Modulating cell state as sarcoma therapy
Osteosarcoma is pediatric cancer with peak incidence during the adolescent growth spurt. It is the most common bone cancer and is mostly found in the long bones such as the legs. Since the introduction of chemotherapy in the early 1970s, surgery combined with chemotherapy has been the standard treatment. Osteosarcoma patients have approximately a 70% chance to live longer than five years after diagnosis. This rate drops to less than 30% in patients who relapse or develop secondary tumor growth at sites other than bone. These statistics haven’t changed for over 40 years. Novel therapies are greatly needed to combat this devastating cancer. Osteosarcoma is known to have high genomic instability and extensive genetic heterogeneity. Mutation-specific drugs have had disappointing clinical results in part because of these features. Therapeutic strategies that cross mutation signatures are necessary. Our fundamental premise is that mutations may vary widely, but for them to cause cancer, they must funnel their actions through a more limited set of molecular programs that govern the cell processes of differentiation, proliferation, and self-renewal. These are the signature processes perturbed in cancer. Compounds that overcome the differentiation blockade and alter cell state have been developed as effective, curative therapy in some blood cancers. Our goal is to test the cell-state-modulation strategy in osteosarcoma and other sarcoma types, and we have evidence that we are making progress. We conducted in vitro drug screening platforms that enabled us to define two compounds that act synergistically to induce a therapeutic cell state transition of mouse and human osteosarcomas in vitro and primary human osteosarcomas in vivo in mice. Tumor cells lost their tumorigenesis, proliferation, identity signature, and self-renewal during this cell state transition. Notably, these effects were not limited to osteosarcoma as Ewing sarcoma, rhabdomyosarcoma, and chondrosarcoma similarly respond. We identified a key molecular driver of this cell state transition. It is the poorly studied gene ELMSAN1, a regulator of gene expression by epigenetic modification. We seek to conduct studies that will encourage the biopharma development of this approach to sarcoma. Specifically, we will 1. Test our compound combination on metastases, 2. Define the in vivo state transitions accompanying drug response and drug resistance, 3. Advance ELMSAN1 as a validated molecular target to induce therapeutic cell state transitions on osteosarcoma.