Each year in the United States, more than a million men with an elevated serum PSA (prostate specific antigen) or abnormal digital rectal exam undergo a prostate biopsy, and nearly 200,000 are found to have prostate cancer (CaP). Decisions to treat CaP are heavily influenced by the Gleason score (GS) of the tumor in the needle biopsy specimen. GS is a measure of tumor differentiation based on the two most prevalent patterns of tumor growth. Higher GS tumors are generally more aggressive. Patients whose entire tumor is composed of GS6 rarely progress, and recently, more men diagnosed with GS6 tumors on needle biopsy are selecting active surveillance rather than surgery. In contrast, men with more poorly differentiated tumors (GS7 and higher) have a significantly increased risk of progression, and require treatment. Choosing the best treatment options for patients with biopsy GS6 is complicated by the fact that a biopsy procedure only samples a very small part of the prostate, and in about 30% of men, it underestimates the GS. In those cases, men with GS7 and higher (GS7+) CaP are assumed to have GS6 tumors potentially leading to inappropriate treatment. In addition, because of the limited sampling and 30% false negative rate for detecting cancer, many men with a negative biopsy result may have clinically significant CaP. Because of that, many of the 800,000 patients with a negative biopsy undergo repeat biopsies, which can be frustrating for both patients and urologists.When a pathologist examines a prostate needle biopsy specimen, the focus is on the identification of CaP, and appropriate GS, and little attention is paid to the morphologically 'normal' areas. This is despite a considerable body of evidence suggesting that molecular alterations associated with tumor in the adjacent non-neoplastic cells, the so-called 'tumor field effect' (FE), can provide valuable clues regarding the status of the tumor. The prostatic FE was first suggested more than 10 years ago and since then numerous reports have documented molecular alterations in morphologically benign prostate consistent with CaP FE in both prostatectomy and prostate needle biopsy specimens. Remarkably, the FE alterations associated with aggressive prostate tumors have also been reported, supporting our preliminary analysis by microarrays strongly suggesting a FE molecular signature associated with high-grade tumors.This proposal will concentrate on the transcriptome and epigenetic FE alterations associated with CaP. Our hypothesis is that tumor-associated molecular changes in the non-neoplastic prostatic tissue and acini involved by high-grade prostatic intraepithelial neoplasias (HGPIN) can be used to predict the presence of GS7+ tumors in the prostate of men with GS6 biopsies or in men with negative biopsies. Our objective is to develop clinically relevant molecular models to predict GS7+ CaP based on the CaP FE so that men with GS6 CaP on needle biopsy are treated appropriately and that men with negative biopsy specimens receive the appropriate follow-up. These models will be useful in biopsies that have no or limited tumor and can complement other studies that assess tumor directly to predict significant CaP. There will be two aims:Aim I: To identify and validate prostate cancer FE markers associated with GS7 and higher tumors. Aim II: To develop and test molecular models for predicting upgrading in GS6 biopsies (UPGR model) and for predicting GS7 and higher cancer in a repeat biopsy (REBXGS7 model).Aim I will take advantage of our preliminary microarray data, next-generation sequencing (NGS) experiments, and subsequent validation experiments on biopsies to select markers associated with GS7+ tumors. Aim II will use a cohort and a case/control design to develop logistic regression UPGR and REBXGS7 models, respectively. This research is innovative as it can create a paradigm shift in how clinical samples are examined for the diagnosis of clinically significant CaP. Current molecular evaluations rely exclusively on tumor cells, which in challenging biopsy cases are often limited. By elucidating consistent molecular alterations associated with GS7+ in non-tumor areas, this research opens new possibilities for accurate diagnosis of significant prostate tumors. The impact of this research is considerable as it addresses a major concern for the great majority of men who undergo a prostate needle biopsy each year, namely, whether they have a tumor that requires treatment. It will also lead to a better understanding of the early events leading to CaP initiation, and the interactions of benign prostatic tissues and CaP. The transcriptomic and epigenomic NGS data that will be made available publically can be used as the baseline for comparisons in CaP studies or other diseases of prostate. The proposed research directly addresses the Prostate Cancer Research Program overarching challenge area of 'Distinguish lethal from indolent disease.' It is also responsive to the 'Biomarkers' focus area.
|Effective start/end date||9/30/11 → 10/29/15|
- Congressionally Directed Medical Research Programs: $709,650.00