News Release

Outsmarting cancer - new results from novel enzyme inhibitors

Peer-Reviewed Publication

ECCO-the European CanCer Organisation

Smart drugs that can break the chain of command between enzymes and the genes involved in cell division and cell death are a new way forward in tackling breast cancer, according to Dr Stephen Johnston, a consultant oncologist from The Royal Marsden Hospital, London, UK.

Presenting results from the world’s first phase II trial of R115777 (Zarnestra) in breast cancer, Dr. Johnston said that among 41 women with advanced cancer who had previously undergone chemotherapy or hormone treatment, four had a partial response from the new drug and in a further six the disease had been stabilised over a prolonged period. Trials are now planned combining R115777 with chemotherapy or hormone therapy, as laboratory studies indicate that the new drug acts synergistically with conventional treatments to boost their effectiveness.

R115777 is one of a novel drug class called farnesyl transferase inhibitors, he told a news briefing at the 3rd European Breast Cancer Conference in Barcelona. Farnesyl transferase is an enzyme that enables a protein called Ras to function and signal correctly within the cell. Ras plays a prominent part in many types of tumours. Although it is rarely directly mutated in breast cancer, Ras often receives signals from growth factors that make it function in an abnormal way, promoting the growth of breast cancer cells. Interrupting the cellular signals by targeting Ras breaks the chain of command between the growth factors and the nucleus of the cell and appears to inhibit the growth of the cancer cells. In addition, several other proteins involved in cell growth and motility may also be ‘farnesylated’ and so may also be targets for farnesyl transferase inhibitors.

Another key enzyme – the 26S proteasome – is also in the firing line for smart drugs. Proteasome is a protein complex that modulates the behaviour of cells during the cell cycle. It regulates the levels of key proteins that control the fine balance between normal cell division and normal programmed cell death.

In cancer cells normal programmed cell death goes wrong and the cancer cells become immortal. PS-341 is a proteasome inhibitor. It induces the cancer cell to commit suicide by interfering with the proteasome that is allowing the cancer cells to divide uncontrollably. PS-341 has already shown promise against haematological cancers and Dr Johnston is involved with the first trials in breast cancer.

More than half of cancer deaths are due to drug resistance: patients respond well to treatment for a while and then the treatment stops working as the cancer cells learn how to fight back.

Said Dr. Johnston: "It’s very early days yet for these novel drugs and we must not be over optimistic, but they are a new generation of drugs rationally designed to target key enzymes. As such they are potentially very important, especially if, as the accumulating evidence indicates, they enhance the activity of existing conventional therapies and prevent or reverse hormone or cytotoxic drug resistance."

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