protection at a price. a genetic defense against sun damage increases the risk of testicular cancer.
Stockbyte / Thinkstock
To avoid being destroyed by our immune system, cancer cells engage in a little cunning. As they divide to form tumors, they fly under the radar of macrophages, immune cells whose job is to ingest dead cells and harmful invaders. Nowadays, many cancer patients are treated with antibody drugs that work in part by the marking of tumor cells to killing by macrophages. Although these drugs have extended the lives they do not always work very well partly because cancer cells to fight by sending a signal "do not eat me" to immune cells. Now, researchers have created a small protein that cuts the signal and increases the potency of antibody drugs to shrink tumors in mice dramatically.
stem cell biologist Irving Weissman of Stanford University in Palo Alto, California, studied a protein responsible for broadcasting the signal "do not eat me." Known as CD47, it protects the leukemia cells and other cancer cells unchained macrophages. Last year, the group reported that a Weissman antibody that blocks CD47 on cancer cells can stimulate macrophages to destroy tumors in mice. The anti-CD47 antibody will soon be tested for safety in humans with $ 20 million in funding from the California Institute for Regenerative Medicine.
As promising as this approach is, antibodies have drawbacks-their relatively large size limits how they can easily penetrate the tumors, for example, and can have toxic side effects so-effects group Weissman has also partnered with the structural biologist Christopher Garcia's lab at Stanford to test another way to block CD47. The team and Weissman Garcia describe the new work online today Science .
The collaborators began the study of a protein called SIRPα that grows out of the surface of macrophages and connects with CD47 to receive "do not eat me" signal of the tumor cell. Their idea was to block CD47 with a floating form, synthetic SIRPα which was designed so that the real SIRPα macrophage could not lock to the cancer cell and be deceived leaving alone. Garcia laboratory synthesized many versions of the SIRPα protein, determined their structures, and found that two forms related 50,000 times more closely to CD47 that natural SIRPα receiver.
Added to a Petri dish of tumor cells and macrophages, synthetic SIRPα proteins do not have as yet the macrophages ignored the cancerous cells. However, when the researchers threw in a drug-specific antibody of the tumor, that they realized that it was necessary to draw attention macrophages to cancer cells , first, the combination packed a powerful punch in cell cultures and in mice implanted with cancer cells. For example, while lymphoma tumors simply grew more slowly in the mice that received either rituximab drugs or SIRPα protein, the tumors disappeared for at least 7 months in most of the mice treated with both drugs. And adding SIRPα drug against breast cancer Herceptin decreased faster tumors in mice with the disease. "SIRPα weakens the ability of the cancer cell to protect itself from destruction," says Garcia.
Because SIRPα synthetic proteins are relatively nontoxic, Garcia and Weissman hope they can find funds to develop quickly in an experimental drug. "I want to see this test in humans as soon as possible," said Garcia.
Drew Pardoll cancer immunologist at Johns Hopkins University in Baltimore, Maryland, said the idea of blocking CD47 with a small protein instead of a large antibody is "pretty cool. I'm not aware that this kind of approach has been taken before. "However, he warned that, as with other new treatments that work by raising the brakes on the immune system, there could be side effects. "These negative regulatory pathways were not there for no reason at all" but may have an important role in normal cells, he said. For example, the CD47 'do not eat me "signal also protects red blood cells from destruction by the immune system.
Amsterdam University cell biologist Timo van den Berg adds that although" the data is quite convincing and exciting, "because CD47 is expressed on most cells in the body, these cells will suck SIRPα protein, potentially it is difficult to obtain sufficient tumor cells. His own group works an antibody that blocks the receptor SIRPα, which appears primarily on macrophages, as a way to prevent these immune cells receive a misleading message to the cancer cell. Garcia said that although he thinks the approach of his team will work well for patients, "certainly blocking the other direction is a viable strategy and interesting to watch."
0 Komentar