Two drugs have been found to protect bones against cancerous cells originating from breast tumors, potentially providing lines of defense against the spread of the disease.
Hormone positive breast cancers are notorious for their capacity to return when they appear to have been eliminated from the body. The lethal cells are suspected of using a bone to recover their former strength, in this case hiding in the marrow while chemotherapy cleanses the body of all the cancer cells it can find.
In Science Translational Medicine, Duke University's Dr. Dorothy Sipkins reports on promising signs from two drugs that might defeat this curse, one by preventing cancers from getting into the bone in the first place, the other by forcing those that get inside to leave and face the chemotherapeutic treatment.
"Clinical studies have found that breast cancer can be caught early and treated, and patients can have no signs of disease," Sipkins said in a statement. "And then five, 10 or even 15 years later, a patient can relapse. Most often, the site of the metastasized cancer is in the bone."
Sipkins used fluorescence microscopy to observe the way breast cancer cells (BCCs) enter mouse bones, finding that the BCCs have a surface molecule they use as a key. The lock is a molecule called E-selectin, which is present in bone marrow blood vessels.
"Now we know how they are getting in," Sipkins said."We also identified an important mechanism that allows them to remain anchored in the bone marrow.”
The path by which breast cancer cells enter bone marrow has been revealed. Alisa Weigandt for Duke Health
Ideally, oncologists could prevent the cancer cells from entering the bone, something Sipkins says could be done by inhibiting E-selectin. The drug GMI-1271 is already in clinical trials as an E-selectin inhibitor, and Sipkins showed that in mice it can prevent breast cancer cells reaching bone marrow.
Unfortunately, hormone positive breast cancers are so dangerous because they metastasize early in their development, often before they have been detected, reaching bone marrow before treatment has started.
To combat what is bred in the bone while the BCCs are hiding, Sipkins tried another approach, using the drug plerixafor to fight the cancers sucking on the marrow of life. Plerixafor (AMD3100) is used to make bone marrow expel stem cells so they can be harvested for donation. Sipkins found it also works to interfere with CXCR4, the receptors that tether BCCs to bone marrow once inside. Plerixafor then forces BCCs out of the bone and into the bloodstream where chemotherapy drugs should be able to clean them up.
Sipkins indicated more work is required before human trials could be justified. In particular, there is a danger that forcing dormant BCCs from their hiding place might activate them in the process. However, the fact that Plerixafor has already been approved for other uses, and is considered “minimally toxic,” GMI-1271 is being trialed as an adjunct to chemotherapy. Consequently, if either drug shows further promise, approval should be quicker and cheaper than for a completely new medication.
Breast cancer cells are so dangerous because they are so effective at hiding in bone marrow. David Litman/Shutterstock
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