TASTING the VICTORY OVER CANCER
In the last 20 years, researchers have come much closer to understanding the multiple causes of cancer, and consequently are having greater success developing more specific therapies. Fueling this effort is the technological explosion that opened up the world of molecular biology, leading to major new insights on the workings of cells.
"What was once an impenetrable black box is now an encyclopedia of information about the genetic, and therefore the biochemical, changes that lead to cancer," explains William N. Hait, MD, PhD, Director of The Cancer Institute of New Jersey (CINJ). "With this know- ledge, we are currently identifying new targets for medications to prevent cancer, and also to treat established cancers."
Some of that very sophisticated science is being done at CINJ, which is one of 56 National Cancer Institute-designated centers in the U.S., and the only one in New Jersey. An addition to the New Brunswick facility will help cope with the tremendous increase in patient visits - from 0 to 32,000 since 1993. Branches of CINJ are also planned for Newark, at UMDNJ's University Hospital, and in Camden county. Advancing both basic and clinical research are among its missions, and there are multiple projects supporting these missions.
Since tumor growth represents an imbalance between cell proliferation and cell death, one major research target is an understanding of why some cells don't die. "Cancer cells are good at living," states Hait, "but they forget how to die."
The concept of apoptosis - or programmed cell death - was born from studies of a worm called C. elegans. "Apoptosis," says Hait, "means fallen leaves," referring to the predetermined pathways that cells take in their journey from life to death. Scientists discovered how human cells live and die by studying this lowly worm.
Building on these insights, Eileen White, PhD, leader of CINJ's Molecular Mechanisms of Tumor Growth Program, has studied how the controls that maintain the balance between cell proliferation and cell death sometimes go awry. White and her team discovered how viruses can infect normal cells, but not kill them. The viruses accomplish this by short-circuiting the programmed-death cell pathway. This led to her work on how various viruses can transform normal cells into cancer cells.
"Now that we understand which molecules are involved in stopping programmed cell death, we can work to reinstate cell death by targeting a family of molecules called BCL-2," Hait says.
Robert Di Paola, MD, has worked with White and Sidney Pestka, MD, to develop drugs that can destroy BCL-2 family members, making cancer cells more prone to die when treated with standard chemotherapy. These drugs are in Phase 2 clinical trials at sites of the Eastern Cooperative Oncology Group for Advanced Prostate Cancer, of which CINJ is a member. Di Paola is clinical director of the Dean and Betty Gallo Prostate Cancer Institute, a division of The Cancer Institute of New Jersey.
Other researchers are looking at genes that may be implicated in producing certain cancers. Through studies of the genes that allow the fruit fly to develop, Cory Abate-Shen, PhD, and her team discovered NKX3.1, a gene candidate for causation of prostate cancer. Abate-Shen is director of the Dean and Betty Gallo Prostate Cancer Institute. When this gene is deleted from mice, they develop early signs of prostate cancer, which increase in severity with aging. What is known about NKX3.1 is that its absence, rather than its presence, is linked to cancer development, which means that it has tumor suppressor potential. "If we put back the deleted gene, can we stop the transformed cells from multiplying?" asks Hait. The team is working to establish the answer.
C.S.Yang, PhD, a program leader of CINJ's Carcinogenesis and Chemoprevention Program, is testing nutritional agents that may prevent various cancers. He and David August, MD, director of surgery at the institute, are looking at the potential for polyphenols in green tea to reduce the rate of proliferation of mucosal cells in the colon, thereby inhibiting colon cancer development. They are also studying the ability of green tea to inhibit the production of Cox2 (cyclooxygenase 2), an enzyme involved in inflammation, that has been implicated in rheumatoid and osteoarthritis, as well as cancer. They are looking specifically at the effect of reducing levels of Cox2 on colon cancer development.
Other CINJ researchers are searching for the reasons that advanced prostate cancer is resistant to chemotherapy. As prostate cancer progresses from indolent to aggressive, there are sequential changes in the expression of oncogenes, apoptosis genes and multi-drug resistance genes. Greg Sullivan, PhD, a former graduate student in pharmacology, working with Hait and Leroy Liu, PhD, the leader of CINJ's Cancer Pharmacology program, is looking at how a tumor-suppressor gene called p53 regulates multi-drug resistance proteins. Sullivan discovered that damage to p53 leads to the expression of a multi-drug resistance gene called MRP, which appears to be involved in the resistance of prostate cancer to chemotherapy.
Alan Conney, PhD, a member of the Carcinogenesis and Chemoprevention Program, and Roger Strair, MD, PhD, director of stem cell transplantation at CINJ, are testing croton oil - a derivative of a plant imported from China - on patients with refractory leukemia. It's been known for years that this oil can cause leukemic cells to differentiate into normal cells. But it's also known that the oil is carcinogenic in mice, although not in humans. The active ingredients in croton oil - called phorbol esters - inhibit protein kinase C, which is involved in many aspects of oncogenesis. Tumor cells often manufacture high levels of one or more kinases, proteins that sometimes tell cells to keep dividing when they should stop. Novartis is working to develop a drug that will stop the activity of an aberrant protein kinase called bcr-abl.
Hait says the world of cancer research is moving very rapidly, especially in the area of cancer genetics: "For example, we used to study one gene at a time for a very long time. Soon we will use microarrays to study 50,000 to 100,000 genes at a time." DNA microarray technology allows scientists to assess the level of expression of many of the 100,000 human genes in a cell or tissue. This very new technology can quickly produce a picture of the genes that are active in a tumor cell, and helps to define tumor cells based on their unique molecular changes.
It's how genes are processed by each individual that makes every person unique, Hait explains. "Tumors are not grouped in nature by breast cancers or lung cancers," he states. "It's Mr. Jones' lungs that have turned cancerous. The make-up of Mr. Jones' tumor is different from the tumor of any other human being, just as Mr. Jones is different from you and me."
Scientists are going in the direction of being able to understand each individual's tumor or tumors in enormous detail. Rather than flood a person's system with drugs that can potentially damage many parts of the body, Hait says, "We will soon be able to rationally tailor available therapies to that person's cancer."
So what new therapeutic approaches will CINJ be able to offer Mr. Jones in the near future when he is referred in with a just-diagnosed cancerous lung tumor?
According to Hait, Mr. Jones will be taken through the following steps: first, the lung cancer will be surgically removed; second, using cells from the tumor, the genes that are being converted into messages to produce proteins will be analyzed by a lab that will run computer chips - called biochips or DNA microarrays - that can analyze thousands of genes at a time. The lab will identify which genes are producing more or less gene product than is normal; third, Mr. Jones' physician will say, "Aha! Your cancer can best be treated this way, not that way because these particular genes are the culprits and need to be turned off or toned down!" And the CINJ physician will set up a cancer therapy that has been uniquely tailored for the patient.
"We will be able to select therapies based on the genetics of the patient's tumor," explains the Cancer Institute's director. The chip technology, which is just three to five years old, has been driven by the Human Genome Project and the Cancer Gene Anatomy Project.
"There are currently so many avenues for acquiring information about cancer - cancer pharmacology and molecular biology, gene therapy, immunology, bioinformatics, environmental studies," Hait says. "There's still a lot of work to do, but conquering cancer is doable.
"At this point in time, I can almost taste the victory."
The magazine of the University of Medicine and Dentistry of New Jersey