The Pursuit of Cancer
October 03, 2011
The Pursuit of Cancer
By Christie Rizk
Finding cancer early can often mean the difference between life and death. Doctors
stress the importance of colonoscopies, mammograms, and prostate checks, and
patients are warned about the need for constant vigilance, like checking for breast
lumps. Some companies now offer genetic tests to give patients a better idea of which
gene mutations they carry that may influence their risk of developing certain cancers,
and most oncologists say having a family history of cancer can be just as important for
calculating risk as knowing whether the patient smokes or has tested positive for human
papillomavirus. Yet, even armed with all that information, cancer can slip by the most
vigilant doctors and patients.
“Almost any cancer is treatable successfully if you get it early enough. So there has to
be, in my mind, a huge emphasis on early detection,” says the University of Georgia’s
Michael “Hawkeye” Pierce, who conducts research on early detection biomarkers for
pancreatic cancer. “If we had some blood tests that assessed risk for certain
populations and got people in to be screened by more sophisticated means like PET
scans, that would be tremendous. But we need to add as many weapons to our quiver
as we can get, to target specific types of cells and to kill them.”
Pancreatic cancer, by far one of the most aggressive cancers, has an average first-year
survival rate of 24 percent. The five-year survival rate is 5 percent. And yet even a
disease like pancreatic cancer can be stopped if it is caught early enough. Recent data
show that most pancreatic cancers have been growing for about 20 years by the time
they are diagnosed — they may be tiny and buried deep in the pancreas, and patients
may be asymptomatic for many years. By the time those tumors are large enough to be
found, treatment is difficult and rarely successful. “But the good news is that there is a
window of time, that if we could screen people — especially people who are at risk,
maybe familial groups of people with some huge risk factors, if we could focus in on
them — there’s good reason to believe that we could find these things a little earlier,”
Pierce says.
With the ultimate goal of arming clinicians with accurate, non-invasive clinical tests to
detect cancer at its earliest stages, researchers are employing a number of
sophisticated ‘omics strategies. The National Cancer Institute recently awarded grants
for a consortium dedicated to the use of genomics and proteomics in combination to find
and validate cancer biomarkers. Other researchers are turning to the immune system to
see if it can provide early clues to cancer development. And in one of the newest
approaches to cancer research, some scientists are looking to the glycome and the
signatures it leaves in the blood.
Harnessing the immune system
Many researchers say that when it comes to fighting disease — even cancer — the
immune system is a patient’s best friend. Even when the immune system cannot fight
the disease on its own — as it usually can’t with cancer — it still sends up signals that a
person is infected, which can, in theory, be detected by clinicians. “Going back to the
basics, we know from multiple lines of evidence that the immune system is capable of
recognizing the tumor at the early stages of tumor development,” says Samir Hanash
from the Fred Hutchinson Cancer Research Center. Hanash published an editorial in
the April issue of the journal Cancer Epidemiology, Biomarkers, & Prevention, saying
that progress has been made to identify a number of antigens that could serve as
detection tools for cancer.
“This is a situation that I compare to what goes on in HIV,” he says. “Basically, the
immune system recognizes the presence of the virus and it mounts an immune
response, and we take advantage of this immune response to actually detect the HIV
through seropositivity. And the analogy continues to the extent that the kind of immune
response that you have in HIV does not actually get rid of the virus, but it allows you to
make a diagnosis.” Similarly, in cancer, he adds, the immune system recognizes that
there is something wrong with the body and sends out signals in the form of antigens,
though it seems unable to resolve the problem by itself.
Hanash says the question then becomes how to turn the immune response into a
diagnostic. What needs to be done, he adds, is to identify the most informative antigens
associated with a particular cancer, and once they are found, they can then be put on
chips. “And then you can imagine having a chip which contains the antigens for lung
cancer, colon cancer, breast cancer, pancreatic cancer, what have you. And eventually,
as part of your routine checkup, if there’s seropositivity against the breast cancer
antigens, this would be an indication to want to do an imaging study to confirm or rule
out that there is breast cancer,” Hanash says.
At present, researchers are busy identifying panels of antigens, validating them, and
performing studies to show their clinical utility, he adds. The data look promising, but
there are challenges to overcome to bring this kind of test to the clinic — doing a test in
the lab is one thing, but showing that it is reliable in a variable clinical setting is not so
easy. “It’s not enough to say that this set of markers can distinguish people with disease
from people who don’t have disease,” Hanash says. “You have to indicate what the
specifics of the clinical application are — what age group, what would be the indication
that they would get the test in the first place, whether people are asymptomatic or
getting the test on account of their family history, or their age or on account of their
smoking behavior or something, that this test would work for them.”
