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, he said.
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. Vogelstein said.
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(Drug information on 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 community research.
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.