Quantitative PET Imaging with Novel HER3-Targeted Peptides Selected by Phage Display to Predict Androgen-Independent Prostate Cancer Progression
Abstract
Although for many patients with prostate cancer treatment is effective at preventing progression, for a large portion the first line of therapy fails. Even worse, the cancers that fail to respond to the first therapy often are more aggressive and deadly, and less likely to respond to secondary treatments. It is important therefore not only to understand why these individual cancers fail to respond, but also to better predict why and how they are avoiding therapy and even to offer guidance into how to treat this deadly subset of prostate cancer. One of the most important proteins in prostate cancer cells is the androgen receptor, which receives signals from hormones such as testosterone and transmits them to the cells, providing regulation on the growth of new cells and the death of old ones. In prostate cancer, the usually well-controlled signals have become disregulated, and understanding why is one of the crucial aspects to better treating the disease. The first course of action to control androgen receptor signaling is to remove the signals using drugs that block production of the hormones that cause it to signal. Although this usually provides a temporary halt to prostate cancer progression, the disease almost always comes back in an even more aggressive form called castration-resistant prostate cancer. Castration-resistant prostate cancer is extremely difficult to treat because the androgen receptor is able to transmit the same signals usually caused by hormones even though the hormones have been essentially turned off. Today, there is an intense investigative effort to understand how this signaling occurs. One of the ways that has been studied is through a protein called HER3. HER3 is a very unique protein, and it has recently received significant attention because it has been shown to cause resistance to therapy in other cancers, such as breast cancer. In prostate cancer, it has been shown that HER3 interacts with the androgen receptor, and its presence can predict the transition to castration-resistant prostate cancer. Thus, the ability to detect HER3 in patients who are undergoing androgen withdrawal therapy can not only predict the recurrence of their prostate cancer, but also offer new information for their oncologist on how to best treat their disease. Currently, proteins are often detected with a biopsy; however, for this application biopsy is not feasible for several reasons. First, the reoccurrence of HER3 can happen at any time, so a regularly occurring screening would be necessary to detect it in a time frame that allows for the most effective action. Repeated biopsies are rare, as the pain and difficulty of the procedure prevent multiple sampling. Furthermore, tumors are variable across different regions, so that a sample taken from biopsy may not match a second sample taken from a different point. This greatly increases the risk of falsely diagnosing a patient based on a small portion of the entire disease. Non-invasive molecular imaging, such as positron emission tomography can overcome each of these downfalls of biopsy. Molecular imaging uses tiny amounts of radioactive probes to provide a real-time image of the biological processes that are occurring in cells. This snapshot of the prostate cancer can then be used to very accurately determine whether or not HER3 is present, which in turn predicts the recurrence of castration-resistant prostate cancer. Because these biochemical changes occur before the tumor progresses in size, molecular imaging offers the earliest indicator possible that the prostate cancer will be progressing. Furthermore, it directly implicates the protein HER3, and drugs that are currently in clinical trial that block HER3 can be used to potentially prevent the cancer from recurring. For my proposal, I will use a small piece of protein, called a peptide, which I have developed to bind to HER3. I will optimize this peptide and then attach a radioactive metal tha
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610447
Entities
People
- Benjamin Larimer
Organizations
- Massachusetts General Hospital
- United States Army