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P&S Journal

P&S Journal: Fall 1997, Vol.17, No.3
The Winning Side of the War on Cancer

By Devera Pine
The years of investment in cancer research and treatment are beginning to yield results.
Although a diagnosis of cancer still strikes fear in the hearts of those who hear it, statistics offer a more hopeful outcome: Cancer deaths declined 3.1 percent between 1990 and 1995.

In labs, doctors' offices, and hospitals across the nation, small victories are being celebrated in the war on cancer. At Columbia-Presbyterian, a concerted effort through institutional investment, private giving, creative leadership, and dedicated commitment have infused the cancer research and treatment programs with the weapons necessary to earn a place on the front lines of the cancer battles.

In an effort that's beginning to pay off, new research being conducted today and on the immediate horizon promises to improve the statistics even more. "The field of medical research has made major advances in many diseases," says Dr. Herbert Pardes, vice president and dean. "For instance, the diagnosis and treatment of heart disease has improved considerably over the last 10 years. The results we are now seeing from cancer research is a hopeful sign that we will soon be able to have the same kind of impact on cancer."

At P&S, the past few years have been particularly auspicious for cancer research: In 1994 Dr. Riccardo Dalla-Favera first identified BCL6, a gene that is altered in non-Hodgkin's lymphoma, the sixth leading cause of cancer deaths in the United States. Also in 1994, Drs. Yuan Chang and Patrick Moore discovered a novel herpesvirus in Kaposi's sarcoma, paving the way for new insights into the prevention and treatment of this malignancy that frequently affects AIDS patients. And in March of this year, Dr. Ramon Parsons and colleagues identified and characterized P-TEN, a gene on chromosome 10 that appears to be mutated in sporadic brain, prostate, and breast cancers. Sporadic cancers account for more than 80 percent of all cancer cases.

"I don't know of any other center that has seen three major clinically related cancer observations in such a short time," says Karen Antman'74, director of the Herbert Irving Comprehensive Cancer Center, Wu Professor of Medicine, and chief of medical oncology.

The findings are part of a growing body of research that offers physicians new insights into the treatment and prevention of cancer. At P&S, those insights are coming from research on gene therapy, "tandem" stem cell transplants, and immunotherapy. "Much of this research is the product of studies funded a decade ago, and we are now seeing the results," says Dr. Antman. "At a minimum it takes seven to 10 years from the design of a trial to know how a treatment affects survival," she says. "By virtue of the fact that we've been doing cancer research since 1940, we now have a number of diseases that are treatable and curable."

What follows is a look at basic and clinical research at P&S that offers hope in the fight against cancer.

The Laboratory Approach
Dr. Ramon Parsons Photo by Lou Manna
Dr. Yuan Chang, left, and Dr. Patrick Moore: They discovered a novel herpesvirus in Kaposi's sarcoma.
Several advances in laboratory science are offering hope for new cancer treatments.

For 20 years, scientists searched for the cause of Kaposi's sarcoma (KS), a tumor of vascular origin that causes red or purple lesions on the skin and mucous membranes. Until AIDS made it a fairly common disease (KS infects 15 percent to 20 percent of all people with AIDS), KS was a rare cancer found mostly in the elderly or in organ transplant patients who received immunosuppressant drugs. A team led by Drs. Yuan Chang, associate professor of pathology, and Patrick Moore, associate professor of clinical public health (epidemiology), changed all that by characterizing a new type of herpesvirus isolated from the KS tissue of an AIDS patient. Subsequent tests developed by Drs. Moore, Chang, and Shou-Jiang Gao, research scientist in epidemiology, erased any doubt that the virus, named Kaposi's sarcoma-associated herpesvirus, or KSHV, causes KS. The identification of KSHV adds to the growing list of viruses known to be responsible for cancer. Others include papilloma virus, which causes cervical cancer, hepatitis B, and liver cancer, and Epstein-Barr virus, which causes Burkitt's lymphoma and nasopharyngeal carcinoma.

Diffuse large cell lymphoma is the most prevalent type of non-Hodgkin's lymphoma, the most common and most lethal type of cancer of the immune system. Beginning in the 1980s scientists started identifying the oncogenes involved in other non-Hodgkin's lymphomas, but the genetic trigger behind diffuse large cell lymphoma remained a mystery. In 1994, however, Dr. Riccardo Dalla-Favera, the Percy and Joanne Uris Professor of Pathology and professor of genetics and development, and colleagues characterized mutations in the gene BCL6. Dr. Dalla-Favera found that the gene appears to be translocated in tumor cells but not in normal cells.

