Targeting Gli-Mediated Transcription in Bone Metastasis: An Emerging Therapeutic Approach for Patients with Tumor-Induced Bone Disease

Abstract

Bone is a common site of metastasis for advanced breast, prostate, and lung cancer. Most patients with skeletal metastases develop tumor-induced bone disease (TIBD), which is characterized by a vicious cycle of tumor growth and osteoclast-mediated bone destruction. Existing therapies such as bisphosphonates and denosumab prevent bone loss and reduce risk of fracture, but they are not curative. Moreover, these agents are contraindicated for certain patients including those with oral squamous cell carcinoma (OSCC), which frequently invades the lower jaw. Thus, novel therapies are urgently needed to improve patient outcomes. Our previous studies show that the transcription factor Gli2 induced expression of parathyroid hormone-related protein (PTHrP) in metastatic tumor cells to promote osteolytic bone destruction. Here, we demonstrate that the Gli-antagonist GANT58 reduced PTHrP expression in vitro, but had limited efficacy against bone-residing tumors due to its hydrophobicity. Therefore, we encapsulated GANT58 in polymeric micro- (MPs) and nanoparticles (NPs) to improve its bioavailability in vivo. Systemic treatment with GANT58-NPs significantly reduced tumor-induced osteolysis in preclinical models of breast and lung cancer. Likewise, local delivery of GANT58-MPs inhibited mandibular invasion in a semi-orthotopic model of OSCC. Surprisingly, we also discovered that GANT58-MPs reduced bone invasion by tumors that had acquired resistance to erlotinib, a tyrosine kinase inhibitor that is currently in clinical trials for the treatment of recurrent and/or metastatic OSCC. Taken together, these findings suggest that targeting Gli-mediated transcription may be a promising therapeutic strategy for patients with TIBD.