Thursday, March 9, 2017
Bottom Line: Leptomeningeal metastasis, cancer that has spread to the areas surrounding the brain and spinal cord, has long been a formidable clinical challenge for oncologists. Researchers at Memorial Sloan Kettering Cancer Center (MSK) have identified the molecular basis of this increasingly prevalent complication of cancer. With the help of a mouse model, researchers have identified a drug strategy that may combat this virtually untreatable condition.
Journal: “Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis” will run in the March 9 issue of Cell.
Authors: The study was led by Joan Massagué, PhD, Director of the Sloan Kettering Institute at MSK. The first author, Adrienne Boire, MD, PhD, is a neuro-oncologist at MSK. Additional authors include Yilong Zou, Jason Shieh, and Danilo G. Macalinao of the Cancer Biology and Genetics Program at MSK and Elena Pentsova, MD, of the Department of Neurology at MSK.
Background: The leptomeninges are the spaces that surround the brain and spinal cord and contain the cerebrospinal fluid (CSF). Metastases to the leptomeninges are one of the most difficult types of metastatic tumors to treat. The incidence of leptomeningeal metastasis — which currently occurs in 5 to 10 percent of patients with solid tumors — is increasing because patients are living longer after treatment of their primary tumors, and because there are more treatment options for other metastatic sites. Leptomeningeal metastases most commonly spread from lung, breast, and melanoma tumors.
Untreated, patients succumb to leptomeningeal tumor burden six to eight weeks after diagnosis. Current treatments include radiation therapy and chemotherapy, but neither is very effective. Little has been known about how cancer cells cross the blood-CSF barrier and how they are able to grow once they invade the leptomeninges, an environment that offers few nutrients to support cancer cell growth. Additionally, the blood-CSF barrier protects the leptomeningeal space from both chemotherapy and the body’s immune system, creating a “safe space” for the cancer cells to thrive.
Findings: After implanting cell lines of breast and lung cancers into mice, researchers sorted out those that were able to colonize the CSF and noted that they all had in common a protein that was already well known: complement component 3 (C3), which plays a role in the body’s response to infections. The researchers showed that the primary lung and breast tumors that had elevated C3 expression were able to grow in the CSF. The cells employed C3 to disrupt the blood-CSF barrier and allow growth factors and other components to cross it, creating an environment for cancer cells to grow.
Based on these findings, the researchers identified a compound targeting the C3a receptor (which was originally developed to treat asthma but ultimately proved unsuccessful against that disease). In mice, the drug successfully suppressed leptomeningeal metastasis and slowed disease progression. In addition, it is possible that pharmacologic interference could compromise the blood-CSF barrier and allow improved access of systemic chemotherapy into the CSF. The researchers concluded that these findings warrant additional preclinical studies.
Author Comments: “When cancer gets into this space, it’s devastating for the patient,” explained Dr. Boire. “In the past, leptomeningeal metastasis was seen as the end stage of cancer. But as other treatments have improved survival, leptomeningeal metastasis has become a clinical problem that we need to learn how to address. This work not only provides valuable insights into the molecular basis of leptomeningeal metastasis, it also raises a plethora of questions about how we can exploit this pathway and create possible treatment options where there currently aren’t any.”
Method: MSK researchers created the first preclinical mouse models of leptomeningeal metastasis using tumors from breast and lung cancer patients. They also studied spinal fluid from patients with metastases to the CSF. Further studies are warranted to confirm the mice findings in humans.