continued from Project_Archive/Osteosarcoma/
Osteosarcoma is a pediatric bone cancer that affects ~1000 people in the U.S. every year. That’s not very many people (when it comes to cancers, at least), which means there hasn’t been a whole lot of incentive to find better treatments for osteosarcoma. Patient outcomes in osteosarcoma have levelled off since the early 1990s when dosing regimen and surgical strategies became standardized. For many other cancers, advanced drug combinations and prognostic markers have been identified, but not in osteosarcoma.
Osteosarcoma is really interesting though, because it’s a cancer that looks a lot like a developmental bone disease, and it’s a cancer that is not known to be driven by mutations. Instead, it appears to be propagated by abnormal bone growth. Osteosarcoma has been characterized to be heavily dependent on a developmental signaling pathway called “Wnt” (Wingless and integrin-related) signaling. Wnt signaling is known to have its hands on the controls of stem cell space states, osteoblast differentiation, limb segmentation, and a whole entourage of other cellular processes. The last several years of research into Wnt signaling have resulted in some experimental new compounds being developed as possible therapies for cancers which are dependent on Wnt signaling.
Our main goal was to use new, Wnt-inhibiting drugs as means to sensitize osteosarcoma to other chemotherapies which are currently being used in the clinic. Wnt drives the expression of a group of proteins that control intra-cellular drug concentrations, thus Wnt inhibitors could theoretically be used to control drug accumulation in the cell. To test the efficacy of these molecules more realistically, we developed a cell-based model of chemotherapy-resistant osteosarcoma that overexpressed the drug-resistance proteins we were interested in. Subsequently, we began cell toxicity testing with several of the newly available Wnt inhibitors. We found that both chemotherapy insensitive, and chemotherapy-naive osteosarcoma cells were being killed by one class of Wnt inhibitors, but not another class.
That’s an interesting finding by itself, because it means osteosarcomas have endogenous resistance mechanisms relating to Wnt inhibition (or specific sensitivities) that have not yet been characterized. Additionally, that kind of variable response to Wnt had not yet been reported in other cancers. One of the molecules we were working with was highly potent in only the chemotherapy-resistant cells we had produced. Thus, we began more extensive mechanistic work with that compound, even though initial experiments indicated that it did not synergize or sensitize like we were hoping Wnt targeting molecules would. We discovered some unusual functions of this drug, and ended up unraveling the molecular mechanism by which it acts on the cell - explaining some of its unexpected activity.
Our ongoing work has been studying the mechanisms behind the variability in responses to classes of Wnt inhibiting drugs. Answering those questions will lead us to understanding key points about why some cancers would respond to Wnt-targeting therapies, and others wouldn’t - hopefully allowing us to predict patient responses prior to giving them a therapy.