Targeting Discoidin Domain Receptors in Prostate Cancer
Abstract
Scientific Objective and Rationale: Currently, there are no effective treatments for prostate cancer patients once their tumors become non-responsive to androgen therapies and metastatic. Our objective is to investigate a new class of receptor proteins, known as Discoidin Domain Receptors (DDRs), as new diagnostic and therapeutic targets in prostate cancer. DDRs are unique receptors because they mediate the communication between cells and collagen, a major component of the tumor 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 become deregulated and thus shutting down kinase activity can elicit anti-cancer effects. Among all kinases in the human genome, the DDRs are the only ones capable of signaling in response to collagen. When the kinase function of a DDR is activated by collagen, these receptors initiate cellular responses that contribute to the survival of cancer cells. In prostate cancer, this is particularly important because malignant cells are known to preferentially metastasize to bone, an environment that is rich in collagen. In spite of the unique characteristics of DDRs as collagen receptor kinases and the emerging evidence showing a role for these kinases in cancer, there is significant lack of information on DDRs in prostate cancer. We have preliminary evidence that suggests that DDR1, one of these receptors, is highly expressed in tissues of prostate cancer patients but is not found in normal prostate. Moreover, DDR1 expression appears to be associated with disease aggressiveness (high Gleason score). We have also secured specific DDR1 inhibitors that block its activation and are ready to be tested in preclinical models. Thus, we are well positioned to conduct the studies proposed and to contribute to the common effort of identifying new targets for prostate cancer diagnosis and treatment. What types of patients will it help and how will it help them? We expect that targeting DDRs will help patients that failed to respond to androgen therapies and/or are at high risk of developing metastatic disease. It may also help patients that present with clinical evidence of skeletal metastasis. We postulate that drugs that block DDR function will disrupt the ability of prostate cancer cells to communicate effectively with collagen, and consequently interrupt their growth and malignant properties. It is also possible that shutting down the activity of DDRs within the bone will diminish the growth of tumor cells and the damage and pain they cause in patients with bone metastasis. What are the potential clinical applications, benefits, and risks? We hope that targeting DDRs will become part of the arsenal of drugs that will provide a clinical benefit to prostate cancer patients that failed other treatments. Disrupting DDR action may reduce tumor burden and diminish the damage to bone tissues, two major clinical benefits. At present, the general risks of DDR inhibition cannot be predicted without conducting preclinical studies. However, the DDR1 inhibitors to be tested, in particular the blocking antibodies, are highly specific, and thus we expect minimal toxicity. 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 therapeutic effect. What is the projected time it may take to achieve a patient-related outcome? Based on our regulatory system, translation of a promising new drug into the clinic is a lengthy process. However, because the DDR1 blocking antibodies also exist as humanized antibodies (which is required for human use), it is reasonable to predict that successful completion of our preclinical studies will lead to the implementation of a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510226
Entities
People
- Rafael Fridman
Organizations
- United States Army
- Wayne State University