Nav: Home

Research uncovers a potential new strategy to fight ovarian cancer

March 28, 2018

A new discovery opens the possibility of developing a novel way to fight ovarian cancer. Researchers at Baylor College of Medicine and the University of Texas MD Anderson Cancer Center have revealed a previously unknown cellular pathway that selectively regulates a mutant protein, called p53-R175H, linked to ovarian cancer growth. The researchers identified a key regulator of this pathway - USP15 - and suggest that designing drugs directed at this regulator might lead to better ways to control cancer growth in the future. The study appears in Nature Communications.

"Ovarian cancer is currently treated with surgery and chemotherapy. Chemotherapy for ovarian cancer is based on drugs that act on any cell that is rapidly dividing, healthy or malignant, which has side effects," said first and corresponding author Dr. Achuth Padmanabhan, instructor of molecular and cell biology at Baylor College of Medicine. "If we are able to develop treatments that target only cancer cells, then we might be able to minimize side effects."

Research has revealed that mutant p53 proteins might be the target scientists have been looking for. More than 96 percent of high-grade serous ovarian carcinomas, the most lethal and common form of ovarian cancer, have mutations in the p53 gene. These mutations have been shown to play key roles in the production of tumors and in the development of drug resistance. Normal p53 protein is known for playing a tumor suppressor role. In contrast, the mutation studied by Padmanabhan and his colleagues - p53-R175H - can promote tumor growth.

"Normal p53 is rapidly broken down inside most healthy cells, but p53 mutants such as p53-R175H, are not. They form very stable protein clusters inside cells that promote cancer and induce drug resistance," Padmanabhan said. "Researchers have discovered that if we remove the mutant p53 forms from cancer cells, the cells will enter a path toward cell death and become more sensitive to chemotherapy. This is very valuable from the clinical point of view."

These findings have prompted Padmanabhan and his colleagues and other researchers to find ways to reduce the levels of p53-R175H inside cancer cells to promote their own destruction.

A potential new way to fight ovarian cancer

"The question has been how to selectively eliminate p53-R175H clusters. We do not want to affect the normal p53 proteins because this also can lead to cancer. Our goal is to find ways to reduce the levels of mutant p53-R175H only," Padmanabhan said. "We did not know how to do it until we discovered a unique pathway than can regulate the mutant, but not normal p53. Once we identify the specific pathways, we can design drugs to manipulate them."

When Padmanabhan began working in the lab of Dr. JoAnne Richards at Baylor College of Medicine, they were testing a small molecule called MCB613, for its ability to treat ovarian cancer in a mouse model of the disease. In those experiments, Padmanabhan observed that in cells treated with MCB613 the levels of mutant p53 protein rapidly decreased.

"This was interesting because it told me that the drug was doing something unique to this mutant, but not to the other forms of p53," Padmanabhan said. "In this work, we tried to understand how treatment with MCB613 resulted in reduced levels of p53-R175H in ovarian cancer cells."

The researchers found that MCB613 does not decrease the levels of mutant p53-R175H protein directly. It reduces the levels of another protein called USP15 that removes a specific tag from the p53 mutant that targets it to undergo degradation inside cells.

"Having fewer molecules of USP15, results in more mutant p53-R175H protein tagged for degradation in the cell," Padmanabhan said. "As a result, the balance tips toward elimination of mutant p53-R175H proteins, which results in more cancer cell death. We also discovered that mutant p53-R175H is destroyed in the lysosome system of the cell, as opposed to normal p53, which is broken down by another protein-degradation system within the cells called the proteasome."

"Our findings offer a new opportunity for regulating mutant p53-R175H by developing drugs that inhibit USP15," said Richards, professor of molecular and cellular biology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine, who is senior author of this work. "A possible future scenario in the clinic could be to use DNA analysis to determine whether this p53 mutation is present in a patient's tumor. If so, then we may use our approach to treat it or combine it with other anticancer drugs and take advantage of the fact that treatment with inhibitors of USP15 results in the cancer cells becoming more susceptible to chemotherapy."

The researchers also found that mutant p53-R175H is more sensitive to ovarian steroids, so they are looking at how ovarian steroids affect ovarian cancer progression.

"We are combining ways of regulating steroid receptor and coactivator action, as well as p53," said co-author Dr. Bert O'Malley, chair and professor of molecular and cellular biology, Thomas C. Thompson Chair in Cell Biology and associate director of basic research in the Dan L Duncan Comprehensive Cancer Center. "Maybe by manipulating both of those pathways we may have a better chance of regulating cancer growth."
-end-
Other contributors of this work include Nicholes Candelaria, Kwong-Kwok Wong, Bryan Nikolai and David M Lonard.

This work was supported by NIH grant NIH-CA-181808 to JSR. Imaging was supported by the Integrated Microscopy Core at BCM with funding from NIH (DK56338, and CA125123), CPRIT (RP150578), the Dan L. Duncan Comprehensive Cancer Center and the John S. Dunn Gulf Coast Consortium for Chemical Genomics.

Baylor College of Medicine

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Changing The World
What does it take to change the world for the better? This hour, TED speakers explore ideas on activism—what motivates it, why it matters, and how each of us can make a difference. Guests include civil rights activist Ruby Sales, labor leader and civil rights activist Dolores Huerta, author Jeremy Heimans, "craftivist" Sarah Corbett, and designer and futurist Angela Oguntala.
Now Playing: Science for the People

#521 The Curious Life of Krill
Krill may be one of the most abundant forms of life on our planet... but it turns out we don't know that much about them. For a create that underpins a massive ocean ecosystem and lives in our oceans in massive numbers, they're surprisingly difficult to study. We sit down and shine some light on these underappreciated crustaceans with Stephen Nicol, Adjunct Professor at the University of Tasmania, Scientific Advisor to the Association of Responsible Krill Harvesting Companies, and author of the book "The Curious Life of Krill: A Conservation Story from the Bottom of the World".