Anti-Human VHL (a.a. 70-213) Polyclonal antibody

Background: Challenges still exist in differentiating pancreatic adenocarcinoma from benign disease. The use of adjuvant testing of tissue biopsies has demonstrated potential diagnostic value. We designed a proof of concept study to first validate four individual immunohistochemistry biomarkers and then combine them into a panel to boost overall diagnostic sensitivity. Methods: Malignant and benign pancreas from 27 pancreaticoduodenectomy specimens underwent immunohistochemistry staining with VHL, IMP3, S100A4, S100P. Using ROC curve analysis, threshold criteria for number of cells staining were chosen for each biomarker. Biomarkers were then evaluated as a panel for their ability to discriminate malignant from benign specimens. Results: Diagnostic sensitivity of VHL, IMP3, S100A4, and S100P were 75.0%, 79.2%, 45.8%, and 0%. When VHL, IMP3, and S100A4 were grouped into a panel, they were able to distinguish cancer from normal tissue with a sensitivity of 100% and a specificity of 96%. Conclusions: The high diagnostic value of an IHC panel consisting of VHL, IMP3, and S100A4 on surgical specimens suggests the need for future prospective studies of these biomarkers on biopsy specimens. (C) 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Background: Blockade of mitotic progression is an ideal approach to induce mitotic catastrophe that suppresses cancer cell expansion. Cdc20 is a critical mitotic factor governing anaphase initiation and the exit from mitosis through recruiting substrates to APC/C for degradation. Results from recent TCGA (The Cancer Genome Atlas) and pathological studies have demonstrated a pivotal oncogenic role for Cdc20-APC/C in tumor progression as well as drug resistance. Thus, deprivation of the mitotic role for Cdc20-APC/C by either inhibition of Cdc20-APC/C activity or elimination of Cdc20 protein via induced protein degradation emerges as an effective therapeutic strategy to control cancer. Methods: We designed a proteolysis targeting chimera, called CP5V, which comprises a Cdc20 ligand and VHL binding moiety bridged by a PEG5 linker that induces Cdc20 degradation. We characterized the effect of CP5V in destroying Cdc20, arresting mitosis, and inhibiting tumor progression by measuring protein degradation, 3D structure dynamics, cell cycle control, tumor cell killing and tumor inhibition using human breast cancer xenograft mouse model. Findings: Results from our study demonstrate that CP5V can specifically degrade Cdc20 by linking Cdc20 to the VHL/VBC complex for ubiquitination followed by proteasomal degradation. Induced degradation of Cdc20 by CP5V leads to significant inhibition of breast cancer cell proliferation and resensitization of Taxol-resistant cell lines. Results based on a human breast cancer xenograft mouse model show a significant role for CP5V in suppressing breast tumor progression. Interpretation: CP5V-mediated degradation of Cdc20 could be an effective therapeutic strategy for antimitotic therapy. (c) 2019 The Author(s). Published by Elsevier B.V.