Therapeutically Targeting the Hippo Pathway in Osteosarcoma
Osteosarcoma is a malignant bone cancer that predominantly affects young adults and children. Current treatments include pre-operative chemotherapy, followed by surgical removal of the tumor or amputation, and post-operative chemotherapy. However, despite several decades of study, a significant fraction of patients are refractory to these treatments and overall survival rates remain at only ~60%. Clearly, new therapeutic strategies to combat osteosarcoma need to be defined. One characteristic of osteosarcoma tumor cells that distinguishes them from normal cells is that they frequently harbor twice the normal number of chromosomes and are considered near tetraploid. Tetraploidy is known to facilitate tumor initiation, progression, and relapse. Consequently, tetraploidy confers poor clinical prognosis. Countering this oncogenic effect is a tumor suppressive pathway that restrains the proliferation of tetraploid cells by promoting a durable G1 cell cycle arrest and cellular senescence. We recently demonstrated that signaling from the Hippo tumor suppressor pathway represents this underlying mechanism. Notably, analysis of a broad spectrum of human cancers reveals that high-ploidy tumors, including osteosarcoma, frequently adapt to overcome Hippo signaling, suggesting that functional inactivation or bypass of this pathway may be a prerequisite for the development and/or progression of such tumors. This has an exciting clinical implication: that reactivation of Hippo signaling may be specifically lethal to near-tetraploid cancer cells while having limited effects on normal diploid cells (ploidy-specific lethality). However, mutations in known components of the Hippo pathway are rare, and thus the underlying mechanisms that disable Hippo signaling in near-tetraploid cancer cells remain elusive. Consequently, therapeutic approaches to reactivate this tumor suppressive pathway have been slow to develop. The aims in this proposal are therefore designed to 1) identify common genetic adaptations that enable bypass of Hippo pathway signaling, and 2) to determine the effect of Hippo pathway reactivation on cell viability in near-tetraploid cancer cells. This work has the potential to reveal new therapeutic avenues that selectively kill near-tetraploid osteosarcoma cancer cells while sparing the normal diploid cells from which they originated.