Since his original discovery, Dr. Dalla-Favera has continued work on BCL6. In his most recent study, published in Nature Genetics in June, he found that mice in which BCL6 had been knocked out lack germinal centers (the spleen and lymphoid structures where "virgin" B cells meet antigens for the first time and proliferate and increase their specificity before entering the plasma). He also found that in diffuse large cell lymphoma, the promoter of BCL6 is somehow changed so that B cells can't leave the germinal center. The B cells continue to proliferate, leading to malignancy.

Focusing and identifying the genetic lesions of cancer in this way will help improve diagnostic and treatment abilities, says Dr. Dalla-Favera. "Right now we have drugs that kill everything that proliferates. If we know why each cancer type proliferates, we may be able to develop drugs targeted to the specific alterations that are associated with tumor formation. This should increase the efficacy and diminish the toxicity of anticancer treatments." Dr. Dalla-Favera notes that his lab works closely with the Columbia Genome Center, which provides the advanced technology needed for gene searches.

Dr. Ramon Parsons Photo by Jonathan Smith
Dr. Ramon Parsons: His co-discovery of a tumor suppressor gene has potential importance for sporadic breast, brain, and prostate cancers.
Dr. Ramon Parsons, a McDonnell Scholar and assistant professor of pathology and of medicine, made his discovery of the tumor suppressor gene P-TEN in March, only a year after joining P&S. Dr. Parsons and co-author Dr. Michael Wigler of Cold Spring Harbor Laboratory found that P-TEN is mutated in sporadic breast cancer, sporadic brain cancer, and sporadic prostate cancer. (A group of researchers at M.D. Anderson Cancer Center in Houston also identified the same gene in a paper published 10 days later; they called their gene MMAC1.)

P-TEN is located on chromosome 10 and is a tyrosine phosphatase, meaning it removes phosphate groups from certain proteins. Scientists believe this is a crucial step in the suppression of tumors. (See "Research Reports,")

P-TEN has three potential clinical applications, says Dr. Antman. First, it may lead to diagnostic tests that allow physicians to determine whether a patient has cancer. Physicians also may be able to track its inheritance in families. And, finally, it may lead to the development of drugs to treat tumors.

On the Clinical Front
Many clinical studies at P&S also offer promising results against cancer.

Preliminary results of a pilot clinical study of gene therapy have not uncovered any significant side effects so far. Drs. Charles Hesdorffer, associate professor of clinical medicine; Arthur Bank, professor of medicine and of genetics and development; and Antman are collaborating to determine whether genetically altered bone marrow cells can help protect patients against high doses of chemotherapy. In a phase I trial of the technique, the researchers insert the multidrug resistance gene (MDR) into stem cells using a safe, defective retrovirus. The altered stem cells, along with unmodified stem cells, are then reinfused into patients. MDR produces a protein that pumps harmful substances, including chemotherapeutic agents, out of cells. The researchers hope that this property will allow bone marrow stem cells with MDR to survive standard and high doses of chemotherapy.

A Few Other Basic Studies

In addition to the work of Drs. Dalla-Favera, Parsons, Chang, and Moore, many other scientists at P&S are involved in laboratory research about cancer. A few highlights of ongoing work at the Herbert Irving Comprehensive Cancer Center:

Dr. Bernard Weinstein is investigating cyclin D, a marker for many types of cancer. Cyclin D may allow cells to pass through check points in the cell cycle; many tumor cells overexpress it and have unregulated growth.

Dr. Max Gottesman is investigating the v-RAS oncogene and how it affects thyroid cells.

Dr. Marian Carlson studies kinases in yeast cells. Kinases help regulate the activities of proteins that may be key to cancer progression.

Dr. Lorraine Symington studies the rearrangement of DNA in yeast. DNA rearrangements are often the basis of oncogene activation.

Dr. Aaron Mitchell studies the regulation of meiosis and chromosome stability in yeast.

So far, two out of five patients who received modified stem cells have been "positive" for gene transfection. This phase of the study will determine only the feasibility and safety of the technique, not the effectiveness of the gene therapy, says Dr. Hesdorffer. "No gene therapy has yet been shown to have therapeutic benefits. But I think we'll get to a therapeutic level within several years. That is, we'll have clinically significant results other than merely marking cells. It's a small step in the right direction."

A preliminary trial of "tandem" stem cell transplants is producing good results. In this study, patients undergo three courses of high dose chemotherapy and stem cell transplants, says Dr. Linda Vahdat, assistant professor of medicine. The study aims to improve the success rates of the procedure for metastatic breast cancer by adding active drugs to the therapy. In the first two transplants, women receive high doses of taxol then melphalan during their chemotherapy, which they get on an outpatient basis. In the third cycle they receive three drugs and stay in the hospital. Preliminary results of the study indicate a high complete remission rate in women treated with this approach. About 20 percent of women who undergo one procedure are still disease-free after five years. Less than 3 percent of women with metastatic breast cancer who do not undergo high dose chemotherapy and stem cell transplants stay in remission for up to five years.

