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Monitoring Cell Death Could Help Cancer Treatment

An earlier measure of treatment could improve patients’ prognosis.
February 1, 2010

When it comes to aggressive cancers, in the brain or lung for example, oncologists know that the sooner they can determine whether a treatment is unsuccessful, the sooner they can reevaluate and, if necessary, prescribe a new course of action. But typically, it takes two months or more to do the before-and-after comparisons that help determine whether a tumor is shrinking. Now an Israeli company called Aposense says it may have found a way to drastically speed up the process: an imaging marker that, when used with PET scans, indicates the presence of dying cells.

Death of a tumor: This PET scan, taken just days after radiation therapy, shows a hot spot of cell-death activity in a brain tumor–a good indication that the therapy is working.

Apoptosis, the process by which cells commit suicide, is a vital mechanism in the body that weeds out damaged, infected, or otherwise unhealthy cells. No matter what the disease or the tissue, cells undergoing apoptosis have very distinct characteristics–the electrical profile of their membrane changes, the cells become more acidic, and lipids in the membrane lose their rigid order and become jumbled. Aposense believes it has found a way to target a trace marker to this combination of traits, which would let doctors image cell death and thereby determine whether radiation and chemotherapy are working within just a few days after treatment begins.

“We have designed small molecules with very high specificity for the apoptotic cell,” says chief scientist Ilan Ziv. “When this small molecule recognizes the set of alterations in the apoptotic membrane, it binds to the cell, goes through the membrane, and accumulates.”

The tracer is delivered to patients in an inactive state, and the acidic environment surrounding apoptotic cells causes the molecule to activate. The new conformation then recognizes the dying cells by their altered membrane potential, binds to the membrane, and works its way into the cell by taking advantage of the scrambled lipids. The tracer can be linked to the imaging isotope fluoride-18 to make it easy for PET scans to pick up the signal.

In an early study on seven patients with brain tumors, Aposense investigators imaged patients before, immediately following, and six to eight weeks after their radiation therapy. Their results showed a strong correlation between identifying the apoptosis marker and subsequent tumor shrinkage. “Since you can see if a patient gets no benefit from radiation, you could start right away thinking about alternate treatments,” says Aposense CEO Yoram Ashery.

The group is now in phase II clinical trials in collaboration with a few major cancer centers across the U.S., looking at solid brain, lung, head, and neck tumors. “We’re always looking for ways to measure a response to effectiveness of our therapy,” says Aaron Allen, a radiation oncologist at Dana-Farber/Harvard Cancer Center and the trial’s lead investigator. And the more personalized the treatment, the better off a patient will be, he says. “We want to develop a way for each tumor to be treated in the way that it requires. And any tool we can use to accurately measure the effect of our therapy as early as possibly creates an opportunity to personalize the treatment.”

The product also has potential as a research aid. Michael Zalefsky, a radiational oncologist at Memorial Sloan-Kettering Cancer Center in New York and another investigator in the clinical trial, does research on radiational-seed implants for prostate cancer. “As we learn more about [the Aposense tracer], it may help us predict how sensitive the tumor cells are to the particular treatment that we are utilizing,” he says. “It has a lot of great potential benefit, but all this needs to be explored in prospective studies.”

Because the characteristics of apoptotic cells are universal, Aposense says that its tracer might also be used to investigate other ailments. In neurology, the company’s researchers believe, the tracer could be used to image damage from a stroke; in cardiology, it might identify areas of blood vessels with unstable atherosclerotic plaque; in organ transplantation, it might identify rejection at its earliest stages.

But the technology still has a long way to go to prove itself, and some worry that Aposense may be getting ahead of itself. Francis Blankenberg, an associate professor of radiology and pediatrics at Stanford University who has been working to develop a competing apoptosis-imaging technology, has been following the company’s progress for a long time. He’s unconvinced that the tracer molecule works as described and notes that he has not seen the mechanism they describe proven to his satisfaction.

Whether Aposense’s marker is effective in cancer treatments should be established soon enough. The company hopes to complete its phase II trials with somewhere between 90 and 100 patients this year, and aims to have a larger, phase III trial concluded by 2012. Ashery hopes the results will herald a new era in personalized cancer treatments. “When you’re trying to predict the response of a patient before treatment, you need to account for many variables,” he says. “What we’re providing is a way to see the effects of therapy in vivo. We can do this repeatedly in patient during treatment, and that offers an opportunity to individualize treatment.”

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