RANK Signaling Inhibitors for Treating Breast Cancer Bone Metastasis
Abstract
This proposal seeks to develop better drugs to treat breast cancer bone metastasis. Thus, this application will focus on breast cancer patients with bone metastasis and address the Overarching Challenge: Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. RANKL is a protein that was identified in the late 1990s as a critical factor regulating the formation of osteoclasts, the body’s bone-resorbing cells. Postmenopausal osteoporosis is caused by increased osteoclast formation as a result of decline in estrogen levels due to cessation of ovary function in postmenopausal women. Given its crucial role in osteoclast formation, RANKL was recognized as an attractive drug target for osteoporosis shortly after its discovery. Thus, Amgen developed an antibody against RANKL (denosumab), which was approved in 2010 by the Food and Drug Administration (FDA) for treating postmenopausal osteoporosis. Breast cancer patients with bone metastasis suffer from skeletal-related events (SREs, including life-threatening hypercalcemia, spinal cord compression, pathologic fractures, and extreme bone pain) and have poor prognosis. SREs primarily result from bone destruction caused by metastatic tumor cells that promote bone destruction by stimulating the formation and function of osteoclasts. Thus, denosumab has been also approved by the FDA for treating breast cancer bone metastasis. However, there are several concerns with denosumab. First, it increases risk of serious infections, osteonecrosis of the jaw, and atypical bone fracture. Osteonecrosis of the jaw and the increased risk of serious infections are due to the suppressive effect of denosumab on the immune system since RANKL also plays important roles in the immune system by regulating immune cell development, function, and survival. Second, as a biological agent, the cost of denosumab is high, and the method of delivery (injection) is not ideal. RANKL exerts its functions by binding to a protein termed RANK, which is expressed on the surface of target cells such as osteoclast precursors and immune cells. Binding of RANKL to RANK activates RANK, and activated RANK in turn interacts with distinct proteins inside cells to initiate intracellular signaling pathways (i.e., a signaling pathway consists of a cascade of molecular events such as protein-protein interaction and chemical modifications of proteins). These signaling pathways lead to the activation of effector proteins that modulate cellular differentiation, function and/or survival. It is not uncommon that a signaling pathway is selectively involved in regulating cell function in some cell types, but not others. Given the issues with denosumab, a better targeting strategy would be to target RANK signaling pathways that are involved in osteoclast formation/breast cancer bone metastasis, but not in the immune system, with small molecules. Our laboratory previously identified two small segments (termed motifs) in the intracellular region of RANK. We have recently generated mice in which these RANK motifs are inactivated. Osteoclast formation is dramatically reduced in the knockin 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, function, and survival. Based on these data, we hypothesize that specifically targeting these two RANK motifs has the potential to serve as an effective strategy for breast cancer bone metastasis without the deleterious side effects seen with denosumab. Our ultimate goal is to develop more efficacious and safer small molecule drugs targeting the two RANK motifs for treating breast cancer bone metastasis. To this end, we have identified several compounds that potently inhibit osteoclast formation and possess promising drug-like properties. Thus, the objective of this Breakthrough Award applicati
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210528
Entities
People
- Feng Xu
Organizations
- United States Army
- University of Alabama at Birmingham