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The Function of CDK5 in Metastasis

Award Number: R01CA239660
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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The Function of CDK5 in Metastasis - This application focuses on the cyclin-dependent kinase 5 (CDK5). The overarching goal of this proposal is to test whether inhibition of CDK5 kinase might represent an effective therapeutic strategy in treatment of metastatic melanomas. In our study, we will utilize human cancer cell lines as well as mouse cancer models. Our work may lead to a novel therapeutic approach for cancer patients centered on CDK5 inhibition. Despite its name, CDK5 is not regulated by cyclins. CDK5 is inactive in its monomeric form, and its kinase activity is triggered by interaction with non-cyclin proteins termed p35 and p39. During normal development, CDK5-p35 and CDK5-p39 kinases are active in the nervous system. CDK5-p35/p39 kinases were shown to regulate a wide range of neuronal functions, including terminal differentiation, synapse formation and plasticity, axon guidance, neurite outgrowth, membrane transport and neuronal migration, through phosphorylation of various neuronal substrates. Growing evidence indicates that CDK5 plays an important role in tumorigenesis. Several studies documented that human cancer cells express CDK5 and p35/p39, and contain catalytically active CDK5-p35/p39 complexes. High expression of CDK5 in tumors was shown to confer overall poor prognosis. The exact molecular function of CDK5 in tumor cells is not fully understood. It has been postulated that CDK5 affects cell proliferation, or regulates tumor cell migration, or survival, with different studies ascribing activating or inhibitory roles for CDK5 in these processes. In our study, we decided to focus on melanoma, as this tumor type expressed particularly high CDK5 levels. We obtained preliminary evidence that CDK5 plays an important role in tumor cell invasiveness and metastasis. We obtained preliminary results about the molecular role played by CDK5 in the metastatic spread of tumor cells. We also developed a novel mouse strain that allows us to switch off CDK5 activity in vivo. In the work proposed in this application, we will extend these findings. In Specific Aim 1, we will utilize our strain of mice that allows an acute shutdown of CDK5, along with a well- established mouse model of melanoma, to further study the role of CDK5 in melanoma metastasis in vivo. In Aim 2, we will follow up on our preliminary results, and we will determine the exact molecular function played by CDK5 in melanoma metastasis. Lastly, in a translational Aim 3, we will perform a pre-clinical study to test whether inhibition of CDK5 kinase would block the metastatic spread of human melanomas, using a large collection of human patient-derived xenografts (PDX). The expected overall impact of this proposal is that it will elucidate the molecular function of CDK5 in melanoma cells, and will lead to novel targeted therapeutic strategies centered on CDK5 inhibition.


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 = -$774 )
2025	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	5	6/23/2025	NON-COMPETING CONTINUATION	-$774
														Subtotal = -$774

Issue Date FY: 2023 ( Subtotal = $432,500 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	5	2/27/2023	NON-COMPETING CONTINUATION	$432,500
														Subtotal = $432,500

Issue Date FY: 2022 ( Subtotal = $432,500 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	4	5/25/2022	NON-COMPETING CONTINUATION	$35,310
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	4	2/1/2022	NON-COMPETING CONTINUATION	$397,190
														Subtotal = $432,500

Issue Date FY: 2021 ( Subtotal = $441,325 )
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	3	2/23/2021	NON-COMPETING CONTINUATION	$441,325
														Subtotal = $441,325

Issue Date FY: 2020 ( Subtotal = $441,325 )
2020	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	1/23/2020	NON-COMPETING CONTINUATION	$441,325
														Subtotal = $441,325

Issue Date FY: 2019 ( Subtotal = $441,325 )
2019	2019	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	1	2/14/2019	NEW	$441,325
														Subtotal = $441,325

Grand Total All Awards = $2,188,201

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The Function of CDK5 in Metastasis

Award Number: R01CA239660

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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