BALTIMOREThe past as prologue to the future served as an
unspoken but elegant theme for the seminar that marked the 25th
anniversary of the Johns Hopkins Oncology Center.
Although certainly a celebration of a quarter century of
accomplishments in basic and clinical research, the day-long meeting
sought to emphasize the science of the past as a guide for what
we all know will be a tremendously exciting future in cancer
research, said Martin D. Abeloff, MD, director of the Oncology Center.
Albert H. Owens, Jr., MD, the centers founding and now director
emeritus, ventured his vision of the state of oncology 25 years from
now when the center marks its golden anniversary:
I should think we would have the methodology to detect people
who are at high risk. I dont necessarily mean only genetic
predisposition, but I think we should be able to identify people who
have acquired methylation abnormalities or oxidative damage to their DNA.
- We should be able to detect the very
earliest indications of disease, and I really expect we are going to
hear about effective preventive therapy.
- I expect there will be effective cancer
vaccines. I can envision a world in which young girls are inoculated
against HPV [the human papillomavirus], and, worldwide, cancer of the
cervix is quite a different story than it is today.
Reaching such a world, however, will require advances along many
research fronts, as a number of speakers made clear during the
symposium, which was underwritten by PRR, Inc., publisher of Oncology
News International, ONCOLOGY, and Primary Care & Cancer;
Roche Laboratories, Inc.; and Rhône-Poulenc Rorer Oncology.
Bert Vogelstein, MD, professor of oncology, noted the progress in
recent years in understanding the genetics of colon and rectal
cancers. The future challenge, of course, is to gain an
understanding of the genes involved in colorectal tumorigenesis,
From this will come better ways to identify people predisposed to the
disease; diagnose tumors at the earliest stage; and improve
treatment. However, its not at all simple to move from an
outline of the understanding of the gene to actual improvements in
patient care, he said.
Genetic studies have created a revolution in cancer research
with broad implications far exceeding colon cancer, Dr.
Vogelstein said. He cited as one example the very active quest to
understand precisely why cancer drugs work at all. In his view, the
most promising premise is that oncologic agents counter defects
in checkpoints that occur in cancer cells.
Checkpoints are a series of control steps in the cell cycle that
regulate mitosis. They are defective in cancer cells, and cancer
drugs somehow work to kill cells that contain defective checkpoints.
Johns Hopkins researchers have created a cell line with defective
checkpoints by knocking out the genes that control the checkpoints.
Through screening 100,000 compounds, we hope to find drugs
similar to the drugs already discoveredbut more efficacious and
more specificthat will specifically kill cancer cells with
defective checkpoints and leave normal cells alone, Dr.
He believes that research to exploit these checkpoints will allow the
development of drugs targeted specifically to individual cancers,
because obviously, the checkpoints that are defective in any
individual cancer vary, he said. In order to be maximally
effective, it would be best to have treatments that match the genetic
defect present in the cancer.
Cancer With a Small C
The genetics of cancer cut swaths big and small, said John Tod
Isaacs, PhD, professor of oncology and of urology. Much attention in
recent years, he pointed out, has focused on cancer with the
big Cresearch findings with broad implications such as
changes in cell progression, oncogenes, and tumor suppresser genes.
I think were going to enter a new era, Dr. Isaacs
said, of going back to studying cancer as a small C. Were
going to talk about organ-site-specific cancer and how therapies need
to be targeted.
As an example, Dr. Isaacs cited recent work at Johns Hopkins in
prostate cancer. A significant finding within the last decade is that
androgen not only stimulates prostate cell proliferation but also
suppresses apoptosis (programmed cell death). Moreover, it appears
that many cancerous prostate cells in time lose their need for
androgen and become androgen independent, which could explain why
androgen ablation is not more curative. We dont have
targeted therapy for androgen-independent cells, he said.
To provide such a drug, Dr. Isaacs team is working with
thapsigargin, an extract from a plant that grows around the
Mediterranean. The drug can activate programmed cell death
independent of androgen status.
