Identification of Prometastatic Genes Involved in Bone Metastasis of Prostate Cancer
Abstract
Objective and Rationale: Metastases associated with advanced prostate cancer are responsible for the majority of patient morbidity and mortality. Compared with other epithelial cancers, prostate cancer has a predilection for bony metastases, which leads to bone pain, spinal cord compression, decreased mobility, and a rapid degradation of life quality. Although significant progress in the treatment of prostate cancer has been achieved by targeting the androgen receptor (AR) and the AR signaling axis, systematic management of metastatic prostate cancer is still a big challenge: the molecular mechanisms underlying tumor dissemination and metastases formation are not well understood, and both in vitro and in vivo mouse models of prostate cancer metastasis are lacking. My project seeks to identify pro-metastatic factors involved in prostate cancer bone metastasis, elucidate the molecular mechanisms underlying bone tropism in mouse models and to determine whether they can be applied to human prostate cancer treatment. We have observed that loss of Neogenin expression promotes aggressiveness of prostate cancer. We isolated neogenin-silenced LNCaP cells from bone metastatic sites and propose to use an in vivo gain-of-function cDNA screen to isolate relevant pro-metastatic genes from bone metastases derived neogenin-silenced LNCaP cells. We expect that the screen will help to identify genes that can be used as biomarkers and therapeutic targets for aggressive prostate cancer. Career Goals: I developed a strong interest in cancer research during my undergraduate training. During doctoral study, I focused on testicular germ cell tumorigenesis and identified Rnf2 as an oncogene that is required for germ cell tumor survival. As a postdoctoral fellow in the laboratory of Filippo Giancotti at Memorial Sloan Kettering Cancer Center (MSKCC), I now have a better understanding of the importance of basic and translational cancer research and its potential to impact patient care. The proposed research project involves investigating the role of Neogenin in prostate cancer progression in order to identify prometastatic genes that regulate bone metastases formation. This integrated training will enable me to undertake systematic approaches to understand the mechanisms of bone tropism of prostate cancer and identify biomarkers for aggressive disease. Additionally, my interactions with my co-mentor, Dr. Howard Scher, have given me perspective and clinical experience in order to foster innovative thinking, which is crucial for an independent researcher. My participation in the unique courses for trainees and conferences at MSKCC will also provide opportunities to build collaborative relationships with leading scientific experts in this field. My career goals are to seek an independent faculty position to further investigate prostate cancer metastases. Applicability: The goal of the proposed research is to understand the molecular mechanisms underlying bone metastases from prostate cancer through the discovery of metastatic mediators, which may be exploited to eliminate cancer cells ability to colonize the bone. The clinical benefits of this research would be to find novel bone metastatic regulators, which can be used as biomarkers or therapeutic targets for the diagnosis and treatment of advanced prostate cancer. For clinical application, the targets and the signaling pathways should be well characterized to avoid or minimize the potential side effects to the normal tissue. We anticipate that our screening system will lead to the rapid identification of factors that regulate bone metastatic reactivation. This study will be completed within 6 months. In the following months, identified pro-metastatic regulators will be validated and analyzed. Once a target is found, therapy will be developed through collaboration with MSKCC Molecular Pharmacology and Chemistry Department. If druggable targets are not immediately identified,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510275
Entities
People
- Wenjing Su
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army