In the war against cancer, it looks like matchmaking - between genes and
drugs - could be an important tool, according to new research into the genetic
underpinnings of two rare forms of leukaemia.
By matching a patient's genetic mutation responsible for a rare, rapidly
progressing form of leukaemia with a drug that specifically targets the problem
the mutation creates, researchers report that one patient is experiencing fast,
The new findings shed light on how many forms of cancer may be tackled in the
near future. Scientists are discovering how to differentiate between mutations
that are driving the proliferation of cancer cells and those that are merely
passengers in the process.
"If your car breaks down, you have to open up the hood to see what part has
broken," said study author Jeffrey Tyner, an assistant professor at the Knight
Cancer Institute at Oregon Health & Science University. "Here we have to
open up the tumour cells to see what part is broken to understand what to
After first identifying the genetic drivers of a specific type of cancer,
scientists then match those mutant genes to drugs that will specifically target
'Driver' gene mutations
According to Julia Maxson, study first author and a postdoctoral fellow at
the Knight Cancer Institute, "The move in the field is to take the individual
broken genes and say which of these really promote cell growth. Then, you can
find the right drugs."
The research identified "driver" gene mutations related to two rare forms of
blood cancers: chronic neutrophilic leukaemia (CNL) and chronic myeloid
leukaemia (CML). The scientists identified particular mutations in the gene
responsible for what is called "colony-stimulating factor 3," which signals
kinases, a type of cell enzyme.
A patient with CNL who carries that gene mutation was given ruxolitinib, a
drug that specifically inhibits that mutation (and is known as a kinase
inhibitor). Ruxolitinib is already on the market, used to treat a different
blood cancer, called myelofibrosis. But up until now, although it has been
widely available, the drug hasn't been tried with CNL, Tyner said.
Because CNL is rare, most patients with the disease have the same mutant
gene, which somewhat simplifies the process, Tyner explained. Other more common
cancers will be more complicated to tackle because they are more genetically
diverse, he pointed out.
"We'll have to subdivide those common types of cancer into probably tens of
thousands of subtypes of cancer, and then we'll be able to treat them based on
the drivers," Tyner said.
The challenge is to learn which mutations are critical to causing cell
proliferation, co-author Maxson explained. "We're working to try to understand
which of the mutations drive the cancer and which are just passengers in the
car," she said.
Deep gene sequencing
For the research, the scientists started by drawing blood from 27 patients
with CNL or atypical CML, as well as from patients with other types of blood
cancers. They then performed deep gene sequencing, looking at nearly 1 900 genes
representing a wide range of possible culprits in cells, including kinases,
phosphatases (another type of enzyme) and cytokine receptors (cells that receive
messages), among others.
Then, white blood cells were distributed into thousands of different
chambers, with each chamber containing a different drug or drug concentration,
Maxson explained. The concept is much like how cultures of bacteria are tested
against different antibiotics to see which drug works best in combating the
The researchers selected drugs that were either already approved by the US
Food and Drug Administration or were being tested in clinical trials. "We chose
drugs that fall into the category of attacking pathways that are very likely to
be uniquely sensitive on cancer cells, which is called targeted therapy," Maxson
Cells were incubated for three days and then were assessed to see whether
they were dead or alive - or something in between - and that showed which drugs
were effective, she said. The scientists then merged the sequencing data with
the drug sensitivity information.
"Genetic data helps us understand why a drug is effective, and the drug data
helps us prioritise the genomic information, to know if the effect will apply to
a lot of patients or to an individual patient," Tyner said.
Dr Jerald Radich, a member of the clinical research division at the Fred
Hutchinson Cancer Research Center in Seattle, wrote in an editorial accompanying
the research that "the study provides an example of the future of target
discovery in cancer."
In an interview, Radich said that "in five to 10 years, scientists will be
able to assess what the best possible fits are between your tumour and the drugs
that are out there." Already, the US National Cancer Institute is trying put
people into specific clinical trials based on their genetic profiles, he
The research may be especially helpful for those who don't respond to
traditional therapy. "What we now describe as good luck or bad luck is genetics
that we don't understand," Radich said. "We'll look at those who completely fail
regular therapy, and we'll do whole genome sequencing - probably each patient
will have 400 000 pieces of data - and from that we'll put together a sense of
what drives the genetics of nonresponders."
For study author Tyner, the research is just the beginning. "While this study
is a nice advance, it's certainly not the end," he said. "We're ramping up to
apply this paradigm to as many patients as we possibly can."
Learn more about leukaemia from the US Centers for
Disease Control and Prevention.
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