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Novel NEK2 signaling pathways in myeloma progression

Award Number: R01CA236814
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Novel NEK2 signaling pathways in myeloma progression - Project Summary Multiple Myeloma (MM) is a plasma cell malignancy characterized by extensive structural and numerical chromosomal abnormalities. By comparing consecutive gene expression profiles (GEP) of samples at baseline, during intensive chemotherapy and at relapse, we have identified chromosomal instability (CIN) genes associated with poor prognosis in MM disease. One of the CIN genes, the serine-threonine kinase NEK2, is the most significantly upregulated gene in myeloma cells in patients in complete remission (CR) with minimal residual disease (MRD) and at relapse early during chemotherapy following tandem transplantations. We have shown that pharmacological or genetic inhibition of NEK2 delays tumor growth and induces cell apoptosis in myeloma and high expression of NEK2 has also been related to poor outcomes in many other cancers. The deubiquitinase (DUB) USP7 stabilizes NEK2 protein resulting in the activation of the NF- B/heparanase pathway, also involved in bone destruction. However, it is unknown whether NEK2 also activates USP7. In addition, we have found that NEK2 negatively regulates PD-L1 expression, most likely via epigenetic modification. High-risk myeloma cells show low levels of PD-L1 expression and are resistant to immune checkpoint blockade. Therefore, we hypothesize that NEK2 promotes myeloma cell survival, drug resistance, and disease progression by activating the deubiquitinase USP7 and the histone methyltransferase EZH2. In order to rigorously test this hypothesis, we will: (1) Identify the major deubiquitination targets regulated by the Nek2-Usp7 complex using Nek2-transgenic mice with varying levels of Nek2 expression and controls. We will focus on selecting probable proteins as a proof-of-principle to establish the role of Usp7 as the signaling hub in this complex. (2) Determine the mechanisms by which NEK2 inhibits responses to immune checkpoint blockade in myeloma cells using Nek2-knockout mice and biochemical approaches. And, (3) Develop novel immune therapies for drug-resistant and relapsed myelomas using primary myeloma cells, a genetic Nek2-knockout mouse model, and a myeloma mouse model. Supported by strong preliminary data that provide strong rationale for this application, the proposed research is poised to facilitate novel, targeted approaches to the prevention and treatment of myeloma progression and relapse. We predict that our results will extend beyond myeloma and also apply to other hematological and solid tumors.


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: 2024 ( Subtotal = $330,316 )
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Biology Research	000	5	5/21/2024	NON-COMPETING CONTINUATION	$330,316
														Subtotal = $330,316

Issue Date FY: 2023 ( Subtotal = $512,052 )
2023	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Biology Research	001	4	7/10/2023	SUPPLEMENT FOR EXPANSION	$171,306
2023	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Biology Research	000	4	5/17/2023	NON-COMPETING CONTINUATION	$340,746
														Subtotal = $512,052

Issue Date FY: 2022 ( Subtotal = $502,257 )
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Biology Research	001	3	8/31/2022	SUPPLEMENT FOR EXPANSION	$161,511
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Biology Research	000	3	5/23/2022	NON-COMPETING CONTINUATION	$340,746
														Subtotal = $502,257

Issue Date FY: 2021 ( Subtotal = $347,700 )
2021	2021	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Biology Research	000	2	5/25/2021	NON-COMPETING CONTINUATION	$347,700
														Subtotal = $347,700

Issue Date FY: 2020 ( Subtotal = $347,510 )
2020	2020	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Biology Research	000	1	5/28/2020	NEW	$347,510
														Subtotal = $347,510

Grand Total All Awards = $2,039,835

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Novel NEK2 signaling pathways in myeloma progression

Award Number: R01CA236814

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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