VU researchers develop nanobodies targeting a viral chemokine receptor to impair glioblastoma growth

In a recent publication in Oncogene, Medicinal Chemistry researchers Raimond Heukers, Tian Shu Fan, Raymond de Wit and colleagues under supervision of Martine Smit (STW, Vici project) reveal the implications of a virally-encoded receptor in the acceleration of glioblastoma growth and provide a means to inhibit this activity using nanobodies targeting this receptor.

05/04/2018 | 1:24 PM

Glioblastoma is the most common high grade primary brain tumor in adults. With a median survival of only 12 months, there is an increasing need for new insights and therapies to treat this type of cancer.

Viral chemokine receptor US28 in cancer
Human herpesviruses are widely prevalent but are also implicated in the pathogenesis of several diseases, including glioblastoma. Human cytomegalovirus (HCMV), like some other herpesviruses, expresses virally-encoded G protein-coupled receptors (GPCRs), which share great homology to human chemokine receptors.

The HCMV-encoded chemokine receptor US28, shown earlier to constitutively activate inflammatory and proliferative signaling pathways, was detected in glioblastoma tissue. In this study, the authors found that the expression and constitutive activity of the viral chemokine receptor US28 drastically enhances glioblastoma tumor growth in in vitro and in animal models.

Nanobodies as diagnostics and modulators of US28
To enable the detection of US28 in glioblastoma and to inhibit its constitutive activity, the authors generated nanobodies, llama-derived antibody fragments, against the extracellular domains of this receptor. These nanobodies appear ideal tools to bind and modulate GPCR function. The generated nanobodies detected the presence of US28 in animal and patient material, and impaired the activity of the receptor, thereby inhibiting glioblastoma tumor growth.

The findings on the contribution of HCMV-encoded US28 in glioblastoma and the inhibitory potential of nanobodies provide new insights and opportunities to battle this devastating disease. Based on the encouraging findings presented in this study a patent on US28-targeting nanobodies was filed in collaboration with IXA.

Nanobodies glioblastoma