Two Nickels Are Worth a Dime, and Sometimes More: Proteasome Inhibitors for GVHD

In this paper, Vodanovic-Jankovic and colleagues show that the proteasome inhibitors bortezomib and PS-1145 can block the induction of graft-versus-host disease (GVHD) in mice. Although PS-1145 is the less powerful proteasome inhibitor of the two drugs, it is more effective because it has fewer systemic side effects, likely reflecting its narrower specificity of activity. The impact of thalidomide and bortezomib in multiple myeloma has led to a new interest among experimental hematologists in understanding the biology of the 26S proteasome and a surge of curiosity among clinical researchers about the full potential of proteasome inhibitors as drugs for common hematologic disorders. Proteasome inhibitors block the degradation of intracellular "molecular breaks," such as IκBα, which leads to decreased activity of their molecular targets, such as NF-kB. This leads to blunted activation of downstream genes, and so cellular activity is depressed. Although the therapeutic efficacy of proteasome blockade first made its mark in the treatment of multiple myeloma, in theory any pathophysiologic process with overactive cell activation could be potentially targeted.

Since GVHD is fundamentally characterized by donor T cell activation and proliferation, Vodanovic-Jankovic et al. first asked whether bortezomib could block GVHD in mice irradiated and transplanted with bone marrow (BM) cells and lymphocytes from completely unrelated donors, mismatched at the major histocompatibility locus. The answer was "yes, but only partially, only if it is given in a very narrow dose range, and only if given for a short period of time, less than 10 days." Otherwise the mice suffered severe GVHD as well as an unusual colitis, and mortality was actually increased. Rather than throw in the towel on proteasome inhibitors for GVHD, the authors wondered whether the toxicity of bortezomib might be due not to its potent proteasome inhibitory ability, but rather to its diverse other mechanisms of action, such as mitochondrial inhibition. They reasoned that a purer proteasome inhibitor might be safer and more effective, even if one had to give higher doses for longer periods of time. Using the same mismatched mouse BMT model, the authors found that PS-1145, a slightly weaker inhibitor of T cell activation overall but a more selective proteasome inhibitor, was extraordinarily effective at preventing lethal GVHD if given from day 0-10, without the side effects seen with bortezomib. Thus, pulse prophylaxis with PS-1145 is an attractive candidate for the prevention of GVHD in the clinic.

These results teach two broader lessons for pre-clinical and clinical pharmacology in hematology. First, proteasome inhibitors may have a future as anti-immune drugs in many diseases. And second, the best drugs are the ones with the most specific and limited molecular targets, even if one needs to give higher doses of the drug to inhibit its target receptor. After all, broad activities mean more side effects, and, as we all know, two nickels are worth a dime.