About 50 percent of cancer patients have tumors that are resistant to radiation because of low levels of oxygen—a state known as hypoxia. A startup in San Francisco is developing proteins that could carry oxygen to tumors more effectively, increasing the odds that radiation therapy will help these patients.
Last month, the National Cancer Institute (NCI) gave that startup, Omniox, $3 million in funding. Omniox is collaborating with researchers at the NCI to test whether its oxygen-carrying compounds improve radiation therapy in animals with cancer.
This image shows a mouse’s legs, with a tumor in the left leg. Hypoxic regions are indicated in light blue.
Most tumors have hypoxic regions, and researchers believe they have a significant impact on treatment outcomes in about half of patients. Tumor cells proliferate with such abandon that they outstrip their blood supply, creating regions with very low levels of oxygen. This lack of oxygen drives tumor cells to generate more blood vessels, which metastatic cells use to travel elsewhere in the body and spread the cancer.
Radiation therapy depends on oxygen to work. When ionizing radiation strikes a tumor, it generates reactive chemicals called free radicals that damage tumor cells. Without oxygen, the free radicals are short-lived, and radiation therapy isn't effective. "Radiation treatment is given today on the assumption that tumors are oxygenated" and will be damaged by it, says Murali Cherukuri, chief of biophysics in the Center for Cancer Research at the NCI in Bethesda, Maryland. "Hypoxic regions survive treatment and repopulate the tumor."
Since the 1950s, researchers have tried many ways to get more oxygen into tumors, without success. Having patients breathe high levels of oxygen prior to radiation doesn't work, and developing an agent to carry oxygen through the blood to a tumor has proved very difficult. Artificial proteins that mimic the body's natural oxygen carrier, hemoglobin, can be dangerously reactive—destroying other important chemicals in the blood. And other oxygen carriers tend to either cling to oxygen too tightly or release it too soon, before it gets to the least oxygenated regions of the tumor.
"We're hoping that since most tumors are hypoxic, we could improve the effectiveness of radiation therapy in a large number of people," says Stephen Cary, cofounder and CEO of Omniox. The company has developed a range of proteins that are tailored to hold onto oxygen until they're inside hypoxic tissue. These proteins are not based on hemoglobin, so they don't have the same toxic effects.
The company's technology comes from the lab of Michael Marletta, a professor of chemistry at the University of California, Berkeley. "Most blood substitutes have failed," says Marletta, because they were based on globin proteins, which includes hemoglobin. Hemoglobin is able to work in the body because it's encased in red blood cells. Unprotected, oxygenated globin proteins react with nitric oxide in the blood, destroying the oxygen, the nitric oxide, and the protein itself.
Marletta began looking for protein fragments that bound to oxygen, but not to nitric oxide. He started with the genetic sequence for the section of the globin proteins that binds to oxygen. He then used a computer program to scan through genome databases for similar sequences. This turned up a group of similar sequences in single-celled organisms. Marletta studied these protein sequences and found a group of them that bind to oxygen but not to nitric oxide. By altering the sequences slightly, Marletta found he was able to tailor how tightly the protein binds to oxygen. This level of control means Omniox can design a protein that releases oxygen only when the surrounding levels of the oxygen are very low—meaning the protein must travel all the way to the hypoxic part of the tumor before it releases the oxygen.
Cary, who was formerly a postdoctoral researcher in Marletta's lab, cofounded Omniox in 2006 to develop a therapeutic oxygen-carrying agent. The company has raised a total of about $4 million from the NCI and the University of California's Institute for Quantitative Biosciences. The company is currently housed in the university's biotech startup incubator, the QB3 Garage.
Omniox has so far demonstrated that its proteins accumulate in tumors in living animals, and that the proteins increase the oxygen concentration there.
Studies of the proteins are now underway at the NCI. Cherukuri, who is not affiliated with Omniox, has developed a tracer for use with magnetic resonance imaging that allows him to make a high-resolution, 3-D map of tumor oxygen concentrations.
Cherukuri is using this method to study the effects of Omniox's agents in mice with hypoxic tumors. "When you have a very hypoxic tumor, and you inject the animal with [the Omniox agent], the oxygenation increases," he says. He is working with General Electric to develop a human-scale prototype of this imaging system.
The Omniox and NCI studies are aimed at figuring out which of the company's proteins works best, when the proteins should be administered, and whether the treatment truly improves the effectiveness of radiation therapy. The studies will also look out for any dangerous immune responses to the foreign proteins. If the results are promising, the company hopes to begin tests in human patients in 2013.
By Katherine Bourzac
From Technology Review