Abstract 6396: Sarcoma treatment using HSP90 inhibitors in combinatorial synergy with doxorubicin

Abstract

Abstract Synovial sarcoma, a rare muscle cancer, has few targeted therapies, and is most commonly treated using doxorubicin (DOX). Even as a primary treatment agent, successful treatment and remission rates are low, and the significant cardiotoxicity of DOX limits dosage options. Synovial sarcoma, and other sarcomas, have a high expression of HSP90, a protein that acts as a chaperone molecule to stabilize and help fold other proteins within the cellular matrix. Under high stress situations, HSP90 is upregulated and acts to stabilize other more thermally labile proteins, including many oncogenes. Using FDA approved drug panels, it was determined that HSP90 is a suitable target for treatment. We look to use a novel HSP90 inhibitor (HS10) compound, to target the high expression of HSP90 within synovial sarcoma and osteosarcoma in combination with the chemotherapy standard DOX to determine if a synergistic effect is observed. This synergistic effect would allow for an overall decreased dose to induce effective cancer cell targeting, reducing overall systemic toxicity within patients. Our results indicate such synergism does occur between DOX and HS10, at a dosage of 5-25 nM DOX and 1000 nM HS10, reducing cell survival to 37-68%, dependent on cell line. DOX dosage alone reduced cell survival to 74% in the most effective case, with no reduction in the least effective case, at a dose of 100 nM. This dose is four times stronger than the highest DOX synergistic dose. It can be concluded, then, that synergistic combination does exist between DOX and HS10, and dosage of DOX can be reduced with more effective targeting for synovial and osteosarcoma cell lines. Protein expression was evaluated using immunoblotting to isolate protein fractions within the cytoplasm and cell membrane, showing high expression within the cytoplasm. Isolated blood plasma from mice with and without tumors was analyzed through ELISA, showing elevated HSP90 presence in mice with tumors (236.4±190pg) vs mice without tumors (6.5±3.5pg). This confirmation of elevated HSP90 expression within sarcoma patients suggests targeting using HS10 to induce synergy to be a viable approach for advanced sarcoma treatment. Citation Format: Matt Kirkham, Sarah Luelling, Kaniz Fatema, Jared Barrott. Sarcoma treatment using HSP90 inhibitors in combinatorial synergy with doxorubicin [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6396.