The search for glycans
At her glycomics lab at New York University, Margaret Huflejt is another one of those
researchers looking to use the immune system as a tool in the early detection of cancer.
As part of her work with NCI’s Tumor Glycome Laboratories, Huflejt is seeking to
determine the validity and utility of diagnostic or prognostic anti-glycan auto-antibody
signatures in cancer patients, using printed glycan arrays — a high-throughput
technology containing multiple probes made up of synthetic carbohydrates. “We print
glycans on our glyco-chips and we then query human serum for the presence of natural,
anti-glycan auto-antibodies that would be binding to the glycan-probes on the glycochips,” Huflejt says. “Using our glyco-chips, we ultimately immuno-profile the anticarbohydrate auto-antibodies of the individual, thus gaining information about his or her
immune health status. We believe this will be fabulous technology in the service of the
detection of pathology, and in following patients’ responses to therapies.”
The immune system knows everything and is constantly sending out signals, she adds,
so paying attention to those signals is important for finding cancer biomarkers. The
immune system sees the surface of the cell, and the glycans that it reads on the cell
surface give it an indication of what’s going on inside the cell, including any genes that
are mutated, abnormally expressed, or abnormally located inside the cell.
This is a new approach to cancer detection, Huflejt says, but already she is seeing
results. “While developing methods for early detection of cancer and cancer risk, we
should be in parallel identifying biological targets, which suggest ways to protect those
individuals whom we identify are at risk,” she says. In this case, cancer should be
treated almost like diabetes, in that clinicians know how to measure for glucose levels,
and know what to do when those levels hit a certain limit. “In the situation where we are
looking for the immune-identifiers of risk, we would be looking for the auto-antibodies
whose proportions are already altered as the result of a disease — because the
immune system has seen the problem and it has to do something about it,” Huflejt says.
“So there’s going to be an imbalance among these auto-antibodies in high-risk patients
as compared to healthy individuals. Persistence of these alterations would mean a
physician should call back this patient and determine the best course of action; for
example, starting a preventive therapy, or removing a suspicious tissue as opposed to
leaving it alone because the original biopsy said it was benign.”
Eventually, she adds, if researchers learn enough about the immune response to
cancer and what the various anti-glycan auto-antibodies indicate, it may be possible to
develop vaccines in conjunction with early detection diagnostics.
Northeastern University’s William Hancock — co-chair of the Tumor Glycome Labs
project — says that part of the challenge of finding cancer biomarkers in the blood for
early detection is that blood is a complex fluid to analyze. His work in glycomics —
which he dubs glyco-proteomics — is different than Huflejt’s in that he and his team
analyze proteins rather than auto-antibodies. “Until recently, this was a difficult area,
and it still is,” Hancock says. “People would do one of two things — they’d capture the
glycoprotein and strip off the glycan, and, of course, they didn’t know what the glycan
was. Or the other approach is that you clean the glycans off, and throw away the
proteins. The problem is you’ve lost the protein interaction, which can give you some
idea of the tissue of origin.” Hancock says he and his team decided to analyze the
glycoproteins in blood as potential markers for early detection, in order to get the value
of the protein and glycan information together.
“If we are clever enough, we can develop diagnostic tests or measurement tests so that
we can not only find a particular protein in the blood, but a protein that has a unique
glyco-signature on it,” says Georgia’s Pierce, another member of the Glycome Labs
project. “Looking for the signature adds another dimension of specificity.” Instead of just
looking for a protein in the blood, he and his team are looking for specific proteins
attached to specific glycans, which will not only tell a clinician if there are signs of
possible cancer, but what the tissue of origin is and possibly at what stage the cancer is.
If researchers find that those markers are on the cells themselves, there may be a way
to develop therapeutics by targeting the glycans with monoclonal antibodies. “What is it
on these cells that’s unique? Can we exploit that by finding those molecules that the cell
is releasing that tells us that the cancer is there?” Pierce asks. “And then if the molecule
is still on the surface, can we develop reagents to go in and direct chemotherapy to kill
that cell?”
The metabolomics approach
Metabolomics might also be used to detect cancer in its early stages. In February,
Robert Gardiner at the University of Queensland Centre for Clinical Research in
Australia and his colleagues published a review in theKorean Journal of
Urology proposing metabolomics as an early and non-invasive approach for the
detection of prostate cancer.
