Clinical trials of an anti-cancer drug for leukaemia begin, vindicating 25 years of Bcl-2 research.

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In 2011, the first clinical trials of a new anti-cancer agent are begun, based on the 1988 discovery of Bcl-2 and subsequent 15 years of research.

The story of Bcl-2

The fruits of medical science are hard-won. 

It was in 1988 that Walter and Eliza Hall Institute scientist Professor David Vaux discovered that a protein produced by a particular gene, Bcl-2, caused blood-cancer cells to live a long time.

By 2017 a drug that targets the protein is expected to be available to treat millions of leukaemia and lymphoma patients around the world. The drug, venetoclax, was co-developed for clinical use by US pharmaceutical companies AbbVie and Genentech, a member of the Roche Group, and discovered in a joint research collaboration with Walter and Eliza Hall Institute scientists. Venetoclax has been approved for use in some patients with chronic lymphocitic leukaemia in Australia, the US and European Union.

“It’s vindicating more than 25 years of research,” says Professor Andrew Roberts, who is leading the Australian team overseeing the international clinical trials of venetoclax.

Achilles’ heel of cancer

Roberts describes the Bcl-2 protein as the “Achilles’ heel” of some forms of leukaemia and lymphoma. “It’s also being trialled with breast cancer,” he says.

Roberts is also a research professor at The University of Melbourne, holding the Metcalf Chair of Leukaemia Research, and a clinical haematologist at The Royal Melbourne Hospital.

At the institute he is head of clinical translation and laboratory head. “It’s simply the best place in Australia to do the research I wanted to do,” he says.

He has been part of a team of up to 100 scientists that has been working in collaboration with two pharmaceutical companies to develop a drug to target Bcl-2 (B-cell lymphoma 2). This gene is present within every cell of the body and, in some cells, it is turned into a protein.

Targeting Bcl-2 to attack cancer

“Its job is to keep blood cells alive,” Roberts said. “But, if you have too much Bcl-2 in the wrong cell at the wrong time, it can lead to the development of lymphoma or leukaemia – not on its own, but in partnership with other things that go wrong in the genes. So, we thought, maybe you can attack cancer by taking Bcl-2 away, or developing a drug that would reduce the activity of Bcl-2 in the cell.”

This proved very difficult to do. In the end, success was achieved by a huge international collaboration between the institute, the pharmaceutical company AbbVie, and Genentech, a member of the Roche Group.

“This was a fantastic collaboration between industry and academia and it delivered a drug,” Roberts says. “Industry brought rigor around the project goals, focus, and the making of tough decisions. Academia brought marvellous minds, critical tools and essential knowledge about Bcl-2 and cancer. Scientists from all three organisations contributed. Industry also brought money that the institute didn’t have. It was an incredibly unusual circumstance. People would kill to replicate it.”

Positive results

The resulting drug venetoclax – also known as ABT-199 – kills cancer cells by blocking the Bcl-2 protein.

It was first tested in humans in July 2011, with patients from The Royal Melbourne Hospital and the Peter MacCallum Cancer Institute. “Within eight hours, chronic lymphocytic leukaemia cells had plummeted in the blood,” Professor Roberts says. “We immediately knew the drug was effective.”

But it took two more years to work out how to give the drug safely, as breaking down leukaemia cells too rapidly can be catastrophic “We lowered the dose, and built it up again. It is now delivered very safely.”

The drug is part of a group of new, targeted chemotherapies, designed to work very specifically against one weakness of the cancer cell. It is well tolerated by most patients as it is free of many of the side-effects of traditional chemotherapy.

Promising new treatment

“Phase 1 clinical trials have shown almost 80 percent of patients respond to the drug. Many patients have maintained this response more than a year after their treatment began, and some patients remain in remission more than four years on.”

“This is a very exciting result for a group of people who often had no other treatment options available,” Professor Roberts says. “It is now being trialled in people who are newly diagnosed.”

The drug potentially could help people with other blood and solid tumours that involve high levels of Bcl-2. And, says Professor Roberts, “Blood cancers account for one sixth of all lives lost from cancer. More people die because of blood cancers than breast cancer or prostate cancer, because blood cancers affect both sexes.”