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Towards a better understanding of the critical role and therapeutic potential of drug resistant genes in multiple myeloma

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: 05/31/2031

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Towards a better understanding of the critical role and therapeutic potential of drug resistant genes in multiple myeloma - PROJECT SUMMARY/ABSTRACT This application is a renewal of R01 CA236814-01, entitled “Novel NEK2 Signaling Pathway in Myeloma Progression.” The long-term objective of this work is to develop novel treatments for multiple myeloma (MM) that overcome drug resistance and prevent relapse. MM is the second most common hematologic malignancy, with an estimated 35,780 new cases in the United States in 2024. In cancer, drug resistance is a major cause of treatment failure and disease relapse, and our group has a long history of using genomic and genetic tools and leveraging data derived from a large clinical sample database to explore mechanisms of drug resistance. Through these efforts, we identified 10 chromosomal instability (CIN) genes, including NEK2, that are associated with poor prognosis in MM. During the funding period since June 1, 2020, we showed that NEK2 interacts with another CIN gene, TRIP13, to accelerate B-cell tumor development and progression. Importantly, we made novel discoveries and generated preliminary data to support this renewal application: (1) Using mass spectrometry proteomics analysis of human primary MM samples, we identified CDK11A as a potential master regulator of CIN genes in MM cells. (2) We showed that high NEK2 expression in the tumor microenvironment suppresses T-cell immunity. (3) We discovered that MM cells that survive BCMA-CAR-T therapy or conventional chemotherapy highly express both CIN genes and CD24 and represent distinct populations of drug-resistant MM cells. In this proposal, we hypothesize that CDK11A acts as a master regulator of the 10 CIN genes, promoting drug resistance, and that combination therapy involving Bi-BCMA-CD24-CAR-T cells and a NEK2 inhibitor will improve therapeutic efficacy by eliminating both bulk and drug-resistant MM cells while enhancing immune responses. To rigorously test this hypothesis, we propose the following Specific Aims: (1) Determine the mechanisms by which drug-resistance genes are regulated in MM cells. (2) Determine the role of NEK2 in controlling regulatory T cells in MM. (3) Develop a novel combination therapy to overcome drug resistance and improve immune responses in MM. This application proposes the use of vertebrate animals. Because we explore the potential mechanism whereby inhibiting Nek2 in the tumor microenvironment improves the immune response to MM and evaluate therapeutic effects of Bi-BCMA/CD24- CAR T cells using immune competent mice, there is no alternative system for performing such experiments. Supported by our high productivity and strong preliminary data, which provide a sound rationale for this renewal application, the proposed research will likely yield a better network-based understanding of resistance mechanisms to chemotherapy and immunotherapy. This work has the potential to also provide novel insights and facilitate the development of novel targeted therapies to overcome drug resistance and immune suppression in MM.


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 = $507,317 )
2026	2026	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Biology Research	000	6	5/27/2026	COMPETING CONTINUATION	$507,317
														Subtotal = $507,317

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 = $2,547,152

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Towards a better understanding of the critical role and therapeutic potential of drug resistant genes in multiple myeloma

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: 05/31/2031

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