Melanoma, while rare, is the most lethal of skin cancers. A difficulty in treating melanoma, as with most cancers, is that it is difficult to target therapeutics to them in a way that does not damage non-cancerous tissue. Melanomas (as well as neuroblastomas) characteristically express the disialioganglioside marker GD2 on their cell surfaces, which can be targeted by the 14.18 mouse monoclonal antibody. I intend to target a therapeutic agent, the naturally occurring protein interferon alpha 2a (IFN), to GD2-expressing cells using the chimeric activator approach pioneered by the lab of Professor Pamela Silver. The approach works by linking together a targeting element (here the 14.18 antibody) which can bind an antigen expressed on the target cell (GD2) together with a cytotoxic active element (here IFN), which has been mutated to reduce its ability to bind. Thanks to this weakened binding, the cytotoxin will have its effect only at much higher concentrations than the wild type. When the targeting element binds GD2, the linked cytotoxin is kept near the cell surface, resulting in a very high effective local concentration, allowing it to bind. Thus, the chimeric activator approach allows the cytotoxic effect to be concentrated at tumor locations, since the therapeutic will be at much lower concentration anywhere the antibody does not bind. I will approach this specificity enhancement through three avenues. First, the original chimeric activator approach, as described above. Second, a modeling and simulation approach which aims to offer insight as to the precise mechanism of increased specificity. Third, an alternate approach to reducing off-target effects where instead of mutating the IFN to weaken it I leave it bound to a weakened form of its receptor. The goal of this research is to develop an effective therapeutic for melanoma and neuroblastoma as well as to pave the the way for further therapeutics following the same approach.
The proposed research involves the development of a novel cancer therapeutic, which would have a direct effect on public health. The goal of the chimeric activator approach to cancer therapeutics is to make the drug design process largely independent of the particular targets to be used which, if proven effective, could allow new therapeutics to be created quickly. This would make it possible both to address known illnesses that have been untreated due to lack of resources and to respond to new developments.
|Robinson-Mosher, Avi; Shinar, Tamar; Silver, Pamela A et al. (2013) Dynamics simulations for engineering macromolecular interactions. Chaos 23:025110|