Our research focuses on elucidating the molecular mechanisms by which the Ron receptor tyrosine kinase promotes cancer initiation, progression, therapeutic resistance and disease recurrence. Our ultimate goal is to provide critical mechanistic information to bridge gaps in our current knowledge of this disease for the development of novel and efficient therapeutic targets in human cancer.
A brief overview of projects in the lab is as follows:
i. Ron in Human Prostrate Cancer
Ron expression increases with prostate cancer progression. Primary human prostate cancers have significantly elevated Ron expression compared to normal tissue, but even significantly higher levels exist in hormone resistant prostate cancers. Initially, prostate cancer is dependent upon the hormone, androgen, which stimulates the growth of prostate cancer cells. Therefore, prostate cancer is commonly treated via androgen deprivation therapy to reduce endogenous levels of androgens. However, many prostate cancers become resistant to hormone therapy overtime, reaching an aggressive state of androgen-independent growth and metastasis. Our findings make Ron an attractive target in the study, and potentially treatment, of hormone resistant prostate cancer.
ii. Targeting Ron in a Clinically Relevant Mouse Model of Prostate Tumorigenesis and Metastasis
Ron knockdown in the luciferase-tagged human prostate cancer cell line, PC-3, significantly reduced tumor growth and metastasis when orthotopically implanted into the prostate glands of nude mice. Our data suggest that targeting Ron in prostate tumor cells can improve patient prognosis and increase metastasis-free survival. Currently, there is a robust pipeline of receptor tyrosine kinase (RTK) inhibitors in clinical trials. Many of these inhibitors target a spectrum of related receptors involved in tumor growth and angiogenesis. In particular, RTK inhibitors such as XL880 (foretinib/GSK1363089), BMS777607, and XL184 (cabozantinib) showed efficacy in Phase I and II trials, with ongoing trials evaluating a variety of tumor types. XL880, BMS777607 and XL184 target Ron with XL880 shown to block Ron phosphorylation in human tumor samples. In addition to Ron, XL880 targets Met, VEGFR1, VEGFR2 and Flt-4 with IC50s all within the 0.4-6.8nM range. BMS777607 also targets Axl, Ron, Met and Tyro3 while XL184 targets a wider spectrum of RTKs including Ron all in the nM range. XL184, while exhibiting some toxicity, has demonstrated antitumor activity in men with advanced prostate cancer with dramatic improvement observed in bone metastases. A current Phase I trial also exists evaluating the safety profile of an anti-Ron antibody. While the above RTK inhibitors lack specificity in targeting the Ron receptor, understanding the mechanisms and cell-types that are affected by Ron in the promotion of prostate cancer may lead to the development of new or more effective targeting strategies to combat the death associated with hormone resistant prostate cancer.
iii. Relationship between Ron and β-catenin in Breast Cancer
Studies by our laboratory have demonstrated a strong, positive correlation between Ron and β-catenin expression in primary mammary tumors of mice and women. β-catenin is a downstream signaling target of the Ron receptor and transcriptionally regulates many genes in various biological functions, including cell proliferation. Additionally, high β-catenin expression in human breast cancer is associated with a poor patient prognosis. Thus, targeting Ron and/or downstream β-catenin signaling may be efficacious in the treatment of aggressive breast cancers.
iv. Immunosuppressive role of Ron in the tumor microenvironment
Signaling interactions among the different cell types within the tumor microenvironment are shown. Of note, Ron expression in the tumor-associated macrophages promotes the expression of Arginase-1 and the phosphorylation of STAT3. Ron expression is also associated with the modulation of various signaling molecules in the tumor microenvironment. These molecules may inhibit the cytotoxic activity of CD8+ T cells and allow for growth and survival of the tumor cells.