Repurposing FDA-approved drugs can help fight back breast cancer

November 16, 2018

Screening Food and Drug Administration (FDA)-approved compounds for their ability to stop cancer growth in the lab led to the finding that the drug flunarizine can slow down the growth of triple-negative breast cancer in an animal model of the disease. Led by researchers at Baylor College of Medicine and the National Taiwan University College of Medicine, the team shows in the journal Scientific Reports proof of concept that this approach can potentially lead to the discovery of drugs in a way that is quicker and less expensive than traditional drug development strategies.

"We focused on finding ways to disrupt the effects of a class of protein called Ras, which are powerful drivers of a wide range of cancers. In this proof-of-concept study we have established a strategy to target N-Ras for therapy," said co-corresponding author Dr. Eric C. Chang, associate professor of molecular and cellular biology and the Lester and Sue Smith Breast Center in the Dan L Duncan Comprehensive Cancer Center at Baylor. "N-Ras drives a form of triple-negative breast cancer, a very aggressive form of cancer for which there is no targeted therapy available. So we thought that, if we could target one of the drivers, we might be able to make a contribution toward finding effective therapies."

Directly interfering with Ras proteins has proven to be difficult, Chang explains, "but this is important because RAS can drive resistance to other forms of treatments targeting downstream pathways." Therefore, he and his colleagues sought safe and approved compounds that can reduce the amount of N-Ras in cancer cells by altering the cell's natural ability to degrade this protein.

"Our assay allows us to visually determine which drugs promote N-Ras degradation," Chang said. "We tagged N-Ras proteins with a green fluorescent tag. If the fluorescent N-Ras proteins were destroyed, the fluorescence would be lost. These assays were conducted with an automated microscopy system in the laboratory of co-author Dr. Stephen Wong at the Methodist Hospital Research Institute."

Chang and his colleagues tested a number of FDA-approved compounds on their green cells. The drugs that made the green color disappear were those that degraded N-Ras in the cells and were potential candidates for further testing their effect on cancer growth. Of all the compounds they tested, flunarizine worked best in this test.

A potential new purpose for an old drug

"Flunarizine has been used in medical practice for decades to treat dizziness and vertigo and to prevent migraines," Chang said. "Our study shows a new function; it also can promote degradation of cancer-promoting N-Ras."

The researchers also tested the effect of flunarizine in a mouse model of triple negative breast cancer and found that it slowed down tumor growth. They also determined that flunarizine promotes N-Ras degradation by enhancing a natural cellular pathway called autophagy. This pathway was first discovered by the ability to provide cells a way to survive starvation by degrading and recycling cellular materials.

"Screening existing relatively safe drugs for new functions is a valuable strategy for identifying drugs that can potentially be used to treat diseases for which currently there are no available treatments," Chang said. "Reprograming pathways that degrade cellular materials may be an effective strategy to remove a cancer driver that is otherwise hard to target."
-end-
This study was speared by Ze-Yi Zheng, the first author on this paper. Other contributors to this work include Jing Li, Fuhai Li, Yanqiao Zhu, Kemi Cui, Stephen T. Wong and Yi-Hua Liao. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, the Methodist Hospital Research Institute Houston, National Taiwan University Hospital and National Taiwan University College of Medicine in Taiwan, and the Southwest Medical University in China.

This project was supported by a P30 Cancer Center Support Grant from the National Cancer Institute (P30CA125123), the Susan G. Komen Foundation (SAC150059), the Department of Defense (W81XWH-16-1-0538), the Nancy Owen Memorial Foundation, the National Institutes of Health (R21CA185516, R21CA226567 and P50CA186784), the Cancer Prevention and Research Institute of Texas (CPRIT, RP180844) and the Ministry of Science and Technology of the Republic of China (Grant No. MOST 103-2314-B-002-067-MY3.)

Baylor College of Medicine

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.