MRNA therapy rescues p53 function and inhibits ovarian cancer tumor growth

High-grade plasmacytoid ovarian cancer (HGSOC) is the deadliest gynecologic malignancy, which interacts closely with the tumor mesenchyme, grows rapidly, metastasizes widely, and exhibits an aggressive course. The current standard of care includes surgery, chemotherapy, monoclonal antibodies, and PARP inhibitors. However, approximately 70% of patients relapse within 3 years of surgery and chemotherapy and die of disease progression. This situation has hardly improved in the last 20 years.

Mutations in the TP53 gene are the most common mutations in human cancers, and the Cancer Genome Atlas Research Network reveals that up to 96% of HGSOC cases are characterized by inactivated or truncated TP53. Furthermore, TP53 mutations appear to occur early in ovarian cancer, which supports the role of mutant TP53 as a driver of this malignancy.

Recently, researchers from the University of Frankfurt published a research paper in the journal Cancer Communications entitled "Rescue of p53 functions by in vitro-transcribed mRNA impedes the growth of high-grade serous ovarian cancer".

Mutations in the oncogene TP53, which is expressed by the p53 protein, recognize and repair DNA damage in cells and induce cell death when the damage cannot be repaired, thus preventing abnormal cell proliferation and preventing cancer development. This prevents the proliferation of abnormal cells and prevents cancer from occurring. When the TP53 gene is mutated, the resulting mutant p53 protein loses its cancer-suppressive effect.

In this study, the team tried to restore normal p53 protein expression using mRNA. They synthesized mRNA encoding the correct p53 protein in the lab and then loaded it into liposomes for delivery, which expressed functional p53 protein in various human cancer cell lines.

Next, the team obtained tumor samples from ovarian cancer patients from the University Hospital Frankfurt and constructed patient-derived ovarian cancer-like organs that began to shrink and die after treatment with the mRNA.

To further test whether the mRNA therapy was effective in vivo and could combat abdominal metastasis of ovarian cancer, the team constructed an ovarian cancer mouse model by implanting human ovarian tumor cells into the ovaries of mice and injecting mRNA liposomes into these mice after a period of time.

The results showed that these mRNAs produced a large number of functional p53 proteins in the mouse models, and the tumors and metastases in their ovaries almost completely disappeared.

The researchers say that the mRNA therapy in this study was so successful in part because of advances in mRNA technology, which have greatly extended the lifespan of mRNAs by modifying them, and that the mRNAs in this study could be expressed in mice for as long as two weeks. In addition, the modified mRNAs did not trigger an inflammatory response.

Overall, this study demonstrates that in vivo expression of the p53 protein using mRNA promises to be a potential therapeutic strategy for high-grade plasmacytoid ovarian cancer and also provides valuable insights into the molecular mechanisms of p53 function and its relevance in ovarian cancer treatment.liposomes for delivery

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