,016,999 )
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	5	7/31/2020	NON-COMPETING CONTINUATION	$1,016,999
														Subtotal = $1,016,999

Issue Date FY: 2019 ( Subtotal = $986,489 )
2019	2019	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	4	8/1/2019	NON-COMPETING CONTINUATION	$986,489
														Subtotal = $986,489

Issue Date FY: 2018 ( Subtotal = $1,017,000 )
2018	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	3	7/31/2018	NON-COMPETING CONTINUATION	$1,017,000
														Subtotal = $1,017,000

Issue Date FY: 2017 ( Subtotal = $1,017,000 )
2017	2017	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	2	7/27/2017	NON-COMPETING CONTINUATION	$1,017,000
														Subtotal = $1,017,000

Issue Date FY: 2016 ( Subtotal = $1,017,000 )
2016	2016	CORNELL UNIVERSITY, MEDICAL COLLEGE	1300 YORK AVENUE, S 217	NEW YORK-NEW YORK	NY	10021		USA	Cancer Biology Research	000	1	9/5/2016	NEW	$1,017,000
														Subtotal = $1,017,000

Grand Total All Awards = $10,243,863

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Role of Phosphoinositides and Protein Kinases in the control of Cancer Metabolism

Award Number: R35CA197588

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/05/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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