by Yale University
In a new study led by Yale Cancer Center,
researchers show the nucleoside transporter ENT2 may offer an unexpected path
to circumventing the blood-brain barrier (BBB) and enabling targeted treatment
of brain tumors with a cell-penetrating anti-DNA autoantibody. The study was
published today online in the Journal of Clinical Investigation Insight.
"These findings are very encouraging
as the BBB prevents most antibodies from penetrating the central nervous system
and limits conventional antibody-based approaches to brain tumors," said
James E. Hansen, MD, associate professor of therapeutic radiology, radiation
oncology chief of the Yale Gamma Knife Center at Smilow Cancer Hospital, and
corresponding author of the study.
Deoxymab-1 (DX1) is an unusual
cell-penetrating autoantibody that localizes into live cell nuclei, inhibits
DNA repair, and is synthetically lethal to cancer cells with defects in the DNA
damage response (DDR). Researchers have now found that the transporter ENT2
facilitates brain endothelial cell penetration and BBB transport by DX1. In
efficacy studies in mice models, DX1 crossed the BBB to suppress orthotopic
glioblastoma and breast cancer brain metastases.
"Our data demonstrate the ability of
DX1 to cross the BBB and suppress brain tumors in multiple models, and we are
particularly impressed that DX1 was able to yield these results as a single agent
in these difficult to treat tumor models," said Jiangbing Zhou, associate
professor of neurosurgery at Yale School of Medicine and co-corresponding
author of the study.
"We believe that the ENT2-linked
mechanism that transports DX1 across the BBB and into tumors has potential to
contribute to multiple new strategies in brain tumor therapy," added
Hansen. "In addition to establishing proof of concept for single agent use
of DX1 in brain tumor models, we also now recognize the potential for DX1 to
target linked cargo molecules to brain tumors or to be useful as a platform for
designing additional brain tumor targeting antibodies, including DX1-based
bispecific antibodies."