Abstract
Sarcoma represents a rare, malignant group of tumors originating from connective tissues that have a disproportionally high rate of metastases and recurrence. This is largely due to the clinical and biological complexities of sarcoma. As such, the median survival of patients diagnosed with metastatic sarcoma is approximately one year despite considerable advancement in anti-cancer therapies. Recently, evidence supporting a new cancer development model offers an explanation for the poor prognosis of sarcoma patients. This new model postulates the existence of a small subset of cells found within the bulk of the tumor that can metastasize and are resistant to cytotoxic therapies due to their stem cell like ability to self-renew and differentiate. Given their unique stem cell like properties, this population of cells is aptly described as cancer stem cells (CSCs). Indeed, consistent with what others have observed, we identified a CSC population within established human sarcoma cell lines and a sarcoma sample freshly disassociated from a patient. Based on the CSC hypothesis, though cytotoxic therapies are effective towards the bulk of the tumor, it simultaneously can enrich for resistant CSCs. As such, we hypothesized that treatment of sarcoma cells with the cytotoxic agent, sorafenib, will enrich for CSCs. Sorafenib is a multi-kinase inhibitor that belongs to a class of molecular targeting agents. Its broad targeting spectrum against molecular structures commonly overactive in many cancer types led to its FDA approval in advanced kidney and liver cancer. For that matter, sorafenib is an ideal therapeutic agent for treating the notoriously complex nature of sarcoma. As hypothesized, we observed significant anti-proliferative effects on the bulk of sarcoma cells and enrichment of CS Cs in vitro and in vivo after treating cells with sorafenib. Although enrichment of CSCs is a negative effect, this allows for the development of a more specific approach for cancer eradication. It has been demonstrated in various groups including our laboratory the efficacy of natural killer (NK) cell immunotherapy against CSCs. NK cells have been an attractive anticancer therapy due to its ability to recognize and rapidly kill both virally infected and tumor cells and have been observed to preferentially target CSCs. We thus hypothesized that combining sorafenib with subsequent NK immunotherapy offers a more effective therapeutic approach for treating sarcoma. Indeed, ex vivo expanded NK cells from healthy donor blood independently demonstrated preferential cytolytic capability against CSCs. More importantly, we observed, in vitro, an enhanced killing effect when sarcoma cells were pre-treated with sorafenib. Our results suggest the efficacy of combining both sorafenib and NK immunotherapy for eradicating all populations of sarcoma cells and thus have the potential for clinical translation for the treatment of sarcoma.