Targeting the key bio synthetic enzymes has yielded important scientific tools and some clinical success. Difluoromethylornithine, an inhibitor of the first enzyme in kinase inhibitor JQ1 the mammalian polyamine biosynthetic pathway, ornithine decarboxy lase, is approved for use in trypanosomiasis and has shown promise in the therapy of brain tumours. It has also displayed excellent activity as a chemoprevention for colon polyps, when used in combination with sulindac. However, enzyme inhibitors of the polyamine path way have generally had limited clinical success to date. A second approach uses dysfunctional synthetic polyamine analogues to competitively inhibit natural polyamine functions. Many of the analogues synthesized to date take advantage of the self regulatory properties of the natural polyamines and significantly modulate the activity of the biosynthetic and catabolic enzymes, lowering endog enous polyamine levels.

Additionally, Inhibitors,Modulators,Libraries some of these com pounds may function as polyamine mimetics, binding to normal polyamine binding sites in the cell to attenuate normal functions. The compound utilized in this study, PG 11047, is a sec ond generation polyamine analogue of N1, N12 bisethyl spermine. PG 11047 is a conformationally restricted analogue of BESpm with a cis double bond between the central carbons. It is thought to inhibit pro liferation and other cellular functions by competing with natural polyamines. Inhibitors,Modulators,Libraries It is active against human cancer cells both in vitro and in mouse xenografts. It has shown positive results in the treatment of lymphoma in a phase I human clinical trial as well as in a phase II study for pros tate cancer.

It has thus far displayed Inhibitors,Modulators,Libraries a very benign toxicity profile and a phase I monotherapy trial is nearing comple tion. It is also in a phase 1b trial in combination with each of seven different approved drugs. For the combination of PG 11047 with docetaxel or gemcitabine maximally tolerated doses have been reached. Dose escalation of PG 11047 in combination with either bevacizumab, erlotinib, cispla tin, 5 fluorouracil or sunitinib malate is ongoing. With phase II trials emerging as the next step in the Inhibitors,Modulators,Libraries evaluation of the efficacy of PG 11047, specific pre clinical studies are being undertaken to help guide the choice of appropri ate clinical subjects. Such preclinical studies include extensive in vitro screens in order to provide an insight into the subpopulations of specific cancer Inhibitors,Modulators,Libraries types that might be amenable to treatment with PG 11047, while at the same time identifying putative molecular markers for the prediction of sensitivity pathway signaling or resistance to treatment. Breast cancers develop through multiple genetic and epi genetic changes resulting in a wide range of cancer pheno types.