Abstract 5626: Exploring a new therapeutic strategy through hyperactivation of the unfolded protein response pathway in bone cancer treatment

Abstract Bone cancer is the third leading cause of cancer-related deaths among children and teenagers. Malignant subtypes such as osteosarcoma (OS), Ewing sarcoma (ES), and chondrosarcoma (CS) originate from distinct cell types within the bone. These malignant bone sarcomas pose significant treatment challenges, particularly in cases of relapse or metastasis due to chemoresistance. Therefore, there is a clinical need for newer, effective therapies for recurrent or relapsed disease. This study explores the therapeutic potential of ErSO, a small molecule previously shown to selectively kill estrogen receptor alpha (ERα)-positive breast cancer cells by hyperactivating the unfolded protein response (UPR) and TRPM4. We evaluated anti-cancer activity of ErSO across multiple bone cancer subtypes. Our findings categorized human bone cancer cell lines, including patient-derived xenograft (PDX) cell lines, into ErSO-sensitive and ErSO-insensitive groups. Surprisingly, unlike in breast cancer cells, ErSO sensitivity in bone cancer cells did not correlate with ERα expression. However, ErSO treatment consistently activated ATF6 and PERK in the UPR pathway in ErSO-sensitive OS cell lines. Furthermore, ErSO-induced cytotoxicity was specifically linked to ATF6 activation. Importantly, we discovered that TRPM4 expression on the membrane was a critical determinant of ErSO-induced cell death. Additionally, ErSO-resistant clones derived from ErSO-sensitive OS cell lines consistently showed a reduction in ErSO-induced ATF6 activation and, in some cases, decreased TRPM4 expression. In mouse models of experimental lung metastasis using ErSO-sensitive human OS cells, a single ErSO injection dramatically reduced tumor burden in the lungs. In models with tumor burdens ranging from low to high, ErSO treatment significantly extended survival. In conclusion, ErSO demonstrated potent anti-cancer activity against certain bone cancers via ATF6 activation, acting independently of ERα expression. These effects were particularly dependent on the expression of TRPM4 on the membrane. Our findings highlight the potential anti-cancer activity of ErSO as a therapeutic agent for bone cancer, including advanced cases with lung metastases. Ongoing studies aim to further evaluate the effectiveness of ErSO in models of spontaneous lung metastasis and chemoresistant OS to support its potential for treating late-stage patients. Citation Format: Yoongyeong Lee, Michael Mulligan, Brooke Bouwens, Jenny Drnevich, Keith Bailey, Michael Spinella, David Shapiro, Paul Hergenrother, Timothy Fan. Exploring a new therapeutic strategy through hyperactivation of the unfolded protein response pathway in bone cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5626.