WASHINGTONOncology is in transition from its
traditional methods of diagnosing and treating cancer to a reliance on
molecular changes within cellsand the science behind this paradigm shift
will lead to new drugs to attack precancerous conditions as well,
several cancer researchers said at a congressional briefing.
Carcinogenesis occurs over many years, said Andrew J.
Dannenberg, MD, director of cancer prevention, New York Presbyterian
Hospital-Cornell, and professor of medicine, Weill Medical College of Cornell
University. Advances in genetics, biochemistry, and cellular biology have begun
to identify cellular
changes and molecules that can be used to diagnose, classify, and treat
cancers, Dr. Dannenberg said.
A key finding for the future is that "in virtually any
tissue one can think of, there are molecular changes that occur in association
with precancer," he said.
"We tend to talk about anatomic diagnosisabout cancer
of the breast, cancer of the lung, cancer of the colon," said Larry
Norton, MD, head of the Solid Tumor Division, Memorial Sloan-Kettering Cancer
Center, and president of the American Society of Clinical Oncology.
This sounds reasonable, he noted "until you start talking
about infections. We never say any more, as doctors, that someone has an
infection of the lung; we say they have a streptococcal infection of the lung.
We talk about causative organisms because that organismwhether it is
involved in the lung, liver, skin, or any other part of the bodywill be
treated with the same antibiotic. Classifying things by their cause is a much
more useful way of classifying a disease." Both cancer researchers spoke
during a Capitol Hill briefing to House and Senate staff members working on
health issues. The meeting was organized by the National Coalition for Cancer
Research (NCCR) as one of its regular educational efforts known as "Cancer
Current cancer therapies are complicated, often toxic, require
specialists to administer them in specialized settings, and need supportive
care, Dr. Norton said. "We can’t tell in an individual case if someone
is going to get better or not, or whether the cancer is going to recur. And we
can only tell if we’ve been successful by looking to see if the lumps are
coming back," he said. "This is currently where we are, and we
shouldn’t be too excited about it. Fortunately, we are in the process of
Researchers and drug developers are searching out genetic and
molecular changes that can be used for more specific cancer diagnosis,
classification, and treatment, Dr. Norton said. Each cell type has a specific
pattern of gene expression in its normal form and different patterns in cancer.
It is by identifying and understanding specific variations that researchers
expect to change how oncology deals with the disease.
"You can see this is an entirely different way of looking
at the cells. It is not just saying this cell is growing faster than that cell,
but actually saying what is making it grow faster," Dr. Norton said.
He cited imatinib mesylate, also known as STI-571 (Gleevec), an
oral agent recently approved for the treatment of chronic myelogenous leukemia,
as an example of the targeted, nontoxic cancer therapies that will make their
way into clinical practice based on rational drug design.
Imatinib targets and blocks the functioning of an abnormal
protein, Bcr-Abl. The protein is created as the result of a reciprocal
translocation between chromosome 9 and 12 (the Philadelphia chromosome), and it
leads to an uncontrolled proliferation of white blood cells.
"Where we are going is to make molecular diagnoses, to
classify cancers by the molecules that are driving them," Dr. Norton said.
"As we know more about how cancers work, therapy and prevention become the
same topic. The same interventions that can work for therapy can work for
Indeed, Dr. Dannenberg said, the current focus on drug
development is limited to existing cancers. "In my opinion, that needs to
shift in emphasis, not just to target the person who has cancer, but to develop
more effective therapies for the individual who has precancer," he
Dr. Dannenberg cited celecoxib (Celebrex)approved for the
reduction of adenomatous colorectal polyps in patients with familial
adenomatous polyposis (FAP)as an example of how precancerous cells might be
treated early in carcinogenesis to prevent them from becoming cancerous.
Celecoxib inhibits cyclooxygenase-2 (COX2), an enzyme whose
overexpression is linked to FAP and the development of colon and rectal
tumors, he said. The preventive powers of COX2 inhibitors are currently being
tested in several other precancerous conditions, including leukoplakia.
"Importantly, numerous other agents are being evaluated as
treatments for precancer," Dr. Dannenberg said. "And ultimately, it
seems likely that combinations of agent that target different molecules that
are aberrant during carcinogenesis are likely to be more effective than any
However, he added, the Food and Drug Administration needs to
offer more encouragement to industry to develop drugs to halt carcinogenesis in
the precancerous stage.
"For the pharmaceutical industry to invest, it needs to
understand how success can be achieved," Dr. Dannenberg said. "It is
well understood from the standpoint of treating cancer, but more needs to be
done to develop guidelines that will facilitate the development of drugs to
20 Years of Research Bear Fruit
It remained for Lynn Mara Schuchter, MD, to point out to the
Congressional staffers the importance of federal research funds to the
successes so far and the future potential for targeted drugs to treat and
prevent cancer. She cited the years of fundamental research that led to the
development of trastuzumab (Herceptin), now approved for treating HER2-positive
"Years and years of basic science went into studying a
growth factor [HER2] that turned out to be very relevant to breast cancer;
then, very specific therapies were developed to target this growth
factor," said Dr. Schuchter, associate professor of medicine, University
of Pennsylvania Cancer Center. "Funding in the basic sciences over the
last 20 years is what has truly revolutionized cancer now in terms of
diagnostics and treatment. We are really seeing the fruition of that