While there are effective treatments for many forms of cancer, once cancer has metastasized it is very difficult to treat. In general, if cancer is detected early when a small tumor has formed and the cancer has not spread, the cancer can be treated and patients will survive. However, if cancer is detected after it has spread to another location, treatment will not be effective and patients will die. It is the movement of the cancer that is the difference between life and death.
One of the main goals of cancer research is to identify drugs that can prevent cancers from metastasizing. While compounds have been identified that reduce cancer cell motility, they are highly toxic or have other biological effects making them unsuitable for use in humans.
Researchers at Northwestern University, Chicago, and Oregon Health & Science University (OHSU) believe they have found a compound that specifically inhibits cell motility and metastasis. Further, the drug appears not to have any toxicity and causes no major side effects.
The researchers first attempted to find a compound that would stop cancer cells from moving, and once a suitable compound was identified, it was further refined to achieve that action without causing side effects. That compound is KBU2046, a small-molecule drug that can be administered orally.
Previous in vitro studies conducted by the researchers had shown 4′,5,7-trihydroxyisoflavone (genistein) inhibits motility in human prostate cancer and prevents metastasis in a mouse model of the disease. However, genistein is not specific and has other biological effects making it unsuitable for use as a treatment to prevent metastasis.
Genistein was however a good starting point. Various structural modifications were made and compounds that exhibited estrogenic effects, like genistein, or had other off-target effects were discarded. KBU2046 was identified as having no off-target effects but was as effective as genistein at inhibiting metastasis of prostate, breast, colon, and lung cancer cells.
In mice with induced cancer, the compound inhibited metastasis by up to 92%, reduced bone destruction, and greatly improved survival rates.
Studies of the method of action showed the compound decreased phosphorylation of the heat shock protein HSP90β, resulting in selective inhibition of cancer cell motility. In contrast to other HSP90 inhibitors, which impact on cellular kinases and are cytotoxic, there was no effect on kinase function and KBU2046 demonstrated no toxicity.
“KBU2046 binds to a cleft that is formed when HSP90β and CDC37 bind to form a heterocomplex,” wrote the researchers, “This in turn affects the ability of the hetercomplex to bind client kinase proteins in a very precise manner, selectively affecting those that regulate cell motility.”
The aim is to develop a pill that can be provided to a patient with cancer that will prevent that cancer from spreading. “This drug is highly effective against four cancer types (breast, colon, lung, prostate) in the in vitro model so far. Our goal is to move this forward as a therapy to test in humans,” said senior researcher Dr. Raymond Bergan, division chief of hematology and medical oncology and professor of medicine at OHSU.
The research is detailed in the paper – Precision therapeutic targeting of human cancer cell motility – which was published in Nature Communications 9, Article number: 2454 (2018).