Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

RANK Signaling Inhibitors for Osteolytic Lesions in Multiple Myeloma

Award Number: R21CA296500
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2026

Group Awards By:

View Award Description

RANK Signaling Inhibitors for Osteolytic Lesions in Multiple Myeloma - Project Summary Multiple myeloma patients often develop bone lesions, resulting in poor prognosis and skeletal-related events (SREs, including hypercalcemia, spinal cord compression, vertebral collapse, pathologic fractures and bone pain). Bone lesions in multiple myeloma patients are caused by increases in osteoclast formation activity. Hence, antiresorptive drugs such as denosumab and bisphosphonates are presently used to treat bone lesions in multiple myeloma. Nevertheless, both drugs cause osteonecrosis of the jaw by suppressing the immune system. Denosumab is a human monoclonal antibody against RANKL, which is a critical regulator of osteoclast formation. Moreover, denosumab increases risk of serious infections, which is due to the inhibitory effect of denosumab on the immune system since RANKL also regulates immune cell development and survival. RANKL exerts these diverse functions by activating its receptor RANK. Furthermore, as a biological agent, the cost of denosumab is high and the method of delivery (injection) is not ideal. Thus, a better targeting strategy would be to use small molecules to target RANK signaling pathways that are involved in osteoclastogenesis and multiple myeloma- associated SREs but not in the immune system function. Our group previously discovered two motifs in the RANK cytoplasmic domain that regulate osteoclast formation in vitro. To study the role of the two RANK motifs in osteoclast formation in vivo, we have generated and characterized knockin (KI) mice bearing inactivating mutations in the two motifs. Osteoclast formation is dramatically impaired in the KI mice, confirming the role of these two motifs in osteoclast formation in vivo. Importantly, inactivation of these two motifs does not affect the ability of RANK to mediate immune cell development and survival. Therefore, we hypothesize that specifically targeting these two RANK motifs has the potential to serve as effective and selective therapeutic targets for bone lesions in multiple myeloma. Our long-term goal is to develop efficacious and safe small molecule drugs targeting the two RANK motifs for preventing bone lesions in multiple myeloma. We have developed cell-based assays for identifying compounds targeting the two RANK motifs. From a high throughput screen of 200,000 compounds with the cell-based assay systems followed by counter screen assays, numerous compounds were identified that potently inhibited osteoclast formation. Medicinal chemistry efforts on two of these hit compounds has led to the development of one compound that possesses improved potency and drug-like properties that are suitable for proof-of-concept mouse model studies as well as back-up compounds. The objective of this R21 proposal seeks to carry out important translational exploratory and developmental studies to evaluate the conceptual and technical feasibilities of this novel therapeutic targeting strategy for bone lesions in multiple myeloma. Positive outcomes of the proposed work will lay the solid foundation for applying for R01 funding to support future development of efficacious and safe drugs for preventing and treating bone lesions in multiple myeloma patients.


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 = $275,124 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	001	2	4/17/2026	NON-COMPETING CONTINUATION	$27,513
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	000	2	1/26/2026	NON-COMPETING CONTINUATION	$247,611
														Subtotal = $275,124

Issue Date FY: 2025 ( Subtotal = $201,609 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	000	1	12/31/2024	NEW	$201,609
														Subtotal = $201,609

Grand Total All Awards = $476,733

Top

All Categories

About

Search

Reports

Data Submission

Award Information

RANK Signaling Inhibitors for Osteolytic Lesions in Multiple Myeloma

Award Number: R21CA296500

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer