The central hypothesis of this proposal is that combining sorafenib which enriches for sarcoma cancer stem cells (CSCs) with Natural Killer (NK) cell immunotherapy preferentially targeting the remaining sarcoma CSCs will result in a synergistic therapeutic effect against STS. If successful, this novel combination of targeted therapies may translate into clinical trials for human patients with metastatic STS.
The CSC hypothesis postulates that a sub-population of quiescent cells exists within tumors which are resistant to cytotoxic therapies. It is these CSCs which then seed tumor relapse. Therefore, therapies which add a specific anti-CSC strategy to cytoreductive therapies may provide a greater and more durable therapeutic effect.
NK cells represent a subset of cytotoxic lymphocytes which demonstrate an ability to eradicate tumor cells. They are able to recognize targets through direct receptor-ligand interactions mitigate the need for ongoing tumor antigen recognition which is a mechanism of resistance to humorally-based immunotherapies. CSCs appear to be a preferential target for NK cells through upregulation of stress-induced antigens as well as the ability of NK cells to target non-proliferating cells. Therefore, NK-mediated killing would appear to be an attractive candidate for targeting of sarcoma CSCs.
Extending our clinical experience using sorafenib in a Phase I neoadjuvant trial for locally advanced STS, we have in vitro evidence that sorafenib enriches for sarcoma CSCs. The main focus of the proposed studies will be to demonstrate that sorafenib enriches for sarcoma CSCs in pre-clinical models of STS. Mouse xenografts of human STS will be utilized in the first aim since they provide a valuable model to mechanistically explore the timing, plasticity, and mediators of sorafenib enrichment of CSCs as well as the ability of NK cells to hone and kill sarcoma CSCs.
In the second aim, we will test the feasibility and gather preliminary data for efficacy of combining sorafenib and NK immunotherapy in metastatic canine STS. Canine STS are naturally occurring tumors which grow over extended periods of time in the setting of an intact immune system. The growth and metastatic spread in dogs parallels that of humans. Moreover, canine immune systems have extensive homology with humans. These advantages make canines an excellent model for investigating novel anti-sarcoma interventions.
The proposed studies will be meaningful to characterize and validate the expression of CSC markers in pre-clinical models of STS, including in highly relevant and under-utilized canine STS. This research will help to determine if NK immunotherapy and CSC targeting are feasible therapeutic approaches in STS. The answer to these questions will help to advance the field of sarcoma biology. Should targeting of sarcoma CSCs by immunotherapy prove to be feasible for even a select subset of STS histologies, then this approach will have significant impact.