Abstract
Simple SummaryClinical management of ovarian cancer remains a major clinical challenge as many patients develop resistance to standard platinum-based chemotherapy drugs over time. Testing novel targeted strategies and combination therapies may open the door to new possibilities for the treatment of this disease. One such approach includes targeting p53 with a peptide called ReACp53. While mutations in p53 are common in many cancers, ovarian cancers, in particular, are characterized by the dysfunction of this protein. The aim of this study is to evaluate the potential of combining ReACp53 with standard platinum-based chemotherapy to target ovarian cancer tumor cells. Using in vitro and in vivo preclinical models, we demonstrate enhanced efficacy when combining ReACp53 and carboplatin to target a subset of ovarian cancer cell lines and primary patient tumor samples. Collectively, our results indicate that this combinatorial approach may be applicable for targeting human ovarian tumors.Ovarian malignancies are a leading cause of cancer-related death for US women. High-grade serous ovarian carcinomas (HGSOCs), the most common ovarian cancer subtype, are aggressive tumors with poor outcomes. Mutations in TP53 are common in HGSOCs, with a subset resulting in p53 aggregation and misregulation. ReACp53 is a peptide designed to inhibit mutant p53 aggregation and has been shown efficacious in targeting cancer cells in vitro and in vivo. As p53 regulates apoptosis, combining ReACp53 with carboplatin represents a logical therapeutic strategy. The efficacy of this combinatorial approach was tested in eight ovarian cancer cell lines and 10 patient HGSOC samples using an in vitro organoid drug assay, with the SynergyFinder tool utilized for calculating drug interactions. Results demonstrate that the addition of ReACp53 to carboplatin enhanced tumor cell targeting in the majority of samples tested, with synergistic effects measured in 2 samples, additivity measured in 14 samples, and antagonism measured in 1 sample. This combination was found to be synergistic in OVCAR3 ovarian cancer cells in vitro through enhanced apoptosis, and survival of mice bearing OVCAR3 intraperitoneal xenografts was extended when treated with the addition of ReACp53 to carboplatin versus carboplatin alone. Results suggest that carboplatin and ReACp53 may be a potential strategy in targeting a subset of HGSOCs.
Highlights
Ovarian cancer is a deadly gynecologic malignancy responsible for over 13,000 deaths annually in the US [1]
Sought to test if ReACp53 could effectively target Highgrade serous ovarian carcinomas (HGSOCs) tumor cells in vivo when administered at a frequency of 3×/week using an intraperitoneal (IP) model of ovarian cancer
These results demonstrated the administration of ReACp53 resulted in7aofre17 duced tumor burden in mice bearing OVCAR3 human ovarian cancer cells, but not p53null SKOV3 cells using a physiologic intraperitoneal disease model
Summary
Ovarian cancer is a deadly gynecologic malignancy responsible for over 13,000 deaths annually in the US [1]. The most common subtype is high-grade serous ovarian carcinomas (HGSOC) [2]. Standard therapy for HGSOC includes surgical resection of the tumor followed by platinum-based chemotherapy with carboplatin [3]. Patients with advanced-stage disease not amenable to frontline cytoreduction are often first treated with chemotherapy (neoadjuvant chemotherapy) to reduce overall tumor volume, followed by an interval debulking surgery [4]. While many patients achieve remission with initial treatment, approximately 80% of patients with advancedstage disease experience tumor relapse [3] which is associated with the development of platinum-resistant disease. It is platinum resistance that claims the lives of women diagnosed with HGSOC. Effective targeting of these tumor cells and prevention of disease relapse remain a clinical challenge
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