Discoidin Domain Receptors: Novel Targets in Breast Cancer Bone Metastasis
Abstract
Rationale, Objectives, and Aims: One of the major clinical complications of breast cancer (BrCa) is the development of bone metastasis, a condition that results in severe pain, fractures, and/or spinal cord compression, causing significant suffering to BrCa patients. Today, BrCa patients with skeletal metastases have limited therapeutic options, and those only comprise palliative treatments. Therefore, there is an urgent need to discover new targets for treatment of BrCa bone metastasis. The studies of this application provide a new hope in our fight against the damaging effects of bone metastasis by targeting a key set of molecules in the tumor cells, which may disrupt their destructive actions within the bone tissue. Our objective is to investigate the therapeutic potential of a new class of receptor proteins, known as Discoidin Domain Receptors (DDRs), in bone metastasis. DDRs are unique receptors because they mediate the communication between cells and collagen, a major component of the bone microenvironment via a distinct mechanism, known as tyrosine kinase activity. Kinases are like electrical switches that turn on the cell s intracellular machinery in response to external signals, which help the cells to adapt to their microenvironment. In cancer, kinases are usually deregulated, and thus shutting down kinase activity can elicit potent anti-cancer effects. Among all kinases in the human genome, the DDRs are the only ones capable of signaling in response to collagen. Therefore, jamming the stream of signals initiated by DDRs in BrCa cells residing within the collagen-rich microenvironment provides a new therapeutic opportunity that deserves exploration. To accomplish this goal, we will conduct studies of DDR expression in primary tumors and bone metastasis (Aim 1), preclinical studies of DDR inhibition in mouse models of BrCa bone metastasis (Aim 2), and analyses of the role of DDRs in regulation of bone destructive processes in models of bone-BrCa cells. These studies will be conducted by a highly synergistic team of investigators with complementary expertise in bone metastasis (Dr. Bonfil), DDR and BrCa biology (Dr. Fridman), and BrCa pathology (Dr. Kleer). Overarching Challenge(s): Our application addresses the Overarching Challenges of "eliminating the mortality associated with metastatic breast cancer" and "identifying why some breast cancers become life-threatening metastasis." Types of Patients It Will Help and How It Will Help Them: We expect that targeting DDRs will help patients with clinically evident metastatic deposits in the skeleton. We postulate that blocking DDR function will disrupt the ability of BrCa cells to communicate effectively with collagen, and consequently disable their malignant properties. It is also possible that shutting down DDR activity within the bone will diminish pain and bone-related complications. Potential Clinical Applications, Benefits, and Risks: We envision administering anti-DDR therapies (kinase inhibitors and/or neutralizing antibodies) in patients with clinical evidence of bone metastasis. Because single therapies are unlikely to be successful, we envision anti-DDRs drugs to be given in conjunction with other anticancer treatments for bone metastasis, including bisphosphonates. However, the precise combinations and their efficacy/toxicity will need to be evaluated. Disrupting DDR action may bring two major clinical benefits: reduce tumor burden and diminish the damage to bone tissues. At present, the general risks of DDR inhibition cannot be predicted without conducting preclinical studies. However, because DDRs are highly expressed in BrCa cells, we predict minimal toxicity, more so with highly specific inhibitors. We should be aware that kinase inhibition may also induce resistance, and therefore there is a risk that targeting DDRs alone may not be sufficient and require other targets to achieve its maximal therapeutic effect. Projecte
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1610045
Entities
People
- Ricardo Bonfil
Organizations
- United States Army
- Wayne State University