A breakthrough study led by the US National Institutes of Health has identified the mechanism by which breast cancer cells that have migrated away from the original tumor are able to slip into a dormant state, reactivating years to decades later with lethal tenacity.
Writing in Nature Communications, the authors detail how a series of experiments in mice and human cell lines confirmed the long-held suspicion that metastasized breast cancer cells go into an energy-conserving state known as autophagy in response to the stress of colonizing a new part of the body.
And most promisingly, subsequent tests showed that several known autophagy inhibitors greatly reduced the survival of dormant cancer cells, thus paving the way for the development of new treatment methods that may prevent recurrent metastatic breast cancer – a disease that is much more aggressive than primary breast cancer currently estimated to kill 460,000 women worldwide per year.
"Many of the traditional anti-cancer drugs are designed to target dividing cells," co-author Kent Hunter said in a statement.
"Dormant cells, however, are not actively or frequently dividing, and are therefore thought to be resistant to these types of drugs," he added on why it's challenging to treat recurrent breast cancer.
Using a live-mouse model that mimicked metastasis of dormant breast cancer cells to the lungs, the authors first evaluated a chemical autophagy inhibitor, the anti-malarial drug hydroxychloroquine (HCQ). Mice that received HCQ showed 36 times fewer metastatic cells compared with control-treated mice.
In subsequent experiments assessing genetic manipulation of autophagy, blocking expression of a gene called ATG7 resulted in a two-fold decrease in lung tumor cell count.
Both types of inhibition induce cell death by blocking their ability to clear away accumulating toxic metabolic by-products and break down damaged mitochondria.
Unfortunately, the study found that cancer cells are no longer affected by autophagy inhibition pretty much immediately after they transition into a proliferative (aka actively replicating) state and/or become sufficiently adapted to their new environment – switches that are quite difficult to observe within a human patient.
Furthermore, the authors note that any dormant cells remaining after autophagy inhibition – and essentially no treatments are 100 percent effective – will eventually switch.
As such, the investigators conclude that autophagy inhibiting therapies are best suited to be administered alongside therapies for primary breast cancer tumors, creating a one-two punch combination treatment that kills active cells and prevents future recurrence by eliminating cells that are entering autophagy.
If a patient has already been treated for a primary tumor, taking an autophagy inhibitor could reduce the dormant cell population, ultimately improving the patient’s chance of survival.
However, as exciting as this all sounds, Hunter emphasizes that many phases of clinical testing, any of which could fail, lay between this study and a human treatment. It is also unknown if the approach will work for other cancer types.
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