Double trouble: A drug for alcoholism can also treat cancer by targeting macrophages

January 30, 2020

Developing a therapy to combat cancer remains one of the most difficult challenges in medical research. Cancer owes its notorious identity to the fact that the cancer cells use the host's own immune system to grow and spread, ultimately becoming deadly. Immune cells like macrophages, which ordinarily fight to protect normal cells, are hijacked by malignant cancer cells, and populate the environment around the tumors, becoming tumor-associated macrophages (TAMs). In fact, it was found that the cancerous tissue of patients for whom immunotherapy was not successful was indeed rich in macrophages, confirming the link between the cancer and the TAMs. It is these TAMs that produce signaling proteins like chemokines and trigger the inhibitory immune checkpoint releases that create an immunosuppressive tumor environment, which protects the cancer cells and allows their accelerated growth. Since it is the TAMs that facilitate the spreading of cancer cells, regulating them as a therapeutic strategy for combating cancer has gained attention in recent years.

A research group led by Yuya Terashima from the Tokyo University of Science saw this as an opportunity to explore the realm of developing novel anti-cancer drugs. Their seminal work in Nature Immunology 2005 reported the discovery of a new target protein called FROUNT, which is linked to regulation and movement of the TAMs. Since FROUNT amplified "chemokine signaling," a type of cellular communication, an integral process for TAM accumulation and activity, it was therefore linked directly to TAM regulation.

The team decided to expand on these findings, in order to investigate whether a therapeutic strategy can be formulated and have published their findings in Nature Communications. Through animal experiments, the researchers found that by regulating FROUNT expression in TAMs, cancer growth could be suppressed.

Then, in order to reduce any side effects, the team also developed an independent strategy of limiting the effect of FROUNT on chemokine signaling by inhibiting the interaction between the two. The team screened 131,200 compounds and zeroed in on disulfiram, a drug used to treat alcoholism, and known for its potential as an anti-cancer drug. This drug was found to directly bind to the FROUNT site, making FROUNT unavailable for interaction with the components of chemokine signaling. Reflecting on the results, Terashima explains, "When tested on mice, disulfiram inhibited the movement of macrophages and suppressed the growth of cancer cells. Therefore, our findings present a new cancer treatment strategy that can suppress the growth of cancer cells that are difficult to respond to by immune checkpoints when used in combination with disulfiram."

The team is now further pushing the boundary of the finding and has started clinical research at the National Cancer Center Hospital East. Illustrating the outline for further research, Terashima comments, "since macrophages pose as a problem in various types of diseases, the indications for FROUNT inhibitors for a wide range of diseases may be considered." Indeed, the team expects this this to be the first therapeutic strategy to regulate TAMS, and are hopeful that a better understanding of the correlation between the inhibition of the target protein FROUNT and TAMs paint a promising picture for the future of novel therapeutic strategies.
-end-
About The Tokyo University of Science

Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.

With a mission of "Creating science and technology for the harmonious development of nature, human beings, and society", TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.

Website: https://www.tus.ac.jp/en/mediarelations/

About Dr. Terashima from Tokyo University of Science

Dr. Yuya Terashima is a junior associate professor at the Department of Biological Sciences, Tokyo University of Science. He discovered a chemokine signal regulator FROUNT which directly binds to the receptor, and has been studying for the family of the chemokine-receptor associating molecule, aiming for therapeutic applications of their functional inhibitors. He works with his team to understand the molecular mechanisms of living organisms with a specific perspective on inflammation and immunology, and drug discovery.

Funding information

This study was supported in part by Practical Research for Innovative Center Control (JP19ck0106422) and Project for Cancer Research and Therapeutic Evolution (P-CREATE, JP19cm0106204) from the Japan Agency for Medical Research and Development (AMED) and JSPS KEKENHI.

Tokyo University of Science

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.