Winding Biological Clock Shortens Cancer's Meal Time

Cancer cells flout the circadian clock’s rigid rules, which limit the growth and proliferation of healthy cells. Apparently, cancer cells can jam or disengage the circadian machinery, putting time permanently out of joint. Setting cancer cells right, however, could be an effective therapeutic strategy, particularly since this appears to prevent cancer cells from processing nutrients around the clock.

According to scientists based at the Salk Institute, targeting parts of the circadian clock with drugs could limit the recycling of nutrients and reduce fat synthesis in cancer cells. The scientists, led by Satchidananda Panda, Ph.D., activated circadian clock components called REV-ERBs. REV-ERB agonists, the scientists reported in a new study, impaired glioblastoma growth in vivo and improved survival in mice.

The scientists were aware that proteins known as REV-ERBα and REV-ERBβ are responsible for turning on and off cells’ ability to synthesize fats, as well as their ability to recycle materials—a process called autophagy—throughout the day. In healthy cells, fat synthesis and autophagy are allowed to occur for about 12 hours a day when REV-ERB protein levels remain low. The rest of the time, higher levels of the REV-ERB proteins block the processes so that the cells are not flooded with excessive fat synthesis and recycled nutrients.

In the past, researchers developed compounds to activate REV-ERBs in the hopes of stopping fat synthesis to treat certain metabolic diseases. Dr. Panda and colleagues, however, thought that they could take REV-ERB activation in another direction: the fight against cancer. They reasoned that activating REV-ERB could slow cancer growth, since cancer cells heavily rely on the products of both fat synthesis and autophagy to grow.

“When we block access to these resources, cancer cells starve to death but normal cells are already used to this constraint so they’re not affected,” said Prof. Panda. Incidentally, in their study, Prof. Panda and colleagues noted that the mice that were given REV-ERB agonists did not suffer overt toxicity.

Details of the study appeared January 10 in the journal Nature, in an article entitled “Pharmacological Activation of REV-ERBs Is Lethal in Cancer and Oncogene-Induced Senescence.” This article describes how the Salk team took advantage of knowledge about the circadian clock and how it is used to regulate nutrient processing in healthy cells. The most relevant knowledge concerned REV-ERBα and REV-ERBβ, nuclear hormone receptors that are also known as NR1D1 and NR1D2, respectively.

“Here we show that two agonists of REV-ERBs—SR9009 and SR9011—are specifically lethal to cancer cells and oncogene-induced senescent cells, including melanocytic naevi, and have no effect on the viability of normal cells or tissues,” wrote the article’s authors. “The anticancer activity of SR9009 and SR9011 affects a number of oncogenic drivers (such as HRAS, BRAF, PIK3CA and others) and persists in the absence of p53 and under hypoxic conditions….Notably, the selective anticancer properties of these REV-ERB agonists impair glioblastoma growth in vivo and improve survival without causing overt toxicity in mice.”

“While current cancer research was investigating established cancer hallmarks/characteristics, we decided to explore something completely new,” noted research associate Gabriele Sulli, Ph.D., the paper’s first and co-corresponding author. “Given the importance of the circadian clock in the regulation of many cellular and physiological processes, we hypothesize that targeting the circadian clock with drugs may open the way to novel anticancer strategies. This study is very exciting because it shed light on a new uncharacterized way to treat cancer with very limited toxicity.”

Added Prof. Panda, “We’ve always thought about ways to stop cancer cells from dividing. But once they divide, they also have to grow before they can divide again, and to grow they need all these raw materials that are normally in short supply. So, cancer cells devise strategies to escape the daily constraints of the circadian clock.”

Although cancer cells contain REV-ERB proteins, somehow they remain inactive. Prof. Panda’s team used two REV-ERB activators that had already been developed—SR9009 and SR9011—in studies on a variety of cancer cells, including those from T-cell leukemia, breast cancer, colorectal cancer, melanoma, and glioblastoma. In each cell line, treatment with the REV-ERB activators was enough to kill the cells. The same treatment on healthy cells had no effect.

“Activating REV-ERBs seemed to work in all the types of cancer we tried,” remarked Prof. Panda. “That makes sense because irrespective of where or how a cancer started, all cancer cells need more nutrients and more recycled materials to build new cells.”

Prof. Panda then went on to test the drugs on a new mouse model of glioblastoma recently developed by Inder Verma, Ph.D., a professor in the Salk Institute’s laboratory of genetics. Once again, the REV-ERB activators were successful at killing cancer cells and stopping tumor growth, but seemed not to affect the rest of the mice’s cells. Verma says the findings are not only exciting because they point toward existing REV-ERB activators as potential cancer drugs, but also because they help shine light on the importance of the link between the circadian cycle, metabolism, and cancer.

“These are all fundamental elements required by all living cells,” explained Prof. Verma. “By affecting REV-ERBs, you get to the heart of how cells grow and proliferate, but there are lots of other ways to get at this as well.”

Prof. Verma says his group is planning follow-up studies on how, exactly, the REV-ERB activators alter metabolism, as well as whether they may affect the metabolism of bacteria in the microbiome, the collection of microbes that live in the gut. Prof. Panda’s team is hoping to study the role of other circadian cycle genes and proteins in cancer.