Dr. Riccardo Dalla-Favera Dr. Riccardo Dalla-Favera:
His identification of gene mutations provided the first evidence of the genetic trigger behind diffuse large cell lymphoma, the most prevalent form of non-Hodgkin's lymphoma.
Dr. Vahdat is also involved in trials of immunotherapy for breast cancer in the post-transplant setting. "The idea behind immunotherapy is to put the immune system into overdrive, either with cyclosporin A and interferon gamma or with low doses of interleukin 2." The combination of cyclosporin A and interferon gamma may work by inducing a low-grade graft vs. host disease: The therapy inhibits the immune system's ability to distinguish self from non-self, causing the immune system to attack normal cells and, hopefully, cancer cells. Therapy with interleukin 2 increases the number and functional activity of natural killer cells, which have a role in tumor surveillance.

Drs. Kyriakos Papadopoulos, senior clinical fellow in medical oncology, and Gwen Nichols, an Irving Assistant Professor of Medicine, are also working on stem cell transplants but for chronic myeloid leukemia (CML). CML is essentially a chronic form of leukemia that ventually progresses into an acute form that is difficult to treat and causes fatal complications. High dose chemotherapy and a stem cell transplant can slow the progression of the disease, but so far only allogenic transplants--those in which the stem cells do not come from the patient--have cured patients. However, only about 20 percent of people with the disease have a brother or sister for a compatible stem cell match. Drs. Papadopoulos and Nichols are now seeking to improve the response of CML to autologous stem cell transplants. They are recruiting patients for a clinical trial in which they will give patients chemotherapy and collect stem cells early in the patients' recovery from chemotherapy. A significant percentage of these stem cells are normal and will be returned to patients after high-dose chemotherapy. "This is one of the few such protocols available on the East Coast for these patients," says Dr. Papadopoulos.

Dr. Karen Antman Dr. Karen Antman:
leading the fight on cancer as director of the Herbert Irving Comprehensive Cancer Center
In another approach to treating CML, researchers are trying to develop a vaccine that would create an immune response against proteins carried on leukemic cells. Dr. Papadopoulos and colleagues used cells from a patient with CML to isolate peptides bound to the HLA molecules. They found a number of peptides that are specific for leukemic myeloid cells, one of which came from a protein used in NIH in vitro experiments that produced an immune response. These results are encouraging and suggest researchers may be able to develop a vaccine that will activate the immune system against the disease.

Over the past decade--and especially in the past few years--the field of radiation oncology has undergone such rapid advances in technology that radiation therapy can be given at higher--yet safer--doses. "Radiation therapy now offers a greater probability for tumor control and cure, and in most instances the side effects have actually decreased," says Dr. Peter B. Schiff, professor and chairman of radiation oncology. New techniques under development or about to be available offer additional hope. In the next six months, CPMC will be among the first medical centers in the New York metropolitan area to offer intensity modulated radiation therapy. This system relies on multiple computer-designed fields to deliver an optimal dose of radiation to treat a tumor while at the same time limiting the dose to normal tissue. It is more precise than other computer-guided systems now available. CPMC also will be one of the few centers in the area to have a gamma knife, which can give small, focused high doses of radiation while sparing nearby normal brain tissue; it is primarily used for intracranial and base of skull lesions.

Laboratory and clinical research in radiation oncology is advancing knowledge about how radiation can fight cancer. Dr. Howard Lieberman, associate professor of radiation oncology in the Center for Radiological Research, identified the gene HRAD9, a human homolog of the fission yeast gene rad9. "It's likely that HRAD9 plays an important role in how human cells respond to radiation exposure," he says. Another team of researchers, led by Dr. Eric Hall, the Higgins Professor of Radiation Biophysics, professor of radiology and of radiation oncology, and director of the Center for Radiological Research, is working on a gene called ATM, which appears to be involved in radiosensitivity and in susceptibility to cancer induced by ionizing radiation. If these and other genes play a role in how the body responds to radiation, physicians may one day be able to use them to identify people at risk for complications from radiotherapy and from the radiation in diagnostic screenings such as mammograms. People who do not have genes that put them at risk might be able to receive higher doses of radiation therapy without increasing their risk of complications.

The Ritz at CPMC?
Patient's Generosity Makes Long Hospital Stays More Comfortable
By Sally McLain
If you had to stay in the hospital for an entire month, you'd want to make that stay as comfortable as possible. So when Robert Carmel, a cancer patient, learned of a long-term stay at CPMC, he knew he'd have to do something. Because his cancer required an autologous bone marrow transplant (BMT), he would need four weeks of inpatient hospital care with part of that time in partial seclusion. How could he make his stay a little more comfortable? Why not create a setting that would feel more like a luxury hotel suite than a hospital room? Why not, indeed.

