by ecancer reporter Emma Campbell

Early results from research developing a new anti-cancer drug for leukaemias and lymphomas have shown that the drug may be more effective and have reduced side effects compared with its predecessor.

Researchers from the USA, along with international collaborators, found that their new drug, ABT-199, may overcome side effects of the related drug navitoclax and, in so doing, enable doctors to give a higher, more effective dose to kill cancer cells.

Thousands of people in the UK die from leukaemias and lymphomas every year.

Although some patients can be effectively treated with combinations of chemotherapy and immunotherapy, many eventually stop responding to these treatments.

More effective treatments are desperately needed if survival rates are to improve. 

Proteins in the BCL-2 family, such as BCL-2 and BCL-X_L, are known to contribute to the development of leukaemias and lymphomas.

They stop aged and damaged cells dying naturally, and this can lead to cancer.

Blocking the activity of these proteins is therefore an attractive strategy for treating the disease.

The problem is that different proteins in this family have very similar structures.

Drug design strategies currently aim to target BCL-2, but navitoclax also inhibits BCL-X_L, which is needed for the survival of blood platelets.

The effectiveness of navitoclax is limited because giving a high dose of the drug decreases the number of blood platelets, leading to thrombocytopenia.

The researchers hoped that by creating a new drug that could inhibit BCL-2 but not BCL-X_L, doctors would be able to treat patients with a higher and more effective dose, without serious side effects.

In the current study, published online this week in Nature Medicine, they studied the structures of the drug-binding pockets of BCL-2 and BCL-X_L.

They then systematically modified key binding elements within navitoclax and related drug structures, until they found a drug that bound BCL-2 much more strongly than it did BCL-X_L.

They called this ABT-199.

In this study, ABT-199 was effective at killing cancer cells that rely on BCL-2 for survival.

It also inhibited tumour growth in several mouse models of human haematological cancers, and in three patients with refractory chronic lymphocytic leukaemia.

The effects on platelet counts were minor compared with those observed in patients treated with navitoclax in previous trials.

As stated by the authors, “These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent haematological cancers”.

“The lack of BCL-X_L inhibition with ABT-199 should allow for higher circulating concentrations of the drug to be achieved in patients with cancer without dose-limiting thrombocytopenia. This hypothesis is being tested in an ongoing phase 1 study.”

Reference

AJ Souers, JD Leverson, ER Boghaert, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumour activity while sparing platelets. Nat. Med. doi: 10.1038/nm.3048