Endothelin-A receptor antagonist drugs have only limited efficacy against bladder cancer. They block the start of cancer spread to other organs, but they cannot be used in the treatment of large, established primary-or distant-site tumors, it has been shown.
Bladder cancer is the fifth most common cancer in the United States. It will kill about 14,000 Americans this year, most of whom will die as a result of the disease's spread to other organs as a result of metastasis.
Various options are tried against the cancer, but only with limited success.
Endothelin-A receptor antagonist drugs are one such option.
They block the action of a protein called endothelin 1 [ET-1], thought to be involved in stimulating cancer cell growth and spread. In their research at University of Colorado Cancer Center , its director Dan Theodorescu and colleagues discovered that ET-1 attracts immune cells called macrophages to cancer cells lodged in the lungs. The macrophages start making factors that stimulate the cancer cells in the lungs to grow — called metastatic colonization — which significantly decreases the patient's chance of survival.
"We discovered that these drugs block the 'tumor host interactions' found at sites of metastasis, which is what reduces tumor growth at these sites," said Dan Theodorescu, the leader of the new study and professor of surgery and pharmacology at the University of Colorado School of Medicine. "However, unless the drugs are used early, they have minimal or no effect."
In the past decade, two endothelin-A receptor antagonist drugs — Abbott's atrasentan and AstraZeneca's zibotentan — have had difficulties in large phase 3 clinical trials. Both drugs were tested in a large number of patients with advanced cancer, and neither drug attained its desired effects. Most likely, Theodorescu said, the drugs were given after the window of opportunity for them to work had closed.
"Had we known this before the trials, we wouldn't have used them to try to reduce large, established tumors," he said. "We would have used them to try to suppress the appearance of metastasis. This new information has important implications for how we test drugs for effectiveness before human use and then on how we select patients in clinical trials with these agents, especially since many types of cancer secrete ET-1."