So, Mr. Carmel, a real estate executive, set out to redecorate the room he would call home for four weeks. "He noticed that the rooms were bare," says Dr. Charles Hesdorffer, P&S associate professor of clinical medicine and one of the medical oncologists who treated Mr. Carmel. "He felt patients should have better rooms for their month-long stay in the hospital."

BMT (also called peripheral blood stem cell transplant) is a cancer treatment that usually follows chemotherapy, which is devastating to the body's natural immune system. Doctors can replenish blood cells, including immune cells important in fighting infection, that do not survive the toxicity of high dose chemotherapy. This therapy followed other treatments Mr. Carmel underwent for lymphoma.

Hospital Rooms Typically, hospital rooms are sparse, with a bed, a chair, a mounted television, and a tray table. This might not be a particular hardship for a short stay, but when BMT patients are "sentenced" to that room for three to four weeks--a time during which they will feel very sick and weak--a few amenities of home can help.

So, with his own funds, Mr. Carmel transformed the ho-hum hospital room into an elegant suite complete with rich-looking colonial style furniture, floral chintz draperies, an armoire with built-in entertainment center, refrigerator, desk, and comfortable chair and sofa.

After Mr. Carmel's treatment, he contributed funds for redecorating five additional rooms. And later he funded facelifts for four more rooms, decoration of the nurses lounge (including a kitchenette), and two patient lounges with televisions, microwave ovens, and a video library.

In addition to the furnishings, amenities, and decorative touches, Mr. Carmel purchased several video phones to enable hospital-bound patients to "see" the friends or family on the other end. "We have phones on hand that people can borrow to take home," says Joan Kaiser, nurse manager of the BMT unit, "although we've found that many patients end up using the phones just to talk. When they're feeling their worst, they really don't want to be seen."

Although Mr. Carmel died last year, his contribution to CPMC is a legacy that continues to make a difference for other patients.

Dr. Daniel P. Petrylak, assistant professor of medicine and director of genitourinary oncology in medical oncology, is actively involved in clinical trials of drugs aimed at two particularly difficult cancers to treat, hormone refractory prostate cancer and bladder cancer. The outlook for men with hormone refractory prostate cancer is grim: Most die six to 12 months after their disease becomes resistant to hormones. Until recently, systemic chemotherapy was ineffective against this disease. But now, two experimental new drugs--estramustine and taxotere--offer some hope. The drugs seem to have a synergistic effect when given together in the laboratory. In clinical trials, now in the initial dose-finding stage, 70 percent of patients showed a response, as measured by declining prostate-specific antigen levels. They also significantly decreased bone pain. The drugs will now be part of a national trial by the Southwest Oncology Group, a multicenter collaborative effort that includes P&S researchers.

For bladder cancer, Dr. Petrylak is investigating a three-drug combination about to enter phase I clinical trials.

"We are making progress against bladder and prostate cancer," he says. "It's a slow, tedious process that requires a lot of patience and forethought, but it's getting done." The process of fighting cancer is deductive--almost like a detective story, he says. That's much more difficult than an inductive process, where you're creating something, for example, as in the space program that put a man on the moon. "We now have new drugs showing promising activity. The question is how to fine-tune them. It's really an exciting time to be in clinical oncology."

Cancer Genetics Program However, cancer researchers caution that the battles still ahead in the ongoing war on cancer may be long ones. "The major cancers--prostate, colon, breast, lung--remain a problem, and cures are not on the horizon," warns Dr. Max Gottesman, director of laboratory cancer research in the Herbert Irving Comprehensive Cancer Center. "We need to support basic research to figure out how to prevent these cancers."

WAR on Cancer
One way cancer researchers hope to make progress against the disease is through collaborative registry projects. The Metropolitan New York Registry, for instance, is a National Cancer Institute collaborative project. The project is part of a worldwide research registry for women with a family history of breast and ovarian cancers. The program collects family histories and biological samples. (However, all private information about participants--such as names and address--is confidential.) The contact for the Metropolitan New York Registry at CPMC is Donna Russo, (212) 305-0190.

Women at Risk (WAR) is CPMC's research, education, and treatment program for women at high risk for the development of breast cancer. Women who participate in this program are assessed for their cancer risk and may be eligible for genetic screening and counseling. WAR also sponsors services for women who have been diagnosed with breast cancer. More information on WAR is available from Kitty Silverman, (212) 305-9525.

Registry Breast Center

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