Test can predict tumour sensitivity to experimental cancer drugs

Scientists at the Dana-Farber Cancer Institute have developed a way to testing if malignant blood cells in chronic lymphocytic leukaemia are only surviving because of the presence of a protein, called BCL-2, that prevents cell suicide.

Several pharmaceutical firms are developing drugs that could prevent BCL-2 from keeping self-destruct signals at bay. However, the circumstances under which the protein is necessary for tumour survival was poorly understood until now. With the development of this test, that also helps explain the mechanism of BCL-2, pharma companies may be able to select suitable patients for clinical trials and thus ensure their drugs get to the market as soon as possible.

Around 10,000 new cases of chronic lymphocytic leukaemia are diagnosed in America each year. The disease is often difficult to diagnose and there is currently no screening test. Although the exact cause of this type of leukaemia is unknown, it begins in the bone marrow and results in the formation of abnormal white blood cells of a specific type called lymphocytes. The body uses these cells to fight off infection.

"It's essential to figure out which cancers are going to respond to the drug by identifying the cells that are dependant on BCL-2 for survival,"​ said Letai, an assistant professor of medicine at Harvard Medical School and leader of the group who developed the test.

He added: "Up to now, there hasn't been a way to do this."​

How BCL-2 works​

Letai's group tested Abbott's drug candidate AB-737 against CLL cells with striking results. Even with low concentrations of the drugs, the cells died within four hours. Letai explained that this was because they are "primed for death"​; they are surviving only because BCL-2 proteins are blocking powerful cell-death molecular signals by holding them hostage.

He likened the primed cells to a car with a revved-up engine on the edge of a cliff, restrained only by its emergency brake; if the brake were released, the car would plunge over the cliff. Drugs like ABT-737, in effect, release the brake.

The drug molecule liberates pro-death molecules such as a key one called BIM from BCL-2 and allows them to trigger a chain of events leading to cell death. As normal cells don't rely on BCL-2 to survive, the drugs are expected to be relatively non-toxic to them.

The team isolated mitochondria from cancer cells and exposed them to protein fragments called BCL-2 homology domains (BH3).

Letai said: "If they interact, then the cell is primed to die, and the test will identify which of the survival molecules is keeping the cells alive. Then you know that to kill the cell, you have to target BCL-2."​

The team are currently developing a way of automating this 'BH3 profiling' and hope that in the future, the test could be routinely used to assess the vulnerability of a patient's cancer to these drugs.

Several other companies are developing drugs that target BCL-2. US pharmaceutical company Genta are developing an antisense drug that targets BCL-2. Although Genasense, recently had some disappointing results​, the drug is still in clinical trials for several types of cancer and the company are hopeful its efficacy will be proved.

Santaris Pharma's antisense drug, SPC2996, targets BCL-2 and is currently in Phase I/II trials. Infinity Pharmaceuticals are also conducting preclinical studies on BCL-2 inhibitors. Last year, the company announced the drugs would be developed in collaboration with Novartis in a deal that could be worth up to $400m (€308m).

The role of BCL-2 is not just limited to chronic lymphocytic leukaemia. The late Stanley Korsmeyer at Dana-Farber discovered that cancer tumours survive and grow because BCL-2 prevents cell suicide. This is true of a number of a number of different types of cancer, such as non-small cell lung cancer.