The Evolution of cMyc-Driven Prostate Adenocarcinoma to N-Myc-Driven Small Cell Neuroendocrine Prostate Cancer
Abstract
Prostate cancer is usually found only in the prostate at time of diagnosis. Under the microscope, the tumor resembles a collection of badly formed glands and is termed prostate adenocarcinoma. Patients with disease only in the prostate will often receive radiation therapy or surgery as their only form of treatment. However, for some patients, the cancer will return after this initial effort. Relapsed prostate cancers will often be found at sites far from the original disease as the tumor spreads to bone or internal organs. These patients will receive hormone-deprivation therapy with chemicals that block the testosterone signal these cancers need to grow. This leads to another remission, but usually not a durable one. Within 6 months, most patients with metastatic disease will recur. Treatments for this condition are not effective. Recurrent, hormone-insensitive, metastatic prostate cancer is the lethal form of the disease. This final recurrence is often marked by a transition from glandular-appearing adenocarcinoma to a different tumor type known as small cell carcinoma. This transition is also marked at the molecular level as the tumor cells switch from expression of one type of cancer-causing gene known as MYC, to a second member of the same family known as MYCN. Treatment-related prostate small cell carcinoma is poorly understood at the molecular level, and it responds poorly to existing therapies. Most patients with small cell prostate cancer die within a year. Our proposed research will identify the genes involved in the transition from adenocarcinoma to small cell carcinoma so that they may be targeted and blocked with new drugs. The proposed research seeks to gain greater understanding of small cell prostate carcinoma by making a comparison between human prostate cancer cells with high levels of the MYC gene to cells with high levels of the MYCN gene. We hypothesize that defining the genetic differences between these two types of cells will identify those genes that are most important for the poor patient outcomes for small cell prostate cancer. We propose to make these comparisons using DNA sequencing as protein profiling to ensure that we look at all of the possible important genes. Additionally, we will distinguish between "passenger" genetic differences and "driver" genetic differences by using a tumor cell model. This model will test the ability of the individual genes identified above to turn prostate adenocarcinoma into small cell carcinoma. Assigning function to these genes will identify only those most important for the transition of prostate cancer to its lethal form. These genes would represent attractive drug targets for blocking the development of small cell carcinoma in men receiving hormone-deprivation therapy. -Describe the Principal Investigator s career goals in prostate cancer research. This postdoctoral fellowship represents a major change of field for me. I am trained as a chemist and biochemist, and I have experience with designing, making and testing new cancer drug candidates before they enter human trials. I also have training in human medicine as an M.D. graduate. I plan to enter a career in prostate cancer research with multidisciplinary training in prostate cancer. The training detailed in this proposal is designed to give me invaluable experience with prostate cancer cell biology so that I will have an integrated understanding of cancer therapeutics from target discovery to drug development to patient delivery. The research plan also reflects this goal, as it addresses an important question in prostate cancer that could then be addressed from several different disciplines as the start of my independent career. -Describe the ultimate applicability of the research. We have proposed basic science research into how prostate cancer cells change to a deadly small cell cancer form after treatment. Our research will identify genes involved in the transition fro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610216
Entities
People
- John Phillips
Organizations
- United States Army
- University of California, Los Angeles