Bone metastases affect 350,000 people per year in the United States alone. We found that the integrin ?3 global knockout mouse was protected from tumor-associated bone loss and bone metastasis, a finding consistent with the model that tumor cells highjack the ?3 integrin pathways in platelets and osteoclasts, which express express aIIb?3 and av?3, respectively. Both platelets and osteoclasts are host cells that are critical for the growth and survival of tumor cells in the bone environment. A problem with targeting ?3 for bone metastasis is that deletion of the ?3 integrin subunit in all tissues can enhance tumor-associated angiogenesis, most likely as a result of ?3 integrin present on the endothelium and on activated macrophages in the tumor environment. Therefore, pharmacologic inhibition of av?3 may have adverse procancer effects and inhibition of aIIb?3 causes bleeding. To obviate these issues of the germline ?3 knockout we generated mice with a ?3 integrin gene flanked by loxP sites and deleted the gene in platelets and myeloid (macrophage and osteoclast) lineages using tissue-targeted Cre transgenic mice. As alternative approaches to modulating ?3 integrin function in platelets and osteoclasts, we will investigate the roles of the ?3 integrin activating receptor, P2Y12, and a ?3-integrin stimulating protein, CD47, on platelet and osteoclast function and during bone metastasis. In order to avoid the negative effects of global ?3 integrin inhibition and to identify novel therapeutic targets, we will study these ?3 integrin stimulatory pathways that may confer cell type specificity and reduce side effects. Our central hypothesis is that blockade of ?3 integrin stimulatory pathways in platelets and myeloid cells will disrupt tumor growth in bone and tumor-driven osteolysis. Thus, our Specific Aims are to: 1. Define the role of ?3 integrins on platelets and myeloid cells during metastasis to bone and tumor growth in the bone micro-environment. 2. Evaluate the role of the upstream activator of ?3 integrin P2Y12 on platelets and myeloid cells during skeletal metastasis and tumor osteolysis. 3. Evaluate the role of CD47, a ?3 integrin stimulatory protein, as a therapeutic target to abrogate bone metastasis and tumor osteolysis. Intervention strategies to be used in relatively healthy patients with cancer must have side effects that are clinically minimal. Thus the over-arching goal of this project is to design novel neoadjuvant treatment strategies to prevent bone metastasis through targeting ?3 integrin pathways active on platelets and osteoclasts. These studies will lead to identification of optimal drug targets within the ?3 integrin pathway with minimal side effects that overcome the problem of generalized ?3 integrin inhibition, while preventing or decreasing bone metastasis.

Public Health Relevance

3 integrins (av 3 and aIIb 3) play critical roles in tumor invasion and metastasis by mediating bone resorption; platelet aggregation; and neo-angiogenesis. The over-arching goal of this project is to design novel treatment strategies to prevent bone metastasis through targeting 3 integrin pathways active on platelets and osteoclasts. Mice harboring tissue-specific deletions of integrin 3; and inhibitors of integrin modulating molecules; CD47 and P2Y12; will be used to assess the individual roles of 3 integrins in tumor cell homing to and growth in bone and may uncover novel molecular targets to more effectively treat skeletal metastasis. These studies will lead to identification of optimal drug targets within the 3 integrin pathway with minimal side effects that overcome the problem of generalized 3 integrin inhibition; while preventing or decreasing establishment of bone metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097250-11
Application #
8606730
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2003-07-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
11
Fiscal Year
2014
Total Cost
$324,389
Indirect Cost
$110,975
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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