Betulin sulfamate conjugates to overcome the hypoxic radioresistance of breast cancer in vitro and in vivo

• Applicants: Dr. Matthias Bache, Ph.D.; Professor Dr. Ivo Große; Dr. Thomas Müller; Professor Dr. Reinhard Paschke, Ph.D.; Privatdozentin Dr. Iris Thondorf; Professor Dr. Dirk Vordermark
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 410899006

Breast cancer is the most common cause of death of women despite multimodal therapy concepts. The microenvironment of these solid tumors is often characterized by acidification (acidosis) and oxygen deficiency (hypoxia). Both factors are essential indicators of poor prognosis and therapy failure. Carbonic anhydrase IX (CA IX) is a key enzyme of hypoxic and acidotic tumors. CA IX is often overexpressed in breast cancer and is responsible for extracellular acidification, maintenance of physiological intracellular pH, migration and invasiveness of tumor cells. In order to improve the treatment success of conventional tumor therapy, there are first therapeutic approaches to reduce the activity of CA IX. Winum et al. (2005) identified betulin-3,28-disulfamate as an effective inhibitor of CA IX. Betulinic acid, a natural substance of the plane tree bark with high cytotoxicity for tumor cells, is itself a promising anticancer drug. Current studies of the applicants demonstrate that betulin sulfamate conjugates such as betulin-3,28-disulfamate effectively inhibits CA IX, causes high cytotoxicity, induces apoptosis, and inhibits migration in human breast cancer cells. A combined treatment of betulin sulfamate conjugates with radiation increases the response. Further studies are necessary to evaluate the role of betulin sulfamate conjugates for tumor therapy. In this project it is planned to design new structurally-optimized betulin sulfamate conjugates using computer-assisted modeling. In addition, the cellular, molecular or radiobiological effects of the betulin sulfamate conjugates should be evaluated in vitro and in human orthotopic xenografts of human breast carcinomas. In order to identify and examine new genes or metabolic pathways for tumor therapy, it is planned to investigate the molecular mechanisms using cDNA microarray and metabolomic analysis followed by subsequent gene targeting. Structurally-optimized betulin sulfamate conjugates may represent a novel approach for tumor therapy. Specifically, the sulfamate component inhibits the function of tumor-associated and hypoxia-induced CA IX and the betulin component can be released by cleavage of the carrier molecule and additionally act as an anti-cancer drug. The high CA IX levels of hypoxic tumors are useful for drug targeting. The aim of the investigations is the evaluation of new bifunctional betulin sulfamate conjugates to overcome the hypoxic radiation resistance of breast cancer.

• DFG Programme: Research Grants