The difficulty is that the drug will also do this with liver
cells and kidney cells, Dr. Isaacs noted. To counter this
obstacle, the Johns Hopkins team modified the drug to take advantage
of a differentiation-specific enzyme that prostate cancer cells make
in abundanceenzyme-reactive prostate specific antigen (PSA).
Unless this specific form of PSA is available, he said, the drug will
not trigger apoptosis.
The only place there is going to be high enzymatic activity for
this is where PSA is being released at a metastatic site, Dr.
Isaacs said. Now, you say, we diagnose prostate cancer by
detecting PSA in the blood. But PSA in the blood is not enzymatic reactive.
Laboratory tests with thapsigargin have proved quite promising, and
the Johns Hopkins researchers are now working with pharmaceutical
companies to carry the work further. While this is very
exciting for prostate cancer, its not going to work for colon
cancer; its not going to work for lung cancer, Dr. Isaacs
said. So you have an organ-site-specific drug.
Chemoprevention is beginning to emerge as an oncologic reality well
beyond the potential of tamoxifen (Nol-vadex) to reduce breast cancer
incidence in high-risk women, said John Davis Groopman, PhD,
professor of environmental health sciences.
This an area that is really coming of age, Dr. Groopman
said. We can look at chemoprevention research as leading not
only to interventions to prevent initial transformation by blocking
carcinogenic agents that one is exposed to, but also to agents that
retard the growth of lesions, but not normal cells, or reverse the
process, or to agents that can be used to move the onset of the
disease much further out.
Dr. Groopman and Thomas W. Kensler, PhD, professor of environmental
health sciences, have worked for a number of years in areas of China
with high liver cancer mortality.
In a large prospective multicenter study of 18,000 Shanghai men,
which began in 1985, they have found that men infected with hepatitis
B before age 1 year and who suffered specific DNA damage following
exposure to aflatoxins have a relative risk of developing liver
cancer of 60, which is what you get with lung cancer with
smoking or asbestos exposure.
Following up on laboratory evidence that the drug oltipraz,
originally developed for use in schistosomiasis, might prove an
effective chemopreventive agent, the two Johns Hopkins researchers
tested it in rats and found it offered 100% protection against liver
cancer in animals fed aflatoxins.
Recently, Dr. Kensler led a phase II trial in China and found in
humans the same underlying biochemistry pathways that we found
could protect against the hepatic carcinogenic affects of aflatoxin
in the rat, Dr. Groopman said. We are going back next
year for a phase II trial of 1-year duration.
One area of increasing importance to both oncologists and managed
care systems is the relationship between stress and dissatisfaction,
because distressed patients use far more health resources, said James
Robert Zabora, ScD, the oncology centers associate director for
Among 429 candidates for bone marrow in a prospective study at Johns
Hopkins, one-third were depressed prior to transplant. When we
really looked at the stress level, the patients who were most
distressed post-transplant were the same patients who had significant
distress before transplant, Dr. Zabora said. Addressing
depression can help improve patient outlook, he added.
More Distress, More Dissatisfaction
A study at Fox Chase Cancer Center has shown that a patient in high
distress prior to therapy is six times more likely to be dissatisfied
with his or her treatment. A study of 381 Mayo Clinic heart patients
revealed that high-distress patients were 15 times more likely to be
rehospitalized than those with low distress and 12 times more likely
to have a second cardiac event.
If we do not detect distress and treat distress, it will
transform into somatic complaints, which we will respond to in terms
of standard procedures, medications, and so forth, Dr. Zabora said.
He and his colleagues have now developed a new, easily scored
standardized assessment, called the BSI 18, that contains only 18
pertinent questions. They have obtained good results in testing it on
1,300 cancer patients.
We now have a psychological screening instrument that can be
given to people during the first clinical encounter, and it takes
about a minute of the patients time, he said.