PARP inhibitors may offer the first really targeted therapy for CLL.
Although monoclonal antibodies are thought of as targeted therapies they are more like carpet bombers than laser guided missiles. Campath targets CD52 which is present on T cells, monocytes and spermatozoa as well as on B cells. It makes me think of those B52s in Afghanistan. The collateral damage is immense. Rituximab targets CD20, an antigen first known as B1. The B1 bomber is more discriminatory, but as I recall it managed to hit the TV station in Serbia and the Chinese embassy (or were these the real targets?) Compared with imatinib in CML you can’t really call it targeted therapy. The problem is that CLL is a much more heterogeneous disease than CML.
Poly-ADP-ribose polymerase (PARP) is an abundant nuclear protein that binds to a DNA single strand break and catalyses the formation of poly ADP-ribose polymers, which protect the breaks and attract DNA repair proteins to the site of damage. The process is extremely complex, but for our purposes we don’t need to know much more about it, except to say that one of the methods of repair is called homologous recombination. The broken ends of the chromosome are repaired using the information on the intact homologous chromosome. This requires searching around in the nucleus for the homolog.
Two of the proteins used in homologous recombination are encoded by the genes BRCA-1 and BRCA-2. Inherited mutations in these genes predispose women to breast and ovarian cancers. Inhibition of PARP triggers homologous recombination which is ineffective when BRCA-1 or BRCA-2 are non functional. Inhibitors of PARP have been used to kill breast cancer cells.
Now a recent paper has appeared in Nucleic Acids Research http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16556909&query_hl=48&itool=pubmed_docsum
which is likely to be of great importance for CLL patients. The authors, Helen Bryant and Thomas Heeleday from Sheffield and Stockholm, demonstrate that PARP-induced homologous recombination repair of DNA single strand breaks requires intact ATM gene function.
20% of CLLs have deletions of the ATM gene at 11q23. This variant of CLL tends to occur I younger men and is associated with enlarged lymph nodes in the abdomen. After those with del 17p13, those with del 11q23 have the worst prognosis. Several companies have their own versions of PARP inhibitors. I think it very likely that clinical trials of these agents in this variant of CLL will begin later this year.