RON Kinase as a Multifaceted Therapeutic Target for Metastatic Breast Cancer
Abstract
Our proposal addresses three of the overarching challenges: (1) Eliminate breast cancer mortality (2) Revolutionize treatment regimens with less toxic therapy (3) Determine how to prevent recurrence Even before diagnosis of a primary tumor, breast cancer cells can disseminate to distant organs, where they may remain in a dormant and clinically undetectable state for many years. Eventual growth of these disseminated cells into metastases, typically in bone, liver, lung, and brain, occurs in 20%-30% of patients. Metastatic disease accounts for an overwhelming proportion of breast cancer mortality because, unfortunately, metastatic breast cancer is not curable. The mechanisms of clinical “dormancy” prior to metastatic recurrence are poorly understood, but almost certainly require tumor cells to adapt to and modify their new environment and to evade the body’s immune system. More than 70% of metastatic breast cancer patients have bone metastases. Although patients do not die directly from bone metastasis, bone lesions are the most common first site of recurrence, and median survival time from diagnosis of bone metastasis is only 2-3 years. Breast cancer bone metastases activate specialized cells resident in the bone, called osteoclasts, which break down bone tissue in a process known as osteolysis. Osteolysis has profound systemic repercussions, including effects on immune responses. In this proposal, we will test an intriguing idea: that the destructive effects of bone metastasis in breast cancer not only affect tumor growth in bone, but also lead to metastatic tumor growth in other sites by weakening the body’s anti-tumor immune responses. This phenomenon could explain why bone metastasis so often precedes the appearance of metastasis in other organs and why certain agents that block osteoclast activity also seem to improve overall survival in early breast cancer. Using mouse models, we have identified a protein, Ron kinase, that supports the growth of breast cancer cells at metastatic sites. Although Ron acts on the tumor cells themselves, we found that this protein also plays a very critical role in influencing the surrounding immune cells in the bone environment. Ron functions in osteoclasts to promote osteolysis and it also suppresses the anti-tumor immune response, thereby facilitating metastatic outgrowth. We hypothesize that inhibition of Ron eliminates metastasis through a dual effect: blocking osteolysis and enhancing anti-tumor immunity. We propose to (1) determine if Ron promotes osteolysis through its direct activation of osteoclasts or whether other cells are involved; (2) determine if antitumor immunity and distant metastasis are regulated through activation of Ron in osteoclasts and/or other cells; and (3) conduct preclinical and initial clinical development of a novel bone-targeted Ron inhibitor and compare it to systemic delivery of a Ron inhibitor that has already been shown to be safe and well-tolerated in Phase I clinical trials, with some low grade gastrointestinal issues. Targeting this drug to bone could lead to greater effects exactly where it is needed, while avoiding effects in other parts of the body. In summary, we have (1) identified a novel protein target demonstrated in animal models to significantly reduce metastasis by modulating osteoclast activity and immune responses and (2) developed and articulated a path for a new class of drug to human trials. If successful, this approach could reduce mortality in the largest proportion of patients with breast cancer systemic recurrence: those with bone involvement. Moreover, this strategy could replace more toxic systemic therapies and could more effectively combat metastatic disease. This could have an enormous impact since ~500,000 people die each year from metastatic breast cancer worldwide.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810616
Entities
People
- Alana L Welm
Organizations
- United States Army
- University of Utah