Vanderbilt Summer Science Academy

Investigating the Mechanisms of Gli2 Regulation of Parathyroid Hormone Related Protein Expression and Bone Destruction in Tumor-Induced Bone Disease

Breast, lung, and prostate cancers commonly metastasize to bone and cause osteolytic lesion development (1). These diagnoses are difficult to treat and have a high morbidity associated with them (1). This challenge is partially due to the cyclic nature of the biological pathway known as the “vicious cycle” which leads to tumor-induced bone disease (1). Factors in the bone microenvironment stimulate production of Parathyroid Hormone-Related Protein (PTHrP) through the Hedgehog (Hh) transcription factor, Gli2, within tumor cells. This induces differentiation and activation of the bone resorbing cells (osteoclasts) while stimulating tumor growth, perpetuating the cycle (2,3). While some cancer lines contain Hh receptors that stimulate Gli2, some Gli-activated tumors do not, and Hh receptor antagonists failed clinical trials. Therefore, we hypothesized that directly targeting Gli2 would be a promising strategy for reducing bone destruction.  However, to develop inhibitors to Gli2, we first need to better understand how Gli2 stimulates PTHrP expression and bone destruction. To do this, we will perform chromatin immunoprecipitation (ChIP), polymerase chain reaction (PCR), and promoter-luciferase assays to map where in the PTHrP promoter responds to Gli2 activation.  In addition, we will determine if a pharmacological antagonist, GANT58, blocks Gli2 translocation into the nucleus. Targeting transcription factors within the nucleus has proven challenging, but the GANT58’s projected ability to target Gli2 in the cytoplasm would be ground-breaking. These investigations will provide a better understanding of the mechanism behind Gli2 activation of PTHrP, and foster the development of more effective treatments for bone metastatic lesions and tumor burden.