Abstract

Dr Yong Li, Senior Cancer Institute NSW Research Fellow, Head of Cancer Research Program, Cancer Care Centre, St George Hospital, Conjoint Senior Lecturer, Faculty of Medicine, The University of New South Wales, Australia.

Metastatic disease is a major problem for prostate cancer (CaP) therapy. Multi-targeted therapy may increase the likelihood of complete targeting of micro-metastatic disease. The objective in this project was to investigate targeting micrometastatic CaP using Bi-213-labeled multiple alpha-radioimmunoconjugates. In the present study, we established tissue microarrays (TMAs), labelled ²¹³sup>Bi with two monoclonal antibodies (MAbs), an inhibitor, plasminogen activator inhibitor type 2 (PAI2) to form alpha conjugates (ACs) and established CaP spheroid models to mimic micrometastatic cancer in vitro and NOD-SCID metatstatic CaP animal models in vivo including subcutaneous (s.c), intra-prostate and intra-tibial models by PC-3 cell line. We tested multiple ACs (test and control) in our in vitro and in vivo models using different activities. Multiple targeted alpha therapy (MTAT) with a cocktail of test ACs regressed cancer spheroid growth in a dose-dependent and size-dependent manner, and could effectively target small CaP spheroids (<100 μm in size). Furthermore, a single intraperitoneal (ip) injection of MTAT (test) at high and low doses causes regression of the growth of primary tumors and prevents local lymph node metastases in a concentration-dependent fashion, causing cancer cells to undergo necrosis and apoptosis. Prostate cancer-associated antigens recognised by multiple MAbs are potential targets for alpha therapy. MTAT produced cytotoxicity specific to CaP spheroid models in vitro and animal models in vivo. MTAT may be a potent therapeutic agent against metastatic prostate cancer cells exhibiting intermediate to high target antigen expression, overcoming the heterogeneity of expression of targeted antigens.

Host: Prof. Wanjin Hong