Jandial, Rahul; Neman, Josh; Chen, Mike Y.
Current drug treatment options for breast cancer metastasis to the brain are limited, with the development of novel agents hindered by inability to cross the blood-brain barrier (BBB) and effectively target breast cancer cells. The BBB consists of pericytes, astrocytic end-feet, and endothelial tight junctions that serve as a gatekeeper, controlling biochemical and cellular access to the brain microenvironment. Along with this role of creating a sanctuary site, the BBB also prevents effective drug delivery and sensitive tumor diagnosis—this makes both early detection and treatment difficult. Accordingly, their therapeutics must circumvent the protection that tight junctions provide in order to successfully treat central nervous system pathology. One way to improve diagnosis and treatment of brain metastasis is to make the BBB permeable. A number of approaches to transiently create permeability in the BBB have been investigated for the delivery of chemotherapeutics to brain tumors. Connell et al1 describe a new approach to selectively permeabilize the BBB at sites of brain metastases to aid in detection of micrometastases and facilitate tumor-specific access of chemotherapeutic agents and reduced off-target effects.
Connell et al suggest that one way to increase drug effectiveness in breast cancer patients with brain metastasis is to selectively target the BBB of the metastasis-associated vesicles, thereby permeabilizing the very gate that inhibited drugs from entering the brain before. The study determined TNF receptor 1 (TNFR1) is expressed on metastasis-associated endothelium but not normal brain tissue in vivo. Furthermore, TNF receptor 2 (TNFR2) was found in leukocytes within the brain metastases in vivo. Clinical relevance for TNFR1 was confirmed with biopsies from patient brain metastases. The study then aimed to target the BBB by using proinflammatory cytokine tumor necrosis factor (TNF) and its analogue lymphotoxin (LT). Both mouse 4T1 and human MDA-MB-231Br3 (MDA231Br) breast cancer cell lines were utilized to establish in vivo brain metastasis models. In vivo administration of TNF and LT resulted in a dose-dependent permeabilization of the BBB. When radiolabelled trastuzumab was administered intravenously, a significant increase of intra-cerebral drug was found at brain metastatic sites in mice treated with TNF vs control (Figure). From these results, it is suggested that TNF receptor activation, namely TNFR1, on metastasis-associated vasculature could allow effective permeabilization of BBB to allow for entry of diagnostic imaging agents or cancer treatment drugs.
Figure. Detection of...Image Tools
Although the current work shows that by manipulating the stromal cells responsible for the integrity of BBB at the site of metastases results in increased drug permeability, the study fails to mention if this leads to increased tumor cytotoxicity. A caveat for using proinflammatory cytokines to disrupt the BBB, such as TNF, is their cell-dependent synergy with Her2 signaling. Therefore, there needs to be strict scrutiny in considering that TNF permeabilization of BBB does not activate the tumor-specific Her2 signaling pathway, leading to neoplastic cell proliferation. After validating that TNF permeabilization does not potentiate Her2, future consideration for clinical trials could determine the maximum tolerated dose for TNF and LT and in combination with the drug of choice. It would be interesting to show that the selective BBB permeabilization also applies to other types of brain metastases (eg, lung, melanoma, colon). Increasing research in targeting the blood-brain barrier could ultimately improve treatment and early detection, increasing quality of life and survival for patients with brain metastases.
1. Connell JJ, Chatain G, Cornelissen B, et al.. Selective permeabilization of the blood-brain barrier at sites of metastasis. J Natl Cancer Inst. 2013;105(21):1634–1643. doi: 10.1093/jnci/djt276.