Kimberly K. Leslie

Auranofin Synergizes with Cisplatin in Reducing Tumor Burden of NOTCH-Dependent Ovarian Cancer

Abstract The NOTCH pathway regulates cell proliferation, differentiation, and stem cell maintenance. Thus, aberrant NOTCH activation plays a key role in cancer initiation, progression, and chemoresistance. Mutations and amplification of NOTCH pathway genes have been identified in high-grade serous ovarian cancers and are associated with poor clinical outcomes. Among the four NOTCH receptors, NOTCH3 alterations were strongly correlated with poor overall survival. Previously, we identified auranofin, an oral gold salt therapeutic compound, as a novel NOTCH pathway inhibitor that disrupts the DNA binding of RBPJ, the major downstream transcriptional effector of the NOTCH pathway. In this study, we surveyed the response of eight ovarian cancer cell lines to auranofin and found IC50 values ranging from 1.7 to 12 μmol/L, with NOTCH3-negative SKOV3 cells having the highest IC50 value. In NOTCH-dependent OVCAR3 cells, auranofin synergized with cisplatin to enhance cell death. Importantly, auranofin treatment led to a dose-dependent decrease in RBPJ occupancy at the NOTCH-dependent promoters, HES1 and HES4. Furthermore, knocking down NOTCH3 in OVCAR3 cells significantly decreased sensitivity to auranofin, further supporting the notion that NOTCH3 signaling is a major target of auranofin. Moreover, auranofin increased cisplatin efficacy in an OVCAR3-derived xenograft mouse model. Using eight patient-derived cancer organoid models, we found that auranofin increased cisplatin efficacy in killing cancer organoids generated from clinically platinum-sensitive patients but also restored platinum response in a subset of organoid models developed from platinum-resistant patients. These studies underscore the potential of auranofin to improve platinum-based cancer therapy, particularly in NOTCH3-expressing cancers. Significance: NOTCH signaling underlies cancer initiation, progression, and chemoresistance. Our study revealed the potential of auranofin as a NOTCH pathway inhibitor to enhance the efficacy of platinum-based ovarian cancer therapy.

TP53 Sequencing and p53 Immunohistochemistry Predict Outcomes When Bevacizumab Is Added to Frontline Chemotherapy in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study

PURPOSE The status of p53 in a tumor can be inferred by next-generation sequencing (NGS) or by immunohistochemistry (IHC). We examined the association between p53 IHC and sequence and whether p53 IHC alone, or integrated with TP53 NGS, predicts the outcome. METHODS From GOG-86P, a randomized phase II study of chemotherapy combined with either bevacizumab or temsirolimus in advanced endometrial cancer, 213 cases had p53 protein expression data measured by IHC and TP53 NGS data. An analysis was designed to integrate p53 expression by IHC with the presence or absence of a TP53 mutation. These variables were further correlated with progression-free survival (PFS) and overall survival (OS) in the chemotherapy plus bevacizumab arms versus the chemotherapy plus temsirolimus arm. RESULTS In the analysis of p53 IHC, the most striking treatment effect favoring bevacizumab was in cases where p53 was overexpressed (PFS hazard ratio [HR]: 0.46, 95% CI, 0.26 to 0.88; OS HR: 0.31, 95% CI, 0.16 to 0.62). On integrated analysis, patients with TP53 missense mutations and p53 protein overexpression had a similar treatment effect on PFS (HR: 0.41, 95% CI, 0.22 to 0.83) and OS (HR: 0.28, 95% CI, 0.14 to 0.59) favoring bevacizumab plus chemotherapy relative to temsirolimus plus chemotherapy. Concordance between TP53 NGS and p53 IHC was 88%. Concordance was 92% when cases with TP53 mutations and POLE mutations or mismatch repair deficiency were removed. CONCLUSION IHC for p53 alone or when integrated with sequencing for TP53 identifies a specific, high-risk tumor genotype/phenotype for which bevacizumab is particularly beneficial in improving outcomes when combined with chemotherapy.