Large Oncosomes: A Novel Liquid Biopsy for Genetic Profiling in Patients with Castration-Resistant Prostate Cancer
Abstract
Prostate cancer (PC) is one of the most frequent tumors in men and represents a significant health burden in the United States and other countries. Because of significant limitations in prognostic methods, many patients are routinely over-treated or under-treated. Unfortunately, over-treatment results not only in significant side effects, but also in the selection of tumor cells that are resistant to additional therapies. An important goal in the PC field is to understand how validated approaches can be used to help distinguish aggressive from indolent PC. The earlier in the disease process aggressive cancer can be recognized, the more likely it is that it can be effectively treated. One of the main complications in monitoring patients with PC is the difficulty in obtaining cancer tissue biopsies at the point where metastases are detectable. Many such patients harbor tumors that have become resistant to therapy. In these cases, molecular profiling of the evolving tumor(s) may allow estimation of the likely disease course and a determination of the most effective means of therapeutic intervention. Our proposal is focused on using state-of-the-art technology to sequence select amplicons of up to 20 men with aggressive PC from whom we have available plasma before and after bone metastasis, which is a strong clinical indication of rapidly progressing, lethal disease. With this strategy, we will attempt to derive biological information about the state of a cancer by a simple blood test that profiles the tumor-derived somatic alterations using tumor-tissue surrogates circulating in the blood, namely tumor cell-derived particles termed "large oncosomes" (LO) discovered by our group. We will explore the potential and the effectiveness of such tumor surrogates in the circulation at a resolution that has not been feasible before. After determining, in tissue and blood from an additional cohort of patients, if the number of LO correlates with tumor progression, we will determine whether somatic alterations that tumors acquire during their progression can be catalogued in the blood in the absence of biopsies of the tumor tissue itself, derived from a highly invasive and morbid procedure and in most cases not accessible. We will next develop assays that, if reproducible, can be used on blood samples from hundreds of men with prostate cancer in order to identify and prioritize somatic alterations that are more common and "druggable." This will ensure that if there are currently available therapies that could be applied to a subset of patients, we hope to identify them without the necessity of tumor tissue. The discoveries made in the next 2 years of this proposal might have short-term impact on the standardization of the so-called "liquid biopsy" and on the identification of genomic alterations that suggest the likelihood of responsiveness to targeted therapies. If our hypothesis is correct that such determinations can be made using technology we have already developed, the findings from this study would represent a major step forward in the goal of precision treatment for metastatic PC. In conclusion, our study will result in the development of the clinical tools to distinguish aggressive from indolent PC and to identify targetable mutations directly in the blood of individual patients, as a step toward the full realization of personalized medicine.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610397
Entities
People
- Dolores Di Vizio
Organizations
- Cedars-Sinai Medical Center
- United States Army