A dream solution to cancer metastasis has been to develop a method that can track and kill the cancer cells that are on the move. The complexity at which those cancer cells operate– they not only move around but they fly under the radar of the immune system – has long been a formidable obstacle to stopping metastases, which cause 90 percent of cancer deaths.
But that may change with the work being done in the labs of Michael King, a professor of biomedical engineering at Cornell University, Ithaca, N.Y.
King has developed ‘sticky balls,’ which are nanoscale liposomes that quickly attach themselves to the surface of circulating white blood cells (leukocytes). These leukocytes become poisonous to cancer cells upon contact.
“These circulating cancer cells are doomed,” says King. “We have found a way to dispatch an army of killer white blood cells that cause apoptosis– the cancer cell’s own death – obliterating them from the bloodstream. When surrounded by these guys, it becomes nearly impossible for the cancer cell to escape.”
“Our work represents an entirely new approach to target and kill metastatic cells in the bloodstream,” he adds. “The potential impact is significant. If we can successfully use this to eliminate viable tumor cells from the circulation thereby preventing the formation of new blood borne metastases, it could save thousands or even millions of lives.”
King and his associates reported results of their latest work in the Jan. 6, 2014 issue of the Proceedings of the National Academy of Sciences in “TRAIL-coated leukocytes that kill cancer cells in circulation.”
Metastasis is the spread of a cancer cells from the primary tumor to other parts of the body. Surgery and radiation are effective at treating primary tumors, but difficulty in detecting metastatic cancer cells has made treatment of the spreading cancer problematic.
In their work, King and his colleagues injected human blood samples, and later mice, with two proteins: E-selectin (an adhesive) and TRAIL (Tumor Necrosis Factor Related Apoptosis-Inducing Ligand). The TRAIL protein joined together with the E-selectin protein stick to leukocytes, which are ubiquitous in the bloodstream. When a cancer cell comes into contact with TRAIL, the cancer cell essentially kills itself.
“Any cancer cells that enter the bloodstream just need to bump into one of these ‘unnatural killer cells’ and the cancer cell will die soon afterwards,” King says. “The collisions between cancer cells and leukocytes are actually unavoidable because circulating cancer cells will find themselves surrounded by leukocytes due to sheer numbers. The nanoparticles do not harm normal cells, but when they bump into cancer cells the cancer cells commit suicide soon afterwards.”
The sticky ball work grew out of a project King and his Ph.D. student, Kuldeep Rana, started in 2005. They were trying to filter out cancer cells from the bloodstream using a medical device coated with E-selectin and TRAIL that existed outside the body.
“Around 2009 we decided to flip the geometry around and put these two proteins on the surface of nanoscale liposomes that could be injected into the bloodstream,” King says. “When we saw that the therapy worked much better killing cancer cells within whole blood, under flow, than trying to kill isolated cancer cells in a test tube (the ideal setting for most therapeutics), we knew we had discovered something remarkable.”
In the current work, King says laboratory tests showed a 60 percent success rate in killing cancer cells with the proteins in saline. In later tests, where the proteins were added to flowing blood– which models forces, mixing and other real human-body conditions– the success rate in killing the cancer cells jumped to nearly 100 percent. He added that his group is working with a prostate cancer model, breast cancer and soon we will start work on metastatic lung cancer as well.
“We have performed tests in live mice, showing that nearly all cancer cells introduced into the mouse blood are killed by the particles within two hours,” King says. “We are currently running more extended mouse trials, which will hopefully enable human trials in a few years.”
“A spinoff project that we have been working on involves altering the liposomes so that they just attach to natural killer cells,” King adds. “These cells go into the lymphatic system and the lymph nodes, so we will have a treatment option to target lymph node metastases, in addition to the therapeutics designed to treat blood borne metastasis.”