We have recently generated experimental data that validates the CXCR6/CXCL16 axis as a prostate cancer (PCa) therapeutic target. PCa is the second leading cause of cancer death in American men and its morbidity has increased globally in recent years. The high mortality rate is closely associated with the spread of malignant cells to various tissues including bone. Nearly 10% of patients whose conditions are diagnosed as PCa initially present with bone metastasis and almost all patients who die of prostate cancers have skeletal involvement. Identifying new mechanisms that control bone metastasis is of great consequence to facilitate the design of therapeutics aimed at decreasing metastatic risk and/or its complications. To address this unmet medical need, our team is actively engaged in exploring the chemical biology, medicinal chemistry, and therapeutic significance of modulating tumor cell trafficking and metastasis via chemokine receptor inhibition. This R03 application describes an MLPCN HTS-ready research program which is within the interests and expertise of our laboratories. The primary objective of this proposal is to use high throughput screening methods to identify small molecule antagonist probes that selectively inhibit CXCR6. Our team intends to address a key hypothesis: The CXCR6/CXCL16 axis significantly contributes to PCa cell metastasis and subsequent bone invasion. A small molecule antagonist would block cancer cell trafficking;hence mediate a metastatic event and disease progression to bone. We demonstrate supporting data that validates the role of the CXCR6/CXCL16 axis in PCa tumor progression, invasion, and proliferation. Thus, access to pharmacologically available small molecule antagonists will ultimately enable our studies in disease relevant models and allow for a more seamless translational advance to clinical applications.

Public Health Relevance

Prostate cancer (PCa) is the second leading cause of cancer death in American men and its morbidity has increased globally in recent years. The high mortality rate is closely associated with the spread of malignant cells to various tissues including bone. Nearly 10% of patients whose conditions are diagnosed as PCa initially present with bone metastasis and almost all patients who die of prostate cancers have secondary skeletal tumor involvement. We are targeting the discovery of novel chemical probe molecules that block the signaling pathways driven by the CXCR6 receptor through receptor antagonism. This ultimately has utility as a potential therapeutic means to halt PCa disease progression and subsequent bone invasion.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
5R03MH095589-02
Application #
8330241
Study Section
Special Emphasis Panel (ZRG1-BST-F (50))
Program Officer
Yao, Yong
Project Start
2011-09-09
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$53,778
Indirect Cost
$23,228
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Jung, Younghun; Kim, Jin Koo; Shiozawa, Yusuke et al. (2013) Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat Commun 4:1795