Prof. Ronit Sacchi-Painero identified two key proteins – CCL2 and P-Selectin – involved in cancer cell entry into the brain. Blocking either axis significantly reduced metastatic burden in mouse models and “brain-on-a-chip” systems, providing a lifeline for terminally ill patients.
“Brain metastases are a major therapeutic challenge in metastatic cancer. In advanced stages of melanoma, breast cancer, and lung cancer, approximately 70%-90% of patients develop brain metastases, which significantly shortens life expectancy and necessitates preventive solutions,” says Prof. Ronit Sacchi-Painero, Dean of the Grey School of Medical Sciences and Director of the Cancer Biology Research Center at Tel Aviv University. Prof. Sacchi-Painero presented key insights into the molecular processes that enable cancer cells to penetrate the blood-brain barrier (BBB), localize in the brain, and spread, which were obtained in her research with the help of grants from the National Science Foundation.
The blood-brain barrier is a multilayered system: endothelial cells in the blood vessel wall form tight tubes, which are surrounded by astrocytes, pericytes, and microglia that support the structure and cerebrospinal fluid. The combination creates a barrier that makes it difficult for foreign cells, including tumor cells, to penetrate. However, in her studies, Prof. Sacchi-Painero discovered that in the environment of metastases, astrocytes “wake up” and secrete the protein CCL2 at levels much higher than normal. This increase in CCL2 causes a decrease in the stability of the tight junctions in the endothelium and the creation of temporary pores that allow cancer cells to penetrate.
What is the question?
What molecular mechanisms allow cancer cells to cross the blood-brain barrier, and can blocking these pathways prevent or significantly reduce the colonization and growth of brain metastases?
To verify this role, experiments were conducted in two main platforms. First, human melanoma cells were transplanted into a mouse model. Treatment with an antibody to the CCR4 receptor – through which cancer cells “respond” to CCL2 – reduced the number of metastases by approximately 87% and improved survival in the model by 60%. The use of MRI and bioluminescence imaging allowed for precise monitoring of the metastatic burden over time.
Second, the group developed a “Brain-on-Chip” system, a microfluidic chip containing human endothelial cells, astrocytes, and microglia, connected to an electrode array that simulates brain activity. CCL2 inhibition resulted in a 90% reduction in the levels of the inflammatory cytokines IL-1β and TNF-α secreted by microglia, and inhibited the passage of cancer cells through the microfluidic channels.
In addition to the CCL2–CCR4 mechanism, Prof. Sacchi-Painero is investigating the importance of a second axis: P-Selectin and PSGL-1 (P-Selectin Ligand-1). Analysis of microglia from clinical samples of aggressive brain cancer glioblastoma and brain metastases from melanoma, breast cancer and lung cancer revealed a measurable increase in P-Selectin levels, which enhance survival signaling and tumor cell proliferation. In a mouse model, treatment with an antibody against P-Selectin reduced brain tumor volume by 70% after three weeks.
Using these pathways may open a way for preventive treatment of brain metastases, and contribute to improving survival and quality of life for patients with advanced metastatic cancer.
Successful combination
The key step in the study was the combination of two axis blockers in parallel: an antibody to CCR4 with an antibody to P-Selectin. In this combined model, an almost complete reduction in metastases and an even more significant extension of survival were observed compared to single treatment.
At the same time, a correlation between CCL2 and P-Selectin concentrations in cerebrospinal fluid (CSF) and the burden of brain metastases was demonstrated, so that these biomarkers can be used for early diagnosis and therapeutic monitoring.
Based on the experimental results, a Phase I/II clinical trial has begun at Sheba Hospital. The trial is testing the safety and efficacy of the antibody treatment in approximately 10 patients with brain metastases and 20 glioblastoma patients with tumor monitoring by MRI.
The findings from Prof. Sacchi-Painero's lab highlight two complementary therapeutic strategies: precise inhibition of the CCL2–CCR2 and P-Selectin axes and biomarker monitoring to prevent tumor recurrence after resection or radiation. Using these pathways may open a path to preventive treatment of brain metastases, and contribute to improving survival and quality of life in patients with advanced metastatic cancer.
The doctoral students who participated in the fruitful research were Dr. Eilam Yeni, Dr. Sabina Foci, Dr. Sahar Israeli Dangor, Koren Salomon, and Eden Miari.
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