Tumors closer to committing "cellular suicide" are more sensitive to conventional anticancer drugs.
A laboratory test that evaluates how close cancer cells are to a specific form of cell death could help oncologists predict which patients will benefit from chemotherapy drugs. Researchers tested samples from patients at several hospitals and showed that those whose cancer cells were on the edge of self-destructing responded better to various kinds of chemotherapy.
The test helps explain a long-standing puzzle in oncology. Cancer biology dogma holds that chemotherapy drugs target all rapidly dividing cells, leading to both tumor death and side effects such as hair loss and gastrointestinal distress. But some rapidly dividing tumors, such as pancreatic cancers, tend to be highly resistant to chemotherapy, while some slow-growing cancers, such as chronic myelogenous leukemia, respond well to the drugs.
The new research, led by Anthony Letai, an associate professor at Harvard Medical School and the Dana-Farber Cancer Institute, suggests that regardless of how fast the tumor cells divide, the cancer's likelihood of responding to chemotherapy is correlated with, and perhaps determined by, whether they are approaching a type of cellular suicide known as apoptosis. Apoptosis is a natural process in multicellular organisms, but it is often disrupted in cancerous cells. The study was published online last week in Sciencexpress.
"This is a very important paper," says Peter Sorger, a professor of systems biology at Harvard Medical School, who was not involved in the research. He says identifying patients who might be responsive to chemotherapy is "the key issue in contemporary cancer pharmacology—individualizing treatments so specific drugs are given to patients likely to respond."
Letai and his colleagues tested samples from patients with four kinds of cancer: multiple myeloma, acute myelogenous leukemia, acute lymphocytic leukemia, and ovarian cancer. The process involves taking live tumor cells and exposing them to proteins that promote apoptosis. In cells already on the edge of committing apoptosis, the membranes of energy-producing organelles called mitochondria break down and take up more of a fluorescent dye that the scientists used to monitor the process. This mitochondrial disintegration is one of the first steps in apoptosis. The researchers then followed the patients' response to chemotherapy and found that those whose cells took up the most dye had the best outcomes.
Though the test is more complicated than most cancer diagnostics because it involves handling live cells, Letai believes it could be a practical way to predict which cancer patients will respond to chemotherapy. "In the cancer biology world today, people are looking at genetic biomarkers almost exclusively for trying to understand the response to chemotherapy," he says. "Something like this, a more functional assay, comes out of left field."
Letai's lab is already testing whether the assay could be used in clinical cancer therapy, andEutropics Pharmaceuticals of Cambridge, Massachusetts, which Letai cofounded, has licensed the technology. If clinical trials go well, Letai says, the test might be used for acute myelogenous leukemia in about five years. He hopes that ultimately it will be applicable to most kinds of cancer. Sorger calls the possibility "highly likely."
The researchers also investigated whether treating tumors to move their mitochondria closer to the threshold of apoptosis could boost the efficacy of conventional chemotherapy. They treated a myeloid leukemia cell line with an experimental drug, made by Abbott Labs, that mimics the apoptosis-promoting proteins used in their cell assay. The treated cells became more sensitive to three different chemotherapeutic agents. Abbott and Genentech are collaborating on clinical trials of a related drug, which can be taken orally, to see if it increases the effectiveness of various chemotherapy medicines used for both chronic lymphocytic leukemia and various solid tumors.
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