Combining ReACp53 with Carboplatin to Target High-Grade Serous Ovarian Cancers

by Selleckchem | Jul 22 2023

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.

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Ovarian malignancies, particularly high-grade serous ovarian carcinomas (HGSOCs), are a significant cause of cancer-related death among women in the United States. HGSOCs are aggressive tumors with poor outcomes, and they often exhibit mutations in the TP53 gene, resulting in the aggregation and misregulation of the p53 protein. In an effort to target these cancer cells, researchers have developed a peptide called ReACp53, which is designed to inhibit mutant p53 aggregation. Previous studies have demonstrated the efficacy of ReACp53 in targeting cancer cells both in laboratory experiments (in vitro) and in living organisms (in vivo).

Since p53 plays a crucial role in regulating apoptosis (programmed cell death), combining ReACp53 with existing chemotherapy drugs, such as carboplatin, appears to be a logical therapeutic strategy. To evaluate the effectiveness of this combination, researchers conducted experiments using eight ovarian cancer cell lines and ten patient samples of HGSOC. An in vitro organoid drug assay was performed, and the researchers used a tool called SynergyFinder to calculate drug interactions.

The results of the study indicated that the addition of ReACp53 to carboplatin enhanced the targeting of tumor cells in the majority of the samples tested. Specifically, synergistic effects were observed in two samples, additivity (meaning the combined effect was similar to the sum of the individual effects) was observed in 14 samples, and antagonism (reduced effectiveness compared to individual treatments) was observed in one sample. In vitro experiments using OVCAR3 ovarian cancer cells further confirmed the synergistic effect of carboplatin and ReACp53 by promoting enhanced apoptosis (cell death) in these cells.

Additionally, the researchers conducted in vivo experiments using mice that were implanted with OVCAR3 ovarian cancer cells. The survival of these mice was extended when they were treated with the combination of ReACp53 and carboplatin compared to treatment with carboplatin alone.

Overall, these findings suggest that combining ReACp53 with carboplatin may be a potential therapeutic strategy for targeting a subset of HGSOCs. By inhibiting mutant p53 aggregation and promoting apoptosis, this combination treatment could potentially improve outcomes for patients with ovarian cancer. However, further research and clinical trials are necessary to validate these findings and determine the safety and efficacy of this approach in human patients.