Clinical Qualification of DNA Repair Defects as Biomarkers in Metastatic Prostate Cancer Using Integrated Genomics and Tissue-Based Functional Assays
Abstract
Metastatic prostate cancer (mPC) is the advanced form of prostate cancer, once the disease has spread to other organs and is no longer curable. In recent years, several new drugs have been approved for treating mPC, but men keep dying every day from this disease. We believe that having tools to personalize the optimal sequence of treatments can improve patient outcomes and optimize the development of further new drugs. At present, we treat all mPC as if it is the same disease, without attention to differences in the tumor biology that may allow some patients to benefit more from a particular treatment. Several recent studies have identified important differences in tumor biology between mPC patients. One of the key examples of this is that about 20-25% of all mPC patients have defects in genes that repair the DNA of the cancer cells (DNA repair genes). What are we proposing? We are proposing to define the best treatment strategy for the 20-25% of mPC patients with defects in DNA repair genes. We believe these DNA repair gene defects make the cancers respond differently to currently available treatments. How will we do it? We will look for genetic defects in DNA repair genes in a cohort of 419 prostate cancer patients who have already donated their tumor samples and consented to have their response to treatment data annotated over the last few years. This will allow us to correlate the presence or absence of different gene mutations with a specific outcome for each therapy. Next, we plan to recruit a further cohort of patients over a period of 2 years who would consent to have biopsies of their metastatic disease acquired. We will look in more detail into DNA repair gene defects in these samples, as well as investigate how these changes impact how the tumor behaves. We aim to use this information to develop a simpler test that could be used in clinical practice to identify patients with these types of gene defects and aid treatment decision-making. Last, we will run a small clinical trial of a chemotherapy called carboplatin, commonly used in other cancer types, that is particularly effective in patients with DNA repair gene defects. The trial will provide further evidence of the clinical relevance of these gene defects and the tests we are developing, as well as permit a direct impact of this project in patient care. What types of patients will it help and how will it help them? First, patients with metastatic prostate cancer will benefit by receiving more precise medical care based on a better understanding of tumor biology in each individual case. Second, these data could also be relevant for patients with localized prostate cancer, as other studies have identified similar gene defects to be a factor associated with the risk of the disease returning after surgery or radiation. Early identification of patients who are likely to relapse could help in designing more intense treatment plans for them. Lastly, we previously identified that almost half of these genetic defects run in patients’ families (are inherited), and some defects may predispose other relatives to develop cancer. By integrating in our research expertise in genetic counseling through a board of experts, we hope to help identify families at high risk of developing cancer and refer them for proper close monitoring when applicable. What is the projected time it may take to achieve a patient-related outcome? This project will be completed within 3 years, as most of the tumor samples have already been collected. This research will have a direct and real-time impact on patient care by integrating a clinical trial for patients with DNA repair defects and offering them an alternative, tumor biology-driven treatment. Moreover, the clinical trial proposed includes interim “go/no-go” evaluations to minimize the time it takes to identify the population who will benefit most from specific treatments. If the DNA repair gene tes
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810758
Entities
People
- Joaquin Mateo
Organizations
- United States Army