Detection of Prostate Cancer Progression by Serum DNA Integrity

PUBLIC ABSTRACT

Prostate cancer (PCa) is the most frequently diagnosed male cancer in the United States and is a significant cause of cancer-related death. As the baby boom generation enters the fifth and six decade of life, the incidence of PCa will increase and its management will place a major burden on the healthcare system. Although PCa is frequently diagnosed in men aged 50 to 70 years, many do not die of the disease. A primary objective is identifying those patients who are going to develop disease that will affect both their quality and quantity of life. Efficient and routine monitoring to diagnose PCa at the earliest possible stage, either initially or at the time of recurrence, will facilitate disease management and improve overall survival.

There is now considerable information demonstrating that the identification of specific DNA changes related to cancer progression can be used as informative biomarkers to make treatment and management decisions. In PCa, however, this area of research has lagged due the lack of DNA biomarkers in general and blood-based DNA markers in particular. Similarly, in PCa, there are few efficient blood-based biomarkers to monitor patients' response to treatment and to detect PCa recurrence. As we develop new treatment regimens, the identification of more efficient and informative noninvasive biomarkers is needed. As tumors progress, they release specific sizes of DNA repeat sequences and altered DNA into the bloodstream that can be used as signatures for the detection of PCa. The development of serum DNA biomarkers may be valuable both as a diagnostic and prognostic tool, as well as for disease surveillance. Traditionally, genetic markers were evaluated in tumor specimens that were accessible only via surgical procedures or invasive biopsies. We have now developed an innovative molecular genetic diagnostic assay for assessing a tumor's DNA signature using only a blood test. Our assay provides a novel approach to monitor DNA changes that occur during tumor growth without the need to obtain tumor specimens using invasive procedures. The assay is highly informative, and it may be more specific than conventional blood tests. It is cost-effective, rapidly performed (within 6 hours), and can accommodate a large number of samples. This is an exciting new, ultrasensitive approach for PCa diagnosis, prognosis, and surveillance that can improve the diagnostic and prognostic accuracy of current tests using only a few tablespoons of blood.

Multiple types of therapy are available to prostate cancer patients, and it may be difficult to determine the most effective and appropriate course of therapy for a given patient. Monitoring patients before, during, and after definitive treatment using only a small amount of blood will not only facilitate the development of an assay to diagnose PCa at the earliest possible stage, but will allow us to predict the effectiveness of therapy prior to and in the early stages of therapy. We have three aims in the proposal that focus on developing optimal assays for three serum DNA biomarkers. Our preliminary studies on PCa patients and normal male donors suggest these three biomarker assays have significant clinical utility. To further validate our assays, we will initially assess males with benign prostate disease and PCa of different clinical stages. After determining the sensitivity of the assays, we will further validate them by assessing PCa patients before, during, and after surgery and/or radiation therapy.

Our novel approach and unique serum biomarker assay will improve current diagnostic procedures and offer more information about tumor progression than serum PSA, the current gold standard. The approach we have taken is high risk but offers paradigm shifting, and if successful, will be a major advancement in monitoring PCa. This multidisciplinary study will involve the fields of surgery, pathology, molecular genetics, radiation oncology, medical oncology, and nursing. The overall aim is to develop a minimally invasive assay to facilitate the management of prostate cancer patients before, during, and after treatment by improving the clinician's ability to predict and detect disease recurrence and metastasis, as well as predict response to therapy. The study patients will be evaluated from three different clinic sites of two different demographic regions. If this assay proves to have clinical utility, its future impact on patient benefit is unlimited. If the validation of the assays is successful, we expect to reach the commercial stage within 4 years, with the ultimate goal of developing a circulating tumor-related DNA assay that is patient-operated, rapid, minimally invasive, and accurate, similar to a blood glucose meter used to monitor diabetes and guide therapy.