Nav: Home

Combination therapy improved chemoresistance in ovarian cancer

November 01, 2016

PHILADELPHIA- - (Nov. 1, 2016) -- Treating ovarian cancer with platinum-based chemotherapy drugs such as cisplatin is initially very effective, with about four out of five patients responding favorably. However, most of these patients quickly become resistant to chemotherapy and may not respond as well to this standard treatment for the disease.

Researchers at The Wistar Institute have shown that a class of drugs called bromodomain and extraterminal domain (BET) inhibitors can be used in combination with cisplatin to reduce a tumor's resistance to chemotherapy, and therefore increase the effectiveness of the drug and improve long-term survival rates. The results were published in the journal Cancer Research.

"There is a tremendous need for novel therapeutic strategies for patients with chemotherapy resistant ovarian cancer, given the prevalence of the clinical challenge and the limited number of other options available," said Rugang Zhang, Ph.D., professor and co-program leader in the Gene Expression and Regulation program at Wistar and lead author of the study. "This study demonstrates how an existing class of targeted therapies could be used to potentiate the tumor suppression induced by cisplatin."

Several studies have shown how cancer stem-like cells (CSCs) contribute to chemotherapy resistance. Specifically, an increase in the activity of aldehyde dehyrogenase (ALDH) due to higher levels of ALDH1A1 protein expression appears to increase resistance, while reducing its activity sensitizes epithelial ovarian cancer cells to chemotherapy, making the treatment more effective.

Zhang and colleagues were able to show that BET inhibitors are able to suppress the activity of ALDH in epithelial ovarian cancer cells. Prior studies have shown that cisplatin increases ALDH activity, which then leads to cisplatin resistance. They also demonstrated that bromodomain-containing protein 4 (BRD4), one of the members of the BET family that is inhibited by BET inhibiting drugs, is a regulator of ALDH1A1 expression, and the protein is found in higher levels in epithelial ovarian cancer cell lines and high-grade serous epithelial ovarian cancer samples.

To test the combination, mice with epithelial ovarian cancer-derived tumor cells were given either the combination of cisplatin and the experimental BET inhibitor JQ1 or cisplatin alone. The group that received the combination therapy experienced significantly extended survival compared with the group of mice that only received cisplatin. Additionally, the outgrowth of tumors in the group of mice that received the combination was significantly delayed.

"The use of BET inhibitors for the treatment of cancer appears to be both safe and effective in clinical trials," said Yuhki Yokoyama, Ph.D., a postdoctoral fellow in the Zhang lab and first author of the study. "This combination appears to significantly extend the effectiveness of cisplatin, one of the most important drugs for treating ovarian cancer, and we hope our newly discovered approach will be validated in future clinical trials."
-end-
This work was supported by the National Institutes of Health/National Cancer Institute R01CA163377, R01CA202919, CA083639, and K99CA194318, U.S. Department of Defense grants OC140632P1 and OC150446, an Ovarian Cancer Research Fund Alliance (OCRFA) Program Project Development award, and The Jayne Koskinas & Ted Giovanis Breast Cancer Research Consortium at Wistar. Hengrui Zhu is an OCRFA Ann Schreiber Mentored Investigator. Co-author Sherry Wu is supported by the OCRFA, Foundation for Women's Cancer, and Cancer Prevention and Research Institute of Texas training grants RP101502 and RP101489. Support for core facilities in this study was provided by Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute.

Co-authors of this study from The Wistar Institute include Hengrui Zhu, Andrew Kossenkov, Jayamanna Wickramasignhe, Xiangfan Yin, Alessandro Gardini, Louise Showe, Qin Liu, David Speicher, Jose R. Conejo-Garcia, and Benjamin Bitler. Other co-authors include Jeong Heon Lee, Zhiguo Zhag and Tamas Ordog from the Mayo Clinic, Sherry Wu and Anil Sood from the University of Texas MD Anderson Cancer Center, Katherine Palozola and Kenneth Zaret from the Perelman School of Medicine at the University of Pennsylvania, James Bradner from Dana-Farber Cancer Institute at Harvard Medical School.

The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

The Wistar Institute

Related Chemotherapy Articles:

Chemotherapy is used to treat less than 25% of people with localized sarcoma
UCLA researchers have found that chemotherapy is not commonly used when treating adults with localized sarcoma, a rare type of cancer of the soft tissues or bone.
Starved cancer cells became more sensitive to chemotherapy
By preventing sugar uptake, researchers succeeded in increasing the cancer cells' sensitivity to chemotherapeutic treatment.
Vitamin D could help mitigate chemotherapy side effects
New findings by University of South Australia researchers reveal that Vitamin D could potentially mitigate chemotherapy-induced gastrointestinal mucositis and provide relief to cancer patients.
Less chemotherapy may have more benefit in rectal cancer
GI Cancers Symposium: Colorado study of 48 patients with locally advanced rectal cancer receiving neoadjuvant chemotherapy, found that patients receiving lower-than-recommended doses in fact saw their tumors shrink more than patients receiving the full dose.
Male fertility after chemotherapy: New questions raised
Professor Delbès, who specializes in reproductive toxicology, conducted a pilot study in collaboration with oncologists and fertility specialists from the McGill University Health Centre (MUHC) on a cohort of 13 patients, all survivors of pediatric leukemia and lymphoma.
'Combo' nanoplatforms for chemotherapy
In a paper to be published in the forthcoming issue in NANO, researchers from Harbin Institute of Technology, China have systematically discussed the recent progresses, current challenges and future perspectives of smart graphene-based nanoplatforms for synergistic tumor therapy and bio-imaging.
Nanotechnology improves chemotherapy delivery
Michigan State University scientists have invented a new way to monitor chemotherapy concentrations, which is more effective in keeping patients' treatments within the crucial therapeutic window.
Novel anti-cancer nanomedicine for efficient chemotherapy
Researchers have developed a new anti-cancer nanomedicine for targeted cancer chemotherapy.
Ending needless chemotherapy for breast cancer
A diagnostic test developed at The University of Queensland might soon determine if a breast cancer patient requires chemotherapy or would receive no benefit from this gruelling treatment.
A homing beacon for chemotherapy drugs
Killing tumor cells while sparing their normal counterparts is a central challenge of cancer chemotherapy.
More Chemotherapy News and Chemotherapy Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Warped Reality
False information on the internet makes it harder and harder to know what's true, and the consequences have been devastating. This hour, TED speakers explore ideas around technology and deception. Guests include law professor Danielle Citron, journalist Andrew Marantz, and computer scientist Joy Buolamwini.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.