Serum PSA was related to prostate cancer 20 years ago. In the last 5 years serum PSA has only been related to benign prostatic hyperplasia. There is an urgent need for serum markers that reflect the size and grade of this ubiquitous cancer.

Accurate identification of prostate cancer in frozen sections at the time of surgery can be challenging, limiting the surgeon's ability to best determine resection margins during prostatectomy. We performed desorption electrospray ionization mass spectrometry imaging (DESI-MSI) on 54 banked human cancerous and normal prostate tissue specimens to investigate the spatial distribution of a wide variety of small metabolites, carbohydrates, and lipids. In contrast to several previous studies, our method included Krebs cycle intermediates (m/z <200), which we found to be highly informative in distinguishing cancer from benign tissue. Malignant prostate cells showed marked metabolic derangements compared with their benign counterparts. Using the "Least absolute shrinkage and selection operator" (Lasso), we analyzed all metabolites from the DESI-MS data and identified parsimonious sets of metabolic profiles for distinguishing between cancer and normal tissue. In an independent set of samples, we could use these models to classify prostate cancer from benign specimens with nearly 90% accuracy per patient. Based on previous work in prostate cancer showing that glucose levels are high while citrate is low, we found that measurement of the glucose/citrate ion signal ratio accurately predicted cancer when this ratio exceeds 1.0 and normal prostate when the ratio is less than 0.5. After brief tissue preparation, the glucose/citrate ratio can be recorded on a tissue sample in 1 min or less, which is in sharp contrast to the 20 min or more required by histopathological examination of frozen tissue specimens.prostate cancer | Krebs cycle | metabolism | desorption electrospray ionization | mass spectrometry P rostate cancer (PCa) is the most commonly diagnosed solidorgan cancer and the second leading cause of cancer death in men in the United States (1). Because of prostate-specific antigen (PSA) screening in the United States, most PCas are discovered when they are confined to the prostate (2). Many of these localized PCas are treated by surgical removal of the entire prostate (radical prostatectomy). The presence of cancer cells at the edge of the surgical resection, or positive surgical margins, is associated with higher rates of recurrence and death from PCa (3, 4). Therefore, an important clinical challenge in PCa management is to devise a rapid and highly accurate method to detect cancerous cells in real time to allow resection of additional periprostatic tissues and reduce cancer recurrence after surgery. Over the last decade, several innovative analytical techniques (5-12) have been developed to distinguish cancer from benign tissue in various organs. However, none has achieved wide clinical adoption for various reasons including inconvenience, narrow information content, unavailability, poor sensitivity, slowness of adoption, and operating room workflow incompatibility. In PCa, intraoperative frozen sections have been used to attempt to identify PCa at the margin based on analysis of histology. However, frozen sections h...

Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.

Prostate cancer (CaP) subtypes are poorly defined and functional validation of drivers of ETS rearrangement-negative CaP has not been conducted. Here, we identified an ETS− subtype of aggressive CaP (ERG−MAP3K7delCHD1del) and used a novel developmental model and a cell line xenograft model to show that co-suppression of MAP3K7 and CHD1 expression promotes aggressive disease. Analyses of publicly available CaP datasets revealed that MAP3K7 and CHD1 were significantly co-deleted in 10–20% of localized tumors and combined loss correlated with poor disease-free survival. To evaluate the functional impact of dual MAP3K7-CHD1 loss, we suppressed Map3k7 and/or Chd1 expression in mouse prostate epithelial progenitor/stem cells (PrP/SCs) and performed tissue recombination experiments in vivo. Dual shMap3k7-shChd1 PrP/SC recombinants displayed massive glandular atypia with regions of prostatic intraepithelial neoplasia (PIN) and carcinoma apparent. Combined Map3k7-Chd1 suppression greatly disrupted normal prostatic lineage differentiation; dual recombinants displayed significant AR loss, increased neuroendocrine differentiation, and increased neural differentiation. Clinical samples with dual MAP3K7-CHD1 loss also displayed neuroendocrine and neural characteristics. Additionally, dual Map3k7-Chd1 suppression promoted E-cadherin loss and mucin production in recombinants. MAP3K7 and CHD1 protein loss also correlated with Gleason grade and E-cadherin loss in clinical samples. To further validate the phenotype observed in the PrP/SC model, we suppressed MAP3K7 and/or CHD1 expression in LNCaP prostate cancer cells. Dual shMAP3K7-shCHD1 LNCaP xenografts displayed increased tumor growth and decreased survival compared to shControl, shMAP3K7, and shCHD1 xenografts. Collectively, these data identify coordinate loss of MAP3K7 and CHD1 as a unique driver of aggressive CaP development.

Secondary cancers in multifocal prostate tumors did not adversely influence the results of preoperative clinical parameters, including PSA and needle biopsy findings. Percent Gleason grade 4/5 cancer in needle biopsies and prostatectomy specimens is the most powerful predictor of biochemical failure in men with stage T1c prostate cancer after radical prostatectomy.