Tuesday, July 1, 2025 7/1/2025

Mitogenic and Oncogenic Regulation of ERK/RSK Signaling

Award Number: R01CA046595
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/08/1988
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Mitogenic and Oncogenic Regulation of ERK/RSK Signaling - Cancer is the 2nd leading cause of death in the US. The advent of new treatments such as immunotherapy and targeted therapies have revolutionized the fight against cancer, and when combined with surgery, often result in significant positive therapeutic responses. Unfortunately, some tumor cells gain the ability to resist drug- and immune- therapies, which is often linked to their ability to metastasize. Indeed, metastasis ultimately underlies the majority of patient mortality by cancer. A major unmet need in oncology is the prediction and prevention of metastatic progression. Thus, understanding how tumor cells acquire metastatic potential and develop drug resistance is critical to identifying novel therapeutic options and improving patient outcomes. It is of critical importance to define the signaling mechanisms that contribute to altered growth, metabolism, motility and survival associated with metastasis. Our long-standing goal is to uncover the molecular consequences of Ras/ERK-MAP kinase signaling using biochemical, cell biological and genetic approaches in vitro and in vivo. We have provided the foundational studies revealing how subtle differences in ERK signal strength, location and duration are critical determinants of cellular outcomes. More recently, we demonstrated that different ERK isoforms promote different cell fates. Specifically, we found that different docking domains within ERK2, the CD domain and the DEF binding pocket (DBP), regulate different cellular outcomes, with ERK2 playing a major role in promoting the epithelial-to-mesenchymal transition (EMT) through DBP signaling. Additionally, this EMT-like phenotype was associated with increased motility, survival and metastasis in vivo and in vitro. Understanding these mechanisms are part of the long-term goal of our basic research efforts to discover new potential targets and identify new biomarkers, and to help resolve this currently unmet clinical need of targeting the metastatic process. Thus, this grant application proposes to mechanistically investigate underexplored areas associated with EMT and metastatic progression, taking advantage of discoveries made during the previous 30+ years investigating the ERK pathway in my laboratory. Our goals include an investigation into: (i) the regulation and role of H3.3 histone chaperones and H3.3 modifications, (ii) the role SP1/EGR1-downregulated genes and their characterization as new metastasis suppressors, such as CHAF1b and MCEE; (iii) the function of massive reorganization of endomembrane trafficking, lysosome and autophagosome function and the unexplored regulation and function of various plasma and lysosome membrane transporters in the maintenance of cancer stem cell properties, invasion, survival and chemoresistance during cancer progression and metastasis. In conclusion, there is an essential need for greater understanding of the mechanisms associated with metastatic behavior. Our expectations are that successful completion of the proposed work will impact cancer therapies through identification of new biomarkers and novel drug targets that will yield small molecules that target the invasiveness and survival of aggressive 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: 2025 ( Subtotal = $739,895 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Biology Research	003	38	5/22/2025	NON-COMPETING CONTINUATION	$73,989
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Biology Research	002	38	2/19/2025	NON-COMPETING CONTINUATION	$665,906
2025	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Biology Research	001	37	2/14/2025	COMPETING CONTINUATION	$1,809
2025	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Biology Research	000	36	2/14/2025	NON-COMPETING CONTINUATION	-$1,809
														Subtotal = $739,895

Issue Date FY: 2024 ( Subtotal = $739,895 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Biology Research	001	37	1/11/2024	COMPETING CONTINUATION	$739,895
2024	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Biology Research	000	36	1/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $739,895

Issue Date FY: 2023 ( Subtotal = $682,680 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	36	4/19/2023	NON-COMPETING CONTINUATION	$682,680
														Subtotal = $682,680

Issue Date FY: 2022 ( Subtotal = $669,027 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	35	4/29/2022	NON-COMPETING CONTINUATION	$669,027
														Subtotal = $669,027

Issue Date FY: 2021 ( Subtotal = $682,680 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	34	4/23/2021	NON-COMPETING CONTINUATION	$682,680
														Subtotal = $682,680

Issue Date FY: 2020 ( Subtotal = $682,680 )
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	33	5/28/2020	NON-COMPETING CONTINUATION	$682,680
														Subtotal = $682,680

Issue Date FY: 2019 ( Subtotal = $852,180 )
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	32	3/29/2019	COMPETING CONTINUATION	$682,680
2019	2019	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Trans-NIH Research Support	002	32	9/17/2019	SUPPLEMENT FOR EXPANSION	$169,500
2019	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	001	31	9/10/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $852,180

Issue Date FY: 2017 ( Subtotal = $689,580 )
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	001	31	6/7/2017	NON-COMPETING CONTINUATION	$68,959
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	31	4/28/2017	NON-COMPETING CONTINUATION	$620,621
														Subtotal = $689,580

Issue Date FY: 2016 ( Subtotal = $683,673 )
2016	2016	CORNELL UNIVERSITY, MEDICAL COLLEGE	1300 YORK AVENUE, S 217	NEW YORK-NEW YORK	NY	10021		USA	Cancer Biology Research	000	30	4/19/2016	NON-COMPETING CONTINUATION	$683,673
														Subtotal = $683,673

Issue Date FY: 2015 ( Subtotal = $689,580 )
2015	2015	CORNELL UNIVERSITY, MEDICAL COLLEGE	1300 YORK AVENUE, S 217	NEW YORK-NEW YORK	NY	10021		USA	Cancer Biology Research	000	29	4/8/2015	NON-COMPETING CONTINUATION	$689,580
														Subtotal = $689,580

Issue Date FY: 2014 ( Subtotal = $662,044 )
2014	2014	CORNELL UNIVERSITY, MEDICAL COLLEGE	1300 YORK AVENUE, S 217	NEW YORK-NEW YORK	NY	10021		USA	Cancer Biology Research	002	28	6/20/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$662,044
2014	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	27	12/18/2013	COMPETING CONTINUATION	-$689,580
2014	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	27	12/19/2013	COMPETING CONTINUATION	$689,580
														Subtotal = $662,044

Issue Date FY: 2013 ( Subtotal = $689,580 )
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	27	12/18/2013	COMPETING CONTINUATION	-$689,580
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	27	7/3/2013	COMPETING CONTINUATION	$689,580
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	002	27	12/19/2013	COMPETING CONTINUATION	$689,580
														Subtotal = $689,580

Issue Date FY: 2002 ( Subtotal = $479,352 )
2002	2002	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Biology Research	000	16	2/19/2002	NON-COMPETING CONTINUATION	$479,352
														Subtotal = $479,352

Issue Date FY: 2001 ( Subtotal = $465,567 )
2001	2001	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Biology Research	000	15	2/23/2001	NON-COMPETING CONTINUATION	$465,567
														Subtotal = $465,567

Issue Date FY: 2000 ( Subtotal = $452,137 )
2000	2000	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Biology Research	000	14	7/31/2000	NON-COMPETING CONTINUATION	$452,137
														Subtotal = $452,137

Issue Date FY: 1999 ( Subtotal = $439,098 )
1999	1999	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Biology Research	000	13	3/1/1999	NON-COMPETING CONTINUATION	$439,098
														Subtotal = $439,098

Issue Date FY: 1998 ( Subtotal = $407,551 )
1998	1998	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Biology Research	000	12	4/28/1998	COMPETING CONTINUATION	$407,551
														Subtotal = $407,551

Grand Total All Awards = $10,707,199

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Mitogenic and Oncogenic Regulation of ERK/RSK Signaling

Award Number: R01CA046595

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/08/1988

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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