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Bone-Targeted Therapies to Improve Bone Health and Prevent Relapse in Multiple Myeloma

Award Number: R37CA251763
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Bone-Targeted Therapies to Improve Bone Health and Prevent Relapse in Multiple Myeloma - Summary Current chemotherapeutic agents have improved multiple myeloma (MM) patient survival. However, MM remains incurable due to high rate of disease relapse that originate from dormant MM clones resistant to therapy. Further, anti-MM therapies have minor effects on repairing MM-induced bone disease, a leading cause of morbidity and mortality in MM patients. Thus, disease relapse and bone disease remain major unmet medical needs that require innovative approaches to effectively treat MM. The overall goal of this proposal is to evaluate the efficacy of novel bone-targeted therapies blocking key interactions between MM cells and cells of the tumor niche to stop the progression of MM in bone. We will focus on Notch and Wnt signaling, two major signaling pathways mediating tumor-host microenvironment communication. In studies leading to this application, we generated a bone-targeted Notch inhibitor (BT-GSI) that selectively decreases Notch signaling in bone. Inhibition of Notch communication in the tumor niche with BT-GSI reduced MM growth and decreased osteoclast number and bone destruction. Importantly, BT-GSI circumvented the gut toxicity that limits the use of Notch inhibitors in the clinic. Further, we found that interactions between MM cells and osteocytes increase the expression of Sclerostin, a local Wnt signaling antagonist that inhibits osteoblast bone forming function. Blockade of Sclerostin using neutralizing antibodies (Scl-Ab) prevented MM-induced bone disease by increasing osteoblasts and stimulating new bone formation. Importantly, our work leading to this application showed that interactions between MM cells and osteoblasts maintain MM cells in a dormant state, while interactions with osteoclasts promote their reactivation into proliferating MM cells. Based on these preliminary findings, we propose that combined bone- directed therapies inhibiting Notch and activating Wnt signaling will 1) decrease MM growth, 2) prevent reactivation of MM dormant cells, and 3) repair damaged bone, while reducing systemic toxic effects. This hypothesis will be advanced by pursuing specific aims that employ established mouse models of MM-induced bone disease and MM dormancy and new pharmacologic tools targeted to the tumor niche. Two aims are proposed. Aim 1 will determine the pharmacokinetic, pharmacodynamic, and safety profiles of our bone-targeted Notch inhibitor BT-GSI. Aim 2 will examine the effects of combined bone-targeted inhibition of Notch signaling (BT-GSI) and activation of the Wnt pathway (Scl-Ab) on tumor growth, bone repair, and MM cell dormancy.


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 = $306,555 )
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Treatment Research	000	5	5/20/2024	NON-COMPETING CONTINUATION	$306,555
														Subtotal = $306,555

Issue Date FY: 2023 ( Subtotal = $339,514 )
2023	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Treatment Research	000	4	6/2/2023	NON-COMPETING CONTINUATION	$339,514
														Subtotal = $339,514

Issue Date FY: 2022 ( Subtotal = $349,898 )
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 Treatment Research	000	3	5/20/2022	NON-COMPETING CONTINUATION	$349,898
2022	2021	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Treatment Research	001	2	7/8/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $349,898

Issue Date FY: 2021 ( Subtotal = $349,984 )
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 Treatment Research	000	2	5/25/2021	NON-COMPETING CONTINUATION	$349,984
														Subtotal = $349,984

Issue Date FY: 2020 ( Subtotal = $358,966 )
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 Treatment Research	000	1	8/24/2020	NEW	$358,966
														Subtotal = $358,966

Grand Total All Awards = $1,704,917

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Bone-Targeted Therapies to Improve Bone Health and Prevent Relapse in Multiple Myeloma

Award Number: R37CA251763

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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