Feasibility of CRISPR-Cas9-Based in Vitro Drug Target Identification for Personalized Prostate Cancer Medicine
Abstract
Scientific Objective and Rationale: The objective of the proposed study is to utilize our recently discovered ability to define lethal metastatic prostate cancer patients truncal mutations (mutations that are present in all metastases) to create a new testing method that could identify and prioritize drugs that might be effective for an individual man s prostate cancer. We propose to do this in part by leveraging a recently developed powerful new technology called CRISPRCas9 for inserting genetic changes into prostate cell lines cells in a laboratory dish. The cool thing is that using this technology, we should be able to create cell lines whose only differences are the presence or absence of a specific protein-coding mutation that we know is present in all of an individual man s metastatic prostate cancers. We will then expose these specially tailored cells under controlled conditions to a library of 142 already approved drugs and 319 investigational new cancer drugs using a special high-throughput drug testing system we have already set up to find out whether the particular mutation causes the cells to become sensitive to specific drugs. If we find such drugs, we will then use laboratory methods to test whether the drug effects we see make biological sense. If they make sense, we will propose moving forward to create a real clinical test based on this method and to test the ability of this drug identification method to be used in actual clinical practice. We need to test the feasibility of this idea first, and we will do this using data we already have from a test patient called A21, one of 33 volunteers in a group of men with metastatic prostate cancer who gave us permission to perform a research autopsy when he died. Principal Investigator s (PI s) Career Goals: The PI wishes to carry out meaningful prostate cancer research in a setting that allows combining basic research with clinical applicability. The proposed project allows her to pursue this aim and will prepare her to continue her scientific career as an independent investigator. How does the Training Plan support the PI in reaching career goals? The proposed training plan offers a chance to develop as a cancer scientist doing the actual research, but also as a project manager taking new responsibilities to ensure the overall completion of the project. How does the Research Plan support the PI in reaching career goals? The proposed research fits perfectly into PI s career goal of combining basic research with attainable patient benefit. The proposed work combines both basic and the newest methodologies in the laboratory with a starting point in actual prostate cancer patient data and with an end point in the potential clinical feasibility of our approach. Ultimate Applicability of the Research: If the proposed plan is successful, the approach to utilize individual metastatic prostate cancer patient s own truncal mutations in search for the most useful treatment options has significant potential to improve outcomes in men with metastatic prostate cancer. What types of patients will it help, and how will it help them? If feasibility is proven and the method is successfully taken through clinical development and clinical trials, it will improve outcome in men with metastatic prostate cancer by providing new, more effective drug therapy against metastatic disease. What are the potential clinical applications, benefits, and risks? The potential clinical application is a new in vitro tool that could be used to rationally prioritize drug treatment options. The potential benefit is to allow identification of possible drug treatments that would be otherwise hard to justify. A potential risk is that regardless of a drug showing responsiveness in our in vitro testing approach, the situation in the patient is always more complex, thus no response in patient can be guaranteed prior to actual testing. What is the projected time it may take t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610502
Entities
People
- Hanna Rauhala
Organizations
- United States Army
- University of Tampere