Currently, serum prostate-specific antigen remains the standard initial test to detect
prostate cancer in men, but as a biomarker, it leaves much to be desired — the test
gives as many false negatives as false positives, and does not provide prognostic
information. Using a metabolomic approach, Gardiner and his team are hoping to find a
more sensitive and specific set of markers for the disease. They are conducting studies
with nuclear magnetic resonance technology, which allows for the concurrent detection
of multiple metabolites. “We have been trying to detect the presence of prostate cancer
in patients using ejaculate for a number of years using molecular techniques, and our
best results have been with a combination of the non-coding RNA PCA3 and Hepsin
RNA, together with serum PSA,” Gardiner says. “The presence of different mixtures of
metabolites as a result of changed metabolism with cancers and other conditions has
been known for a long time, and various metabolites have been reported in the past to
be different in the ejaculate of men with prostate cancer.”
In addition, Gardiner says, the “metabolic milieu” of prostate cancer is the result of
different genes and proteins interacting, and NMR analysis allows for a comprehensive
assessment of the changes created by those interactions, to provide a clinician with a
more complete evaluation of the patient, rather than the “reductionist approach” of
testing one marker at a time. “The metabonomic findings incorporating multiple
discriminating parameters then can be added to the other two markers with the best
track record — serum PSA and PCA3 in prostatic fluid — to produce a profile,” he adds.
Although it is still experimental, Gardiner hopes his research will lead to a test that can
be used in the clinic. “We are not the first to study ejaculate using NMR, but I believe
that our comprehensive and long-term focused research commitment will result in the
provision of a non-invasive diagnostic test,” he says. “We hope that a test or tests
resulting from our research will be another factor, as a more reliable indicator of
prostate cancer status, to integrate with other considerations essential in formulating
individual patient care.”
Over-diagnosis?
In this zeal to find cancer earlier and earlier, however, are researchers creating a bigger
problem? Over-diagnosis and false positives are already a problem for clinicians and
cancer patients, with increasingly sophisticated imaging technology sometimes showing
doctors things that aren’t there, or benign lumps or nodules that could be left alone with
no harm to the patient. These benign findings can sometimes be interpreted as being
cancerous, leading to unnecessary treatments or biopsies that can be painful and
expensive. And if these early detection tests are less than perfect, the worry is that they
could end up adding to the problem instead of ameliorating it.
“These tests are prospective in nature. We don’t have the data for a side-by-side
comparison to say, ‘This is better, this is worse.’ But we can envision what the
applications would be,” says the Hutch’s Hanash. “Initially it would be a test that would
be used in conjunction with the standard imaging modality — whether mammography
for breast cancer or CT scans for lung cancer — but where the performance is not really
perfect. And so having a blood test that helps confirm cancer or backs up what you see
in imaging can say, ‘No, this looks OK,’ or ‘The test looks positive, you’d better get a
biopsy done.’” Eventually, he adds, when the early detection biomarker blood test
proves its utility in the clinic, doctors could forgo the current standard imaging
procedures by giving their patients the blood test first and letting those results determine
whether further testing or a biopsy is in order.
“Those are the same risks that are applicable right now to imaging modalities,” Hanash
says. “There’s a lot of concern right now that for CT scans of the lung, even though
there’s evidence that you do save lives, a very large percentage of smokers who go to
get a CT scan, they have something on their CT that most of the time is not cancer. So
in that sense, there’s a lot of false positives associated with CT scans. That creates a
tremendous anxiety on the one hand, because it creates a need to go in and get a
biopsy, or then you say, ‘Wait a year, or six months,’ and you can imagine what people
go through knowing they have something in their lung and not knowing if it’s cancer or
not.” These types of situations could be equally applicable to a blood test, he adds, but
in the end, it’s more likely that such early detection tests will actually cut down on the
number of false positives because they add another method of testing to what a doctor
can offer a patient.
Similarly, Northeastern’s Hancock says he and his team hope their work in breast
cancer one day leads to early detection blood tests for women who have had an
“unsatisfactory mammography” and whose doctors are unsure if a biopsy is the next
logical step. “If we’re successful, they could do an actual glycoprotein test — then they
really want to figure out if it’s the less serious in situ form, or if it’s metastasized,” he
says. “It really is meant as a complement to existing tests. This test does not cause a
clinician to do something — it’s to inform the physician to have more information and
have better options to treat the patient correctly.”
From talking to oncologists, Georgia’s Pierce says clinicians need every tool they can
get. “We expect the glyco-markers to be better than what they have, because what they
have isn’t very good. Early diagnosis is what we’re really looking for, and it’s just in the
past five years that we’ve conceived a way to do that,” he adds. “Maybe we can get to
early detection, and maybe we can complement the tests that are out there.”