Whereas traditional chemotherapy aims to kill all rapidly dividing cells, the new compound directly targets cellular machinery that enables solid tumors to spread. WX-UK1 "primarily inhibits uPA," says Olaf Wilhelm, MD, CEO of Wilex, but it also inhibits "other serine proteases which affect tumor progression and metastasis." As a serine kinase, uPA stimulates the conversion of plasminogen to plasmin, which in turn breaks down extracellular matrix proteins. Disrupting the matrix allows tumor cells to invade neighboring tissue or to move into the bloodstream. Inhibiting metastasis should be particularly effective for breast cancer, says Wilhelm, because "breast cancer patients don't die from the [primary] tumor."
Past studies have shown that levels of uPA and the natural inhibitor PAI-1 predict recurrence of breast cancer after surgery. "I think it's safe to say it's the best validated prognostic factor," says professor M. Joseph Duffy of St. Vincent's Hospital, affiliated with University College Dublin, Ireland, who has been studying the uPA system for about 20 years. Duffy says seeing the research evolve from a prognostic test to a possible treatment is "very exciting." He says that the uPA system, through more complex interactions, also plays a role in tumor cell growth and angiogenesis.
Wilhelm says he is confident that there is a therapeutic window in which side effects of this targeted therapy are acceptable, based on preclinical trials. "I'm sure at some very high dose we'll naturally see some side effects," he says. But he adds that none have been found so far in ongoing clinical trials of WX-UK1 in Europe.
In addition to their role in cancer, serine proteases are involved in clot formation and dissolution. However, Wilhelm says the inhibition effect of WX-UK1 depends on enzymes that are not usually active in plasma, but which are activated in tumors during tumor invasion and progression.
This phase I trial will determine the dose for WX-UK1 in conjunction with a traditional chemotherapeutic agent, capecitabine (Xeloda). Wilhelm says that Wilex had well-established contacts and interactions with The Fox Chase Cancer Center even before the award from the Department of Defense.