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Protein Tyrosine Dephosphorylation & Signal Transduction

Award Number: R01CA053840
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/1991
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Protein Tyrosine Dephosphorylation & Signal Transduction - PROJECT SUMMARY/ ABSTRACT The first drugs directed against protein tyrosine kinases (PTKs) have now entered the market and represent breakthroughs in the treatment of cancer; however, challenges remain, including the fact that patients develop resistance to such drugs. Alternative approaches, to target simultaneously different signaling enzymes and events, are required. The protein tyrosine phosphatases (PTPs), which work in combination with the PTKs, have been garnering attention as potential therapeutic targets. Despite major programs in industry focused on developing small molecule PTP inhibitors, technical challenges arising from the chemical properties of the PTP active site have frustrated such efforts. Consequently, they remain a largely untapped resource for drug development. Nevertheless, the extensive biological validation of PTPs emphasizes the importance of discovering new approaches to inhibitor development. This grant, currently in Year 28, focuses on a functional analysis of specific PTPs in models of cancer. The hypothesis to be tested is that PTPs function as specific regulators of tyrosine phosphorylation-dependent signaling pathways and thus manipulation of their function in cell and animal models will reveal new insights into the critical signaling events that underlie the disease. The overall goal is to define functional links between particular PTPs and specific signaling pathways in cancer, with a view to establishing how disruption of such functions affects the etiology of the disease and to reveal novel therapeutic targets from among the PTPs themselves or from the signaling pathways they regulate. In the previous funding period, major breakthroughs were achieved in several aspects of the project: (1) New and improved allosteric inhibitors of PTP1B, including molecules that chelate copper specifically, were developed, creating opportunities to exploit a novel vulnerability in cancer; (2) Identification of PTP1B inhibitors that are cytotoxic to Herceptin-resistant cells; (3) Demonstration that PTP1B inhibitors prevent fatality in the TRALI model of Acute Respiratory Distress Syndrome, attenuating neutrophil activation and formation of NETs, suggesting novel opportunities for therapeutic intervention in cancer; (4) Integration of BioID MS with substrate-trapping mutant PTPs to enhance substrate trapping technology and generate new insights into the function of PTP1B in Herceptin-resistant cells, illustrating an approach can now be applied to the PTP family as a whole to validate new therapeutic targets. Building on the unique and innovative approaches developed during previous funding periods, this proposal assembles a strong team of collaborators to address the following Specific Aims, which represent a logical development of progress to date: 1: To define the mechanism by which PTP1B represents a point of vulnerability in Herceptin-resistant cells. 2: To validate copper chelation and PTP1B inhibition as a new avenue to cancer therapy 3: To define the mechanism by which PTP1B regulates the formation of Neutrophil Extracellular Traps (NETs) and to investigate how this may be exploited therapeutically in a cancer context. 4: Application of Substrate-Trapping/BioID technology to define PTP function in cancer models.


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 = $768,908 )
2025	2025	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPG HBR	NY	11724	SUFFOLK	USA	Cancer Biology Research	000	33	7/21/2025	NON-COMPETING CONTINUATION	$768,908
														Subtotal = $768,908

Issue Date FY: 2024 ( Subtotal = $730,463 )
2024	2024	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPG HBR	NY	11724	SUFFOLK	USA	Cancer Biology Research	000	32	5/28/2024	NON-COMPETING CONTINUATION	$730,463
														Subtotal = $730,463

Issue Date FY: 2023 ( Subtotal = $768,908 )
2023	2023	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Biology Research	000	31	6/14/2023	NON-COMPETING CONTINUATION	$768,908
														Subtotal = $768,908

Issue Date FY: 2022 ( Subtotal = $753,531 )
2022	2022	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Biology Research	000	30	8/12/2022	NON-COMPETING CONTINUATION	$753,531
														Subtotal = $753,531

Issue Date FY: 2021 ( Subtotal = $768,908 )
2021	2021	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Biology Research	000	29	6/22/2021	COMPETING CONTINUATION	$768,908
2021	2019	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Biology Research	001	28	7/27/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $768,908

Issue Date FY: 2019 ( Subtotal = $753,375 )
2019	2019	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Biology Research	000	28	3/28/2019	NON-COMPETING CONTINUATION	$753,375
														Subtotal = $753,375

Issue Date FY: 2018 ( Subtotal = $776,676 )
2018	2018	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Biology Research	000	27	4/6/2018	NON-COMPETING CONTINUATION	$776,676
														Subtotal = $776,676

Issue Date FY: 2017 ( Subtotal = $776,676 )
2017	2017	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Biology Research	000	26	5/1/2017	NON-COMPETING CONTINUATION	$699,009
2017	2017	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Biology Research	001	26	6/7/2017	NON-COMPETING CONTINUATION	$77,667
														Subtotal = $776,676

Issue Date FY: 2016 ( Subtotal = $762,314 )
2016	2016	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Cancer Biology Research	000	25	4/25/2016	NON-COMPETING CONTINUATION	$762,314
														Subtotal = $762,314

Issue Date FY: 2015 ( Subtotal = $776,676 )
2015	2015	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Cancer Biology Research	000	24	5/14/2015	COMPETING CONTINUATION	$776,676
														Subtotal = $776,676

Issue Date FY: 2014 ( Subtotal = $745,634 )
2014	2014	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Cancer Biology Research	000	23	4/18/2014	NON-COMPETING CONTINUATION	$745,634
														Subtotal = $745,634

Issue Date FY: 2013 ( Subtotal = $721,714 )
2013	2013	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Cancer Biology Research	000	22	5/2/2013	NON-COMPETING CONTINUATION	$180,428
2013	2013	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Cancer Biology Research	001	22	7/2/2013	NON-COMPETING CONTINUATION	$541,286
														Subtotal = $721,714

Issue Date FY: 2012 ( Subtotal = $761,643 )
2012	2012	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Cancer Biology Research	000	21	4/16/2012	NON-COMPETING CONTINUATION	$761,643
														Subtotal = $761,643

Issue Date FY: 2011 ( Subtotal = $687,770 )
2011	2011	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Cancer Biology Research	000	20	3/28/2011	NON-COMPETING CONTINUATION	$657,282
2011	2011	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Cancer Biology Research	001	20	5/13/2011	NON-COMPETING CONTINUATION	$30,488
														Subtotal = $687,770

Issue Date FY: 2010 ( Subtotal = $712,640 )
2010	2010	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Cancer Biology Research	000	19	7/1/2010	COMPETING CONTINUATION	$712,640
														Subtotal = $712,640

Issue Date FY: 2000 ( Subtotal = $536,041 )
2000	2000	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Cancer Biology Research	000	10	7/28/2000	NON-COMPETING CONTINUATION	$536,041
														Subtotal = $536,041

Issue Date FY: 1999 ( Subtotal = $515,571 )
1999	1999	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Cancer Biology Research	000	9	3/5/1999	NON-COMPETING CONTINUATION	$515,571
														Subtotal = $515,571

Issue Date FY: 1998 ( Subtotal = $495,885 )
1998	1998	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Cancer Biology Research	000	8	3/16/1998	NON-COMPETING CONTINUATION	$495,885
														Subtotal = $495,885

Grand Total All Awards = $12,813,333

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Protein Tyrosine Dephosphorylation & Signal Transduction

Award Number: R01CA053840

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/1991

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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