YB-1小分子抑制剂提高化疗治疗高级别浆液性卵巢癌的成功率

Ovarian cancer is the most lethal gynecological malignancy. The primary treatment regimen-surgery followed by platinum- or taxane-based chemotherapy-offers limited long-term success, as 85-90% of women diagnosed with late-stage disease will recur post adjuvant combination chemotherapy, an unfortunate outcome largely driven by treatment resistance. Thus, once ovarian cancer recurs, available treatments are palliative only. Clinically, the lack of treatment options for these patients is a critical unmet need, which we propose can be addressed with a novel therapeutic approach that directly addresses treatment resistance-therapeutic inhibition of Y-Box Binding Protein 1 (YB-1), a stress-responsive, multifunctional protein. To test this hypothesis, we collected tumor samples and nearby normal tissues from patients whose high grade serous ovarian cancer (HGSOC) relapsed after four to six treatments. These samples underwent proteomic analysis and were used to develop HGSOC treatment-resistant patient-derived xenograft (PDX) models. Using proteomics to profile these samples revealed that, in comparison to nearby normal tissue, malignant tissues significantly overexpressed YB-1 along with the related mRNA-processing pathways. Similar proteomic profiling of mouse HGSC cells exposed to SU056 confirmed that inhibiting YB-1 activated mRNA processing pathways, consistent with the findings from patient tissues. We subsequently employed mouse studies using PDX models from the HGSOC patient samples to determine whether inhibiting YB-1 with the small molecule SU056 significantly delayed tumor progression. These studies demonstrated that HGSOC tumors are susceptible to YB-1 inhibition. To test whether YB-1 inhibition additionally sensitizes tumors to chemotherapy, we combined SU056 with cisplatin and paclitaxel in the HGSC syngeneic mouse model (HGS1) and the treatment-resistant PDX model, finding that SU056 enhanced chemotherapeutic efficacy and extended overall survival. Proteomic analysis performed on mouse cell lines and tumors from syngeneic and PDX studies indicated that SU056 treatment significantly suppresses YB-1 and mRNA processing pathways in both in vitro and in vivo settings. Overall, these studies indicate that combining a YB-1 inhibitor with chemotherapy could overcome treatment resistance to improve responses in HGSC patients.