Prostate Cancer-Derived Bone Metastasis on a ChIP Platform to Model Immune Response
Abstract
More than 1,740,000 cancer cases are newly diagnosed, and 610,000 cancer deaths occur every year in the United States alone. Among various cancers, prostate cancer is one of the most common cancers and a major cause of death. About 1 in 9 men will be diagnosed with prostate cancer during their lifetime, and 1 in 41 men will die due to prostate cancer. While the recovery rate of prostate cancer has significantly increased due to the advance of recent biomedical technologies, the 5-year survival rate dramatically drops from 90% to 3% when metastasis follows, which mostly occurs in bone (>90%). This is because the genetic and phenotypic profile of cancer cells changes significantly after they are exposed to the unique bone tissue environment, where soft blood vessels are spread in hard tissue composed of high-density bone minerals. As such, this makes the initial treatment strategy for the primary prostate cancer ineffective. Unfortunately, a large portion of the pathological mechanisms of prostate cancer metastasis remains unknown and, as a consequence, prostate cancer bone metastasis is currently incurable. One of the major hurdles for studying pathobiology of prostate cancer bone metastasis is the absence of a standard model platform to simulate its metastasis process. In particular, animal models have a different physiological context from the human system and involve many complicated physiological interactions that make it difficult to analyze the impact of each pathophysiological parameter. Therefore, there is an urgent and important need for the development of an in vitro model platform that can rigorously recapitulate the metastatic bone niche and incorporate key cellular components such as tumor-associated macrophages. In particular, since macrophages compose about 40% of prostate cancer and are significantly involved in the metastatic process, the role of immune cells during prostate cancer bone metastasis should be determined to test innate immunotherapy. In this respect, we aim to design and engineer the first immune-integrated prostate cancer bone metastasis model platform and systematically validate its feasibility compared with an in vivo system to test novel immunotherapy agents. We hypothesize that the precise recapitulation metastatic vascularized bone niche with immune components will provide an accurate in vitro modeling platform that can be useful for predicting the efficacy of an immunotherapeutic. The proposed research will define the pathophysiological condition of metastatic bone matrix and the role of the immune system during prostate cancer bone metastasis. In addition, this project will generate a robust model platform that can be used to predict the effect of a novel immunotherapeutic. In the long term, the proposed prostate cancer bone metastasis platform can be utilized to test personalized medicine and select the best clinical strategy for terminally ill, time-limited patients by using their own stroma cells to recapitulate their individual metastatic niche. Furthermore, this platform can be extended to treat other lethal cancer types that present with bone metastasis, since bone is one of the most frequent sites where cancer metastasis occurs. Taken together, we envisage that this study will significantly improve the fundamental understanding of the pathobiology of prostate cancer bone metastasis and lead to a paradigm shift in the treatment of prostate cancer bone metastasis to reduce the mortality and pain of patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910404
Entities
People
- Hae Lin Jang
Organizations
- Brigham and Women's Hospital
- United States Army