Risk-stratification of Prostate Cancers via Field Carcinogenesis Nanocytology

Project: Research project

Project Details

Description

Main Objective of the Project. Prostate cancer (PC) is the second leading cause of cancer deaths in American men. While the PSA blood test has been used widely, >60% of all PSA screen-detected cancers are slow-growing and would never impact upon longevity. Recent high-profile studies have concluded that PSA screening leads to little or no survival benefit. A most urgent clinical imperative is to improve the identification of the risk of clinically significant PC. An alternative to treatment that has gained increasing acceptance for men with low risk PC is active surveillance (AS) in which men undergo surveillance biopsies every 1-3 years. This approach, while associated with fewer side effects than surgery and radiation, still engenders considerable anxiety, discomfort, expense, and complications associated with multiple biopsies. Thus, what is critically needed is a new methodology that would prospectively distinguish indolent from aggressive PC.
An ideal test for PC would be (i) clinically practical and coupled with existing clinical flow while (ii) being sensitive to any of the multiple molecular pathways of PC and (iii) PC clone independent (multiple different clones are both the hallmark of PC and the determinant of the Gleason score). Biomarkers attempting to detect neoplastic cells or their byproducts, sourced from the serum, secretions, tumor biopsies, or whole body imaging, invariably suffer from the lower sensitivity to small cancers regardless of their aggressiveness. Tumor profiling suffers from biopsy sampling error and polyclonality. Purely molecular (e.g., genetic, proteomics) biomarkers are pathway-specific. Thus, a principally new approach is needed. In search of this optimal diagnostic strategy, we sought to optimize both the biomarker source and the biomarker type.
Biomarker source. We propose to take advantage of field carcinogenesis (FC), which has been shown to reflect the risk for both synchronous and metachronous lesions for a variety of cancers. The genetic/environmental milieu that results in carcinogenesis diffusely impacts upon the entire organ site leading to FC. Focal tumors arise on the background of this field of injury due to further stochastic mutations. Hence, not only tumor cells but a much larger population of cells throughout the affected organ bear the fingerprint of risk. Despite being histologically normal, FC mucosa has molecular and ultrastructural alterations. Although existing biomarkers of prostate FC support the biological phenomenon, the lack of a sensitive and practical biomarker of PC FC has stymied clinical implementation. FC has an advantage over tumor profiling because this reduces the sampling error of biopsy and is clone-independent.
Biomarker type: Alterations in cell nano-morphology are the common denominator for the molecularly heterogeneous carcinogenesis process. We have developed partial wave spectroscopic microscopy (PWS or nanocytology) to sense alterations in intracellular structure (e.g. abnormal chromatin structure) at the nanoscale beyond the resolution of histopathology. Our PWS data in over 800 patients and seven different malignancies showed that PWS-detectable nanoarchitectural alterations in histologically normal cells are a highly accurate biomarker of FC and cancer risk. In a study of PC patients with Gleason 6 disease undergoing AS (n=38), we found that nanocytology of histologically normal prostate epithelium was able to predict subsequent progressors versus non-progressors with 80% sensitivity and 88% specificity.
Clinical Impact. We propose to build upon
StatusActive
Effective start/end date8/14/157/30/21

Funding

  • National Cancer Institute (5R01CA200064-05)

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