Targeting the Hedgehog pathway to inhibit osteosarcoma growth through dual effects on tumor and microenvironment cells

While the 5-year survival rate for localized osteosarcoma (OS), the most common primary bone cancer, is approximately 70%, metastasis decreases this to under 30%, highlighting the need for novel and targeted treatments. We have developed a model of high penetrant, spontaneous occurring OS in Tax+Arf-/- mice that recapitulates many aspects of human disease. Compared to normal osteoblasts, Tax+Arf-/- OS cells have increased expression of Hedgehog (Hh) pathway genes and exhibit increased susceptibility to Hh inhibitors (SMO antagonists). Furthermore, the high rate of bone turnover in Arf-/- mice may support OS growth, mimicking the adolescent growth spurts during which OS is most prevalent.

This proposal will examine if therapies targeting the Hh signaling pathway, which plays critical roles in bone development and homeostasis and cancer progression, exert a clinical benefit in OS through dual actions on tumor cells and host microenvironment cells, including bone-resorbing osteoclasts (OC). Using in vitro and in vivo models, we will investigate if a self-renewing OS-initiating population exhibits an increased sensitivity to SMO antagonists, possibly through modulation of Bmi1. We will also test if the effects of Hh inhibitors on host microenvironment cells including OC and stromal cells can uncouple the ‘vicious cycle’ and reduce host production of OS-supporting growth factors. Such mechanisms of action may prove especially effective in preventing metastasis and local reoccurrence following surgical resection of OS.

We hypothesize that Hh pathway inhibitors will decrease OS growth and metastasis through direct actions on both tumor cells and host microenvironment cells.

Aim 1: Characterize self-renewal, lineage commitment and susceptibility to SMO antagonism of OS-initiating cells in Tax+Arf-/- mice.
Aim 2: Determine the efficacy of SMO antagonists in preventing in vivo OS growth and metastasis.
Aim 3: Investigate if modulating bone turnover with Hh inhibitors decreases OS grow.