ERF Is a Potential ERK-Modulated Tumor Suppressor in Prostate Cancer
Abstract
Scientific Objective and Rationale: Although about 90% of patients with prostate cancer are cured with surgery or radiation, the remainder often suffer and die from the disease spreading to their bones, spinal cord, and other organs. In such cases, the disease is treatable to a certain extent, but not curable. While 10% may not sound like much, prostate cancer is such a common disease that it is the second-most common cause of cancer death among American men, and cancer collectively is overtaking heart disease as the most frequent cause of death in the Western world. Unlike colon and lung cancer, we have yet to apply cancer gene sequencing to prostate cancer clinical care. We know that half of prostate cancer patients have a mutation leading to a lot of ERG protein; we further know that this ERG drives cancer development in combination with other common mutations. However, we do not understand in detail how ERG achieves this or what is happening in the other half of prostate cancers lacking the ERG mutation. To address these shortcomings, I performed a large-scale experiment comparing tumors with a lot of ERG to those with only a little. I discovered that ERG (a tumor "gas pedal") has a counterpart, ERF, which serves as a tumor brake. I also learned that patients without ERG mutations sometimes have an ERF mutation instead (presumably causing the brake to be faulty, leading to cancer). Based on these findings, I predict that tumors with a lot of ERG override the ERF brake, and in this way cause cancer. But in tumors without ERG mutations, ERF functions as an effective brake unless it itself is mutated. Furthermore, it seems that if we administer a drug like trametinib (already Food and Drug Administration-approved for melanoma), we could strengthen the ERF brake in the 50% of patients lacking ERG mutations. Thus, I am asking for funding to support experiments to test this theory, with the promising implications outlined below. Career Goals in Research and Patient Care: My goal is to become an independent physician-scientist who focuses on patients with such advanced prostate cancers. By being an oncology fellow at Memorial Sloan Kettering and carrying out a rigorous training plan consisting of both didactic learning and on-the-job training, I seek to further both lab research and clinical care. Carrying out this project would benefit my training tremendously. It would give me further experience in experimental design, data analysis, and translating science into medicine. In order for me to work as an independent scientist one day, I need to build such a body of work and experience. Applicability of the Research: This project could have direct clinical applications. It could serve as a preclinical launch pad to a clinical trial wherein the 50% of patients lacking the ERG mutation could undergo a combination of standard therapy plus the drug strengthening the ERF brake function and ascertain whether my model holds in patients. The benefits of such a study could be prevention of tumor growth or even tumor regression. The potential risks include the side effects of the drug. It would take nearly a decade in order for standard clinical care to be affected by these studies, which is why I wish to start experiments as soon as possible. Contributions to Advancing Prostate Cancer Research: In addition to the clinical applications above, this project could shed light on how tumors with and without ERG mutations are actually similar; both can get rid of the ERF brake but by different methods. This, in turn, would contribute to our understanding of the 50% who do have the ERG mutation and assist in developing a targeted strategy for them as well.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510277
Entities
People
- Rohit Bose
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army