A
drug that uses a unique ‘double hit’ to kill leukaemia cells could be a
potential new treatment for patients with acute myeloid leukaemia. The
research, majority funded by Cancer Research UK, is published this week in
Leukaemia.
Around 30 per cent of patients with AML have
faults in the FLT3 gene, which are linked to more aggressive leukaemias and
poor survival. While drugs that target these faults are available, the disease
eventually builds resistance, leaving treatments ineffective. To combat this,
researchers at The Institute of Cancer Research (ICR) in London, funded by
Cancer Research UK and Breakthrough Breast Cancer, developed a unique drug that
targets AML cells in a “double hit”.
The drug blocks the protein made by the
faulty FLT3 gene along with another key protein – called Aurora kinase – which
are both involved in driving cancer growth. In healthy blood cells, FLT3 sends
a signal to the cells telling them when to proliferate, while Aurora kinase
plays a role in cell division. Leukaemia cells with faulty FLT3 can proliferate
out of control, while many cancer cells have higher levels of Aurora kinase,
causing errors during cell division.
This ‘double hit’ drug blocks both mechanisms
that otherwise promote leukaemia growth. The drug is also unique because it can
destroy cells even if they develop new faults in the FLT3 genes that would make
them resistant to other inhibitors. The combination led to complete remission
in half of the mice treated with this drug, compared with only 25 per cent with
an existing drug that only blocks FLT3.
Lead author Dr. Spiros Linardopoulos, leader
of the Cancer Drug Target Discovery Team at The Institute of Cancer Research
said: “There has been great interest in using FLT3 drugs to treat AML, but
their effectiveness has been limited because leukaemia cells gain new mistakes
in the FLT3 gene, causing resistance.
“Our new drug has the potential to overcome
this and has a range of possible uses in AML – as a first line of attack for
patients with faulty FLT3, in particular in those over 60 who don’t tolerate
chemotherapy well, and also to treat leukaemia patients who have
relapsed.”
Professor Paul Workman, director of the
Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer
Research, said: “We’re excited about the potential of our new ‘double hit’ drug
and are now planning to take it into clinical trials to see if it is effective
in patients.”
The faults that occur in the FLT3 gene cause
rapid cell division, and one particular mistake is linked to a very poor
outcome in both adults and children with AML. Each year around 2,380 people are
diagnosed with AML in the UK.
Dr. Julie Sharp, senior science information
manager at Cancer Research UK, said: “Cancer Research UK has a long history of
developing drugs to treat leukaemia more effectively. But designing treatments
that overcome resistance is a major challenge for researchers.
“By creating cells in the lab that mimic how
drug resistance develops in AML the researchers were able to show that their
new drug delivers a ‘double hit’ to halt cancer cells in their tracks. Next
they will test the new drug in patients to see if it has the potential to treat
people with aggressive AML.”
More information: Moore AS (2012). Selective
FLT3 inhibition of FLT3-ITD(+) acute myeloid leukaemia resulting in secondary
D835Y mutation: a model for emerging clinical resistance patterns. Leukemia ,
26 (7) PMID: 22354205
Provided by Cancer Research UK
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