PKN1 as Novel Therapeutic Target in Advanced Prostate Cancer
Abstract
What is the long-term goal of this study? Hormone therapy puts prostate cancer into remission, but does not cure prostate cancer. The ultimate goal of the proposed studies is to develop novel forms of therapy to extend remission for or, possibly, cure advanced prostate cancer. Why is the proposed research important? Each year, almost 30,000 men die of prostate cancer in the United States alone. That makes prostate cancer the second leading cause of cancer-related deaths in American men. Patients who present with prostate cancer that has not spread beyond the prostate gland are treated routinely using surgery or radiation therapy that is intended to cure the patient. Unfortunately, some men present with metastatic prostate cancer that cannot be cured by such treatments, and in some men prostate cancer recurs after operation or radiation. For those men, hormone therapy is the standard of care. This is because, for more than 70 years, testosterone, which is the most important male sex hormone, has been known to cause prostate cancer and to drive its growth. Testosterone functions as the key that unlocks the lock that causes the growth of prostate cancer. Hormone therapy prevents testosterone from being made or changes the shape of the lock so that testosterone can no longer unlock it to drive prostate cancer growth. At first, hormone therapy results in remission. Unfortunately, eventually, hormone therapy fails and an advanced form of prostate cancer that kills men develops. One of the reasons for the failure of hormone therapy is that the lock has changed so it does not require testosterone to open it and thus standard hormone therapy no longer keeps it locked. Failure of hormone therapy is responsible for the vast majority of prostate cancer deaths, which amounts to one American man dying of prostate cancer every 16 minutes. There is an urgent need to develop better and more effective forms of therapy to treat advanced prostate cancer that kills men. Using various model systems, our laboratory has discovered that a compound known as lestaurtinib does not target the lock for testosterone action but slows the growth of prostate cancer cells. We established that this compound inhibits the action of an enzyme known as PKN1, and is active in models that represent prostate cancer before hormone therapy and prostate cancer that has recurred after hormone therapy. This is very interesting from a therapeutic standpoint because this compound may become another treatment option to treat prostate cancer patients that cannot be cured using surgery or radiation. Before lestaurtinib was known to inhibit PKN1, it was tested on a very small scale to treat prostate cancer patients but abandoned because patients response to treatment unexpected could not be monitored using serum PSA levels, the chosen indicator of treatment response. Here, we propose preclinical studies using cell and mouse models that carry prostate cancers that express different versions of the lock for testosterone as well as patient-derived prostate cancer tissues that represent different phases during prostate cancer progression. PKN1 inhibition and lestaurtinib treatment is done either before or after hormone therapy. Specifically, we will test how this new drug affects prostate cancer progression compared to the treatment that is standard of care. We will determine how well growth and spread of prostate cancer is controlled, how long remission lasts, and what sort of side effects are induced. We will obtain the information also needed to evaluate how patients respond to these treatments. How will the results of these studies be developed further to advance the treatment of prostate cancer? These studies will tell us whether how effective lestaurtinib and PKN1 inhibition is compared to standard therapy for advanced prostate cancer. Importantly, lestaurtinib has been tested already in clinical trials for cancer treatment in men. Lestaurtin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610404
Entities
People
- Hannelore Heemers
Organizations
- Cleveland Clinic
- United States Army