|Dr. Alexei Protopopov, an associate director at the Institute for Applied Cancer Science, demonstrates a DNA sequencing machine. Technological advances have reduced the time and cost of sequencing a human genome, improving researchers’ ability to develop experimental drugs that target cancer-causing mutations.
Advances in Gene Mapping Technology May Accelerate Cancer Drug Development
By Bryan Tutt
new technology makes DNA sequencing faster and less expensive,
researchers aim to exploit these abilities to develop novel targeted
“It took about 10 years to get the first human genome sequenced,” said
Giulio Draetta, M.D., Ph.D., a professor in the Department of Genomic
Medicine and the director of the Institute for Applied Cancer Science
at The University of Texas MD Anderson Cancer Center. “When the Human
Genome Project’s work was conducted in the 1990s, they had huge rooms
with sequencers, one next to another—these machines read along the DNA
sequence to be able to divine the nucleotides that emerged; these
nucleotides were then assembled together.” Systems are now available
that can sequence a human genome in less than a week with a single
machine, and even faster machines are being developed.
Genetic information and cancer
The information obtained from DNA sequencing is affecting cancer research in three main areas, according to Dr. Draetta.
First, mutations that affect cancer cells’ sensitivity to treatment
have been identified. “Some emerging treatments are based on mapping
the genome to look for mutations that respond to certain drugs,” Dr.
Draetta said. For example, the melanoma drug vemurafenib specifically
targets the BRAF V600E mutation and is approved by the U.S. Food and
Drug Administration for the treatment of melanomas with such mutations.
And non–small cell lung cancers with particular mutations to EGFR are
sensitive to gefitinib and erlotinib. Second, genetic information has
revealed common themes in cancer cells that explain their resistance to
treatment. “Most tumors inactivate certain mechanisms that induce cell
death. The tumors tend to survive even if you bang them with radiation
therapy or chemotherapy,” Dr. Draetta said. “We can develop all sorts
of therapies, but there is resistance because tumors don’t want to die.
Now, at the genome scale, we know that these mechanisms that induce
cell death are the predominant mechanisms of resistance that we have to
Finally, DNA sequencing has revealed a greater extent of heterogeneity
among cancer genomes than was once thought. A recent paper in the New
England Journal of Medicine (2012; 366:883-892) described different
mutations found in biopsy specimens from primary tumors and different
metastatic sites in the same patients. The implication of this finding
is that an agent that targets a specific mutation might be effective
against a patient’s primary tumor but ineffective against metastases.
“The idea had always been that a tumor originates from a single mutated
cell and that as it expands every cell in the tumor is the same. The
reality is that cancer cells keep mutating as they move around the
body,” Dr. Draetta said. “This makes the task of curing cancer
daunting, but I like to believe that knowledge is power. The
countermeasure to this problem of heterogeneity is to find commonality.
The more we learn about the complexity of tumors, the more we can look
for common themes or a common root cause.”
A new approach to drug development
DNA sequencing technology is a contributing factor to what Dr. Draetta
described as a paradigm shift in the approach to drug development. This
new research paradigm seeks to bridge gaps that are not always
addressed, or are not addressed quickly, by academic research centers
and pharmaceutical companies working separately.
|“The more we learn about the complexity of tumors, the more we can look for common themes or a common root cause.”
|– Dr. Giulio Draetta
“Academic institutions have traditionally pursued research on an
individual basis. A particular scientist might be interested in curing
a particular disease—and once the scientist has published reports,
pharmaceutical companies have developed drugs based on the research,”
said Dr. Draetta, who has led research laboratories in both settings.
He pointed out that the traditional approach makes it difficult for
pharmaceutical companies to invest in research for therapies that
target a specific mutation found in a small subset of cancer patients.
“Drugs like blood pressure medication, which many patients may take
every day for 20–30 years, are profitable for pharmaceutical companies
and enable them to invest in research,” Dr. Draetta said. “But the
companies have realized that they are not going to make that kind of
money with a single targeted oncology drug because the complexity of
cancer makes it unlikely that a single drug will be used to treat a
large number of patients.”
At MD Anderson’s Institute for Applied Cancer Science, research teams
work to identify targets for new drugs and then develop the drugs
themselves. So far, the institute has about 70 research professionals
from such fields as medicinal chemistry, pharmacology, genomics,
bioinformatics, biology, and biochemistry. These professionals are
divided into eight teams that work simultaneously on different aspects
of multiple projects.
Dr. Draetta said the ability to quickly sequence a cancer genome makes
the collaboration between work groups possible. “We can immediately go
back and look at gene databases and ask, ‘Is this gene really altered?
Which subtype of breast cancer is it? Can we find cancer cell lines
that carry this alteration?’ Then we can study those cell lines and
make sure there is dependency on the mutation,” he said. Dr. Draetta
explained that the fact that a gene is amplified does not mean that the
cancer needs it to survive. The cancer may have needed the mutation at
one point, but additional mutations can make the first mutation
redundant. Genomic information helps identify such mutations as
unlikely therapeutic targets before drugs are developed.
“Each team is working on a specific time line to make sure a drug
candidate’s mechanism of action is valid before it goes to clinical
trials,” Dr. Draetta said. “The idea is to make sure there are no
obvious mechanisms of resistance to a particular agent so that we
invest our energy in developing the drugs that have the most
potential.” Drug candidates that are validated early can be developed
and brought to preclinical and clinical trials. “If we can find even
small populations of patients who will benefit from a drug, we will
bring it forward. Of course, we want to help as many patients as we
can, are not driven by how many vials of a drug we can sell.”
Not only do the institute’s research teams coordinate with each other,
they also work closely with other researchers and clinicians at MD
Anderson. For example, Dr. Draetta regularly consults physicians in the
Department of Investigational Cancer Therapeutics to determine what
drugs currently in clinical trials are likely to become the standard of
care that might be given along with a drug he is developing for a
particular type of cancer.
Dr. Draetta sees this ability to bring together all aspects of research
as a unique advantage of the institute’s location at a major cancer
center. “I worked in the pharmaceutical industry for many years. My
teams identified many compounds and developed them on our own, but we
missed the ability to go back and open a dialogue with the biologists
who did the initial re search,” Dr. Draetta said. “Now, we are engaging
biologists and clinicians early on.”
Genomic information can also identify which patients are most likely to
benefit from a drug. “We’re seeing in clinical trials that if you match
the therapy with the mutation, you get much better results,” Dr.
Draetta said, adding that matching therapy to mutations also can spare
patients from unnecessary treatment.
“I’m very enthusiastic about this new research model,” Dr. Draetta
said. “We want to use bioinformatics—computational tools—to look at
common points of attack. It’s about working together and coordinating
contact Dr. Giulio Draetta at 713-792-6803.
articles in OncoLog, May 2012 issue:
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