Scientists at The Wistar Institute have finally solved a major mystery in ovarian cancer treatment: why hormone therapy often doesn’t work, even when tumors seem like they should respond to it.
In this breakthrough study, researchers found that a mutated form of a common gene, called p53, blocks the effects of estrogen inside ovarian cancer cells. Because of this, anti-estrogen drugs that are supposed to stop tumor growth end up failing.
The good news is that the same research also uncovered a new way to make these treatments work again—using a drug that is already being tested in clinical trials. Dr. Maureen Murphy, deputy director of The Wistar Institute’s Ellen and Ronald Caplan Cancer Center and senior author of the study, said this discovery could completely change how doctors think about hormone therapy resistance in ovarian cancer.
She explained that for patients with certain p53 mutations, combining existing FDA-approved drugs might finally allow hormone therapy to succeed. Ovarian cancer is one of the deadliest cancers affecting women. The most common and aggressive form, known as high-grade serous ovarian cancer, returns in about 80% of patients after chemotherapy.
Each year, this cancer claims around 13,000 lives in the United States. About 75% of these tumors contain estrogen receptors—proteins that should, in theory, make them respond to hormone-blocking drugs. However, in real life, these treatments only help about 4 in 10 patients. This huge gap puzzled scientists for years.
Dr. Murphy’s team began looking for answers while studying genetic differences in p53 among people of African descent. When they analyzed blood samples, they noticed that certain estrogen-related genes were less active in people with specific p53 variants.
This hinted that p53 might be interfering with estrogen signaling inside cells—a clue that led to their latest discovery. In their new study, published in the journal Genes & Development, the researchers confirmed that mutant p53 physically binds to estrogen receptors, blocking the normal hormone signals that control how cells grow and divide.
As a result, tumors become resistant to anti-estrogen drugs. To test their theory, the scientists worked with the Helen F. Graham Cancer Center & Research Institute and obtained real patient tissue samples.
When they silenced, or “turned off,” the mutant p53 gene in these samples, something amazing happened: tumors that were previously resistant to hormone therapy suddenly started responding again. These results were later confirmed in early-stage ovarian cancer models at the University of Pennsylvania.
The team then tested a promising compound called rezatapopt. This drug has the unique ability to restore a specific defective form of p53, known as Y220C, to its normal shape and function. When the researchers combined rezatapopt with hormone therapy, tumors with the Y220C mutation became much more sensitive to treatment.
Because rezatapopt is already being tested in clinical trials, this new combination approach could move quickly into studies with real patients. Even more exciting, the discovery may help explain why hormone-blocking drugs sometimes fail in other cancers, such as breast cancer, where p53 mutations are also common.
This opens the door to developing similar combination treatments for those cancers as well. Dr. Murphy and her team are now expanding their research to study other types of p53 mutations and to design tools that can help doctors identify which patients would benefit most from this new therapy strategy.
In short, this discovery doesn’t just solve a long-standing puzzle—it offers real hope. It shows that understanding the role of mutant p53 could make hormone therapy effective again for many ovarian cancer patients who previously had few options.
By connecting decades of research on estrogen signaling and genetic mutations, this study offers a roadmap for developing more personalized cancer treatments. If successful in human trials, it could turn what was once a failed treatment into a life-saving option.
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The study is published in Genes & Development.
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