Prostate cancer is the most frequently diagnosed male visceral cancer and the second leading cause of cancer death in the United States. Standard tests such as prostate-specific antigen (PSA) measurement have poor specificity (33%) resulting in a high number of false positive reports. Consequently there is a need for new biomarkers to address this problem. The MIL-38 antibody was first described nearly thirty years ago, however, until now, the identification of the target antigen remained elusive. By a series of molecular techniques and mass spectrometry, the MIL-38 antigen was identified to be the highly glycosylated proteoglycan Glypican-1 (GPC-1). This protein is present in two forms; a membrane bound core protein of 55-60 kDa and secreted soluble forms of 40 kDa and 52 kDa. GPC-1 identification was confirmed by immuno-precipitation, western blots and ELISA. An ELISA platform is currently being developed to assess the levels of GPC-1 in normal, benign prostatic hyperplasia (BPH) and prostate cancer patients to determine whether secreted GPC-1 may represent a clinically relevant biomarker for prostate cancer diagnosis.

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Prostate cancer is responsible for hundreds of thousands of annual deaths worldwide. The current gold standard in early detection of prostate cancer, the prostate specific antigen test, boasts a high sensitivity but low specificity, resulting in many unnecessary prostate biopsies. Thus, emphasis has been placed on identifying new biomarkers to improve prostate cancer detection. Glypican-1 has recently been proposed as one such biomarker, however further exploration into its predictive power has been hindered by a lack of available, dependable glypican-1 immunoassays. Previously, we identified human glypican-1 as the antigenic target of the MIL-38 monoclonal antibody. Additionally, we have now generated another monoclonal antibody, 3G5, that also recognizes human glypican-1. Here we report the development of a reliable, custom Luminex® assay that enables precise quantitation of circulating human glypican-1 in plasma and serum. Using this assay, we show for the first time that circulating glypican-1 levels can differentiate non-cancer (normal and benign prostatic hyperplasia) patients from prostate cancer patients, as well as benign prostatic hyperplasia patients alone from prostate cancer patients. Our findings strongly promote future investigation into the use of glypican-1 for early detection of prostate cancer.

indeterminate PSA results who would be candidates for initial biopsy. The assay should result in a 27% reduction of prostate needle biopsies while missing only 5% of higher grade >/¼ 4+3 cancers.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and new therapeutic strategies are urgently required. A key drug delivery barrier and promoter of tumor progression is the fibrotic and heterogeneous microenvironment of PDAC which is mainly orchestrated by stromal cancer-associated fibroblasts (CAFs). Thus, any novel therapeutic strategy should not only target PDAC cells but should also aim to inhibit the pro-tumor properties of the PDAC stroma. However, to accurately evaluate the clinical potential of novel PDAC therapeutics, preclinical models are required that closely mimic the heterogeneity and multicellular architecture of human disease. Aim: We aimed to investigate the therapeutic potential of novel functionalized benzopyrans (CRO-05 & CRO-67) in a patient-derived PDAC tumor explant model. Methods: We collected PDAC tumor samples from patients undergoing resection of their primary tumor. We cultured whole tumor explants (1-2mm diameter) on gelatin sponges. This model accurately maintains the multicellular tumor and stromal architecture of human PDAC [Kokkinos et al, Scientific Reports, 11,1941 (2021)]. Tumor explants were treated every 3 days with the racemic compound CRO-05 or its active enantiomer CRO-67 and explants were fixed in paraformaldehyde at day-12. Therapeutic response was assessed by immunohistochemistry for markers of tumor cells (cytokeratin), CAFs (α-Smooth Muscle Actin), cell-proliferation (Bromodeoxyuridine), and cell-death (TUNEL). Results: Treatment of human PDAC explants with CRO-05 resulted in reduced tumor cell frequency in 3/4 patients and in 4/4 patients, reduced CAF frequency, decreased cell-proliferation, and increased cell-death relative to controls. CRO-67 treatment in explants from 4/5 patients led to reduced tumor cell frequency, and in 5/5 patients, reduced CAF frequency, decreased cell-proliferation, and increased cell-death relative to controls. Conclusions: This work identifies the functionalized benzopyrans CRO-05 and CRO-67 as novel dual-cell therapeutics that potently inhibit both PDAC tumor cells and their surrounding CAFs and provides support for their clinical development as novel PDAC therapeutics. Citation Format: John Kokkinos, George Sharbeen, Koroush S. Haghighi, Janet Youkhana, Aparna Raina, Omali Pitiyarachchi, Quach Truong, Daniel Wenholz, Olivier Laczka, Naresh Kumar, David Goldstein, Phoebe A. Phillips. CRO-67 is a novel therapeutic for pancreatic cancer: Implications for tumor and stromal reprogramming [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C073.