Researchers from the National Cancer Institute have discovered a new way by which breast cancer cells lie dormant after spreading, before starting to grow again, causing metastatic disease.
The study published today in the journal Nature Communications uses a mouse model of breast cancer to show how cells that spread to the lungs can remain dormant before starting to divide again, forming metastatic tumors, which are often incredibly hard to treat. Whilst in this dormant state, the research reveals that the breast cancer cells use a process called autophagy to survive, which essentially means they can break down worn-out cell components that might ultimately limit their ability to divide and grow into tumors, replacing these with recycled parts.
"We wanted to ask if we could reduce the number of cells that are dormant and potentially reduce metastasis in these people. We were not studying autophagy before this, but during the course of our research we discovered that it plays a role in dormancy," said Dr. Kent Hunter, leader of the study and Senior Investigator in the Laboratory of Cancer Biology and Genetics at the National Cancer Institute in Maryland.
The team used mouse breast cancer cell lines, one of which spreads to the lungs and remains dormant before eventually causing tumors. By blocking autophagy using both genetic intervention and also using a drug called hydroxychloroquine, which is FDA-approved for the treatment of malaria, lupus and rheumatoid arthritis. The researchers found they were able to block the ability of these metastatic breast cancer cells to form tumors after dormancy. Blocking autophagy led to the accumulation of damaged mitochondria and oxidative stress in the cells, resulting in cell death.
Ninety percent of breast cancer deaths are due not to the original tumors in the breast, but due to these cancer cells spreading to form metastases in distant sites in the body, such as the bones or lungs.
"This is an important paper as it shed light on the process by which breast cancers recur, essentially by enabling cells that leave the tumor in the breast to go to other areas to “hibernate” or enter a dormant phase," said Angela DeMichele, MD, Professor of Medicine and Epidemiology at Perelman School of Medicine, University of Pennsylvania.
These tumor cells which spread to other parts of the body often don’t start to grow immediately. They remain dormant for months, sometimes years and are very difficult to detect clinically, as they may just be a single cell.
"Understanding the way in which these cells escape the breast, remain viable, evading the adjuvant treatments we give and how we might eradicate them, will provide a whole new way for patients to do active monitoring for these cells and be proactive in pursuing treatments that can eliminate the cells before they can become incurable metastatic disease," said DeMichele.
However when the metastatic breast cancer cells had already started to grow and form tumors, blocking autophagy had very little impact meaning that there may be a tight window of opportunity as to when such a therapy might be useful.
"A clinical trial to see whether this is useful in humans would be an eventual aim, but I think it would be helpful to have a little more experimental validation first," said Hunter, adding that there are more drugs to try that could potentially block autophagy and that it was important to select the drug with the best efficacy and minimal toxicity.
Hunter adds that the first author of the paper Dr. Vera-Ramirez will be continuing her research by setting up a new lab in Spain.
In fact, DeMichele is already part of a team running a clinical trial which uses hydroxychloroquine, Novartis's afinitor or a combination of both in women who have been identified to be at an especially high risk of recurrence. A second trial using hydroxychloroquine with or without Pfizer's gedatolisib should be recruiting within the next few months.
"These trials are so important because currently there is no established treatment that targets these cells. The standard of care is watchful waiting, which is very anxiety provoking for patients who want to be proactive," said DeMichele.
This is exciting preliminary research, all the more so because it uses a drug which is already FDA-approved for other conditions, but it needs to be proven that these results from mice will be similar in humans. The trials led by DeMichele, along with the research from Hunter and others helping to understand exactly how these drugs are likely to work, should help answer these questions.
