A new study recently published in the journal EMBO Molecular Medicine revealed promising results on a therapeutic small molecule named RK-33 for lung cancer treatment. The study is entitled “Targeting DDX3 with a small molecule inhibitor for lung cancer therapy” and was developed by researchers at the Johns Hopkins Medicine and the University of Maryland in the United States and at the University Medical Center Utrecht, The Netherlands.
Lung cancer is the number one cause of cancer deaths in the United States, with cigarette smoking accounting for the main risk factor for lung cancer development.
Researchers now propose a new therapy for lung cancer. The team has developed a first-in-class molecule called RK-33 that is able to interrupt the cell cycle of lung cancer cells without affecting healthy cells. RK-33 binds to DDX3, a helicase which is involved in protein synthesis, DNA repair and cell cycle progression. DDX3 is known to be overexpressed in several cancer types including lung cancer, where it is associated to lower patient survival rates.
Researchers identified DDX3 when analyzing gene expression in normal breast cells exposed to cigarette smoke. DDX3 mRNA levels were found to be only slightly increased in the exposed breast cells, on the other hand, its protein levels were found to be significantly higher. “We were pleasantly surprised by this finding,” said the study’s senior author Dr. Venu Raman in a news release, “because it’s not just finding a biomarker that matters. The key part is finding a biomarker that is druggable.”
In order to test the druggability of DDX3, researchers designed a small inhibitor molecule that they called RK-33. This molecule was, however, only obtained after several attempts. “It is a lot of intelligent planning and hard work, but we have to get lucky too,” noted Dr. Raman, “because the risk of it not working — using rational drug design — is reasonably high.”
The binding of RK-33 to DDX3 was found to reduce the amount of DDX3 available, and consequently caused cell cycle arrest and induced the death of cancer cells. RK-33 can be used on its own or in combination with radiation therapy, where it potentiates the effects of this therapy through the damage it induces to DNA. The team found that the combination of RK-33 and radiation therapy in mice models of lung cancer induced tumor regression.
“It is hard to find a magic bullet for cancer treatment,” said Dr. Raman, “but because RK-33 is nontoxic and is a phenomenal radiosensitizer, there are so many opportunities.” The team has mainly focused on lung cancer, but studies on RK-33 are being conducted in several cancer types like sarcoma, breast, prostate and colorectal cancers. “DDX3 is an extremely novel target associated with many cancer types, and perturbing its function with a small molecule will enhance efficacy for cancer treatment.” concluded Dr. Raman.
RK-33 has been awarded patents in the United States and several international markets for its composition and use as a radiosensitizer. The team’s goal is to overcome the technical challenge of proper drug delivery and complete the experiments required to file for an Investigational New Drug Application with the U.S. Food and Drug Administration (FDA) so that clinical trials can be initiated.
