Multiplex Functional Interrogation of Oncogenic Networks in Bladder Cancer
Abstract
Cancer is a disease caused by derangement of genes encoded in the DNA of cells. In recent years, sequencing technologies have become cheap enough that scientists have been able to peer into the DNA of thousands of tumors and catalog gene abnormalities in multiple cancer types. In bladder cancer, these data have identified recurrent defects in genes associated with important processes like cell growth, cell survival, and maintenance of DNA integrity. The sets of gene abnormalities found in bladder cancer are different from tumor to tumor, indicating that each bladder cancer is unique. In fact, there are multiple possible paths to convert a normal bladder cell to cancer. The uniqueness or heterogeneity of bladder cancer is a major reason why not all bladder cancers behave similarly or respond to therapies. The goal of this project is to understand how different combinations of gene abnormalities work together to promote bladder cancer. From these studies, we hope to obtain a better understanding of vulnerabilities caused by these genetic alterations that may provide an opportunity to develop more effective treatment strategies in bladder cancer. Dr. Lee is a physician-scientist who seeks to be an investigator that has an enduring and impactful career in cancer research. This award will allow him to establish an innovative cancer research program focused on untangling the diverse network of genetic events in bladder cancer. Dr. Lee intends to use state-of-the-art technologies to rapidly produce new mouse models of bladder cancer and to understand how specific genes and gene abnormalities impact the disease. He has outlined a plan to achieve these goals by (1) adapting expertise in three-dimensional organoid culture and lentiviral engineering and (2) acquiring new skills related to the manipulation of mouse bladder urothelial cells and the use of single cell DNA sequencing. Dr. Lee has also established strategic collaborations with investigators that have diverse scientific strengths to facilitate the successful completion of the project. In addition, he will have the guidance of Drs. Eric Holland and Peter Black, both distinguished physicians and cancer researchers, who will provide scientific and career mentorship. Dr. Lee will leverage his excellent background in cancer biology, a highly promising and impactful project, a well-conceived plan to attain new skills and knowledge, and crucial interactions with both collaborators and mentors to achieve his goal of advancing to the forefront of bladder cancer research. The proposed research is aimed at improving our basic scientific understanding of bladder cancer. Therefore, the results of these studies may not have immediate clinical applicability. However, the interim outcomes that define success would be the generation and characterization of novel, genetically defined bladder cancer mouse models. From these models, gene abnormalities that are cooperative or exclusive in promoting bladder cancer will be determined. The bladder cancer models and knowledge of relationships between genetic alterations in bladder cancer will prioritize studies directed at evaluating the effectiveness of blocking the activity of specific gene products or their signaling pathways. The projected time to a relevant outcome where a clinical trial may be initiated would be approximately 5 to 8 years. The major contribution of this study to advancing the field of cancer research will be to establish a rapid approach to simultaneously evaluate the function of multiple genes and gene abnormalities in cancer initiation. If successful, this system may advance the pace of discovery in the field of functional cancer genomics with potential for broad application to other cancer types beyond bladder cancer. Bladder cancer is the fourth most common cancer among Veterans in the United States. Veterans are especially at risk for bladder cancer based on risk factors including male sex, advancing age, tobacco u
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910569
Entities
People
- John K Lee
Organizations
- Fred Hutchinson Cancer Center
- United States Army