A Mouse Model of Brain Metastasis of Melanomas: Characterization and Treatment

Yolanda Huang
Wellesley College

When malignant melanoma cells metastasize to the central nervous system (CNS), it is considered to be a clinical endpoint for patients with the disease. Melanomas may invade the CNS through the release of trophic factors, such as nerve growth factor (NGF), and the tumors themselves respond to NGF via p75NGF receptors. Hence, it may be possible to reduce metastatic tumor growth in the brain by administering a toxin that binds specifically to p75 receptors. Such toxins exist. Anti-mu-p75-SAPs contain a specific antibody to p75 conjugated to saporin, a ribosome-inactivating protein. When the immunotoxin binds to the p75 receptor, it is transported retrogradely back to the nucleus and eventually kills p75-expressing cells by damaging their protein synthesis machinery. One potential complication to the use of these toxins is that healthy cholinergic neurons also express p75NGF receptors. We hypothesize that melanomas express p75 at higher concentrations than normal neurons, and that we will be able to determine a dose of the anti-mu-p75-SAP that kills the invasive tumor, while sparing endogenous cholinergic cells. Our project contained two major phases: 1) to determine whether the anti-mu-p75-SAP is capable of killing melanoma cells in vitro, and 2) to develop a mouse model of brain metastasis of melanomas in which to test the toxin in vivo. Currently, we have characterized concentration/response curves for two different p75-immunotoxins on mouse B16-B15b melanoma cells in vitro. At the same time, we are developing accessories to a magnetic resonance imaging (MRI) system so that we will be able to monitor non-invasively the progression of melanoma cells injected into the lateral ventricles of mice with and without p75-immunotoxin.