The Future of Epithelial Cancer Therapy

he goal of cancer research is to improve our ability to prevent and cure epithelial cancers like breast cancer. Though our achievements in cancer prevention are less than impressive, Mario's and Joan's stories show that we have made great progress in curing patients. But even in childhood leukemia and stage 3A breast cancer, two types of cancer that are very responsive to modern treatment, we only cure 80 percent of those who are afflicted. That is a huge increase in the cure rate over the nearly fifty years of my experience, but it isn't good enough. We need much more understanding of epithelial cancer biology if we are to develop the treatments that will capture the last 20 percent.

Fortunately, we are gaining that vital knowledge. Cancer is an acquired genetic disease, and we are learning a vast amount about the human genome. As a result, we know much more about the genetic changes that cause cancer. From that knowledge we will gain new and much smarter therapeutic options and have them ready should Mario or Joan relapse. In fact, we already have a very new and effective smart drug in reserve for Mario should he need it. What about Joan? Keeping in mind that her cancer is Her2/neu negative and therefore ineligible for Herceptin or lapatinib—the leading smart treatment for breast cancer today—can we hope for something new that would help her if she relapses somewhere down the line?

Though we lack another general-purpose smart drug for breast cancer at this moment, we are gathering information that will lead to better drugs in the near future. We are learning much more about the precise genetic events that turn a normal cell into a cancer cell. Much of that information has come from Robert Weinberg's laboratory at MIT. Weinberg and Bill Hahn, now at Dana-Farber, have shown that a normal epithelial cell can be turned into a malignant tumor if certain genes are altered. Among the several requirements are high expression of genes like ras that hasten the rate of cell division, another gene called telomerase that prevents the usual erosion of tips of chromosomes during cell division, and defective expression of the genes that produce the sniffing proteins that detect and send damaged cells down the death pathway. Cancer is the result of too much division and too little death.

Weinberg and Hahn's work suggests that several defective genes operate in a coordinated way to cause cancer. That is a worry. It will be very hard to define drugs that will interfere with several different pathways, all of which are responsible for parts of the problem. But both Bob Weinberg and Francis Collins, the latter the director of the National Human Genome Research Institute of the National Institutes of Health, are optimistic that the extensive mutation injury to cancer cell DNA actually creates Achilles' heels in the cells. The mutations increase several drivers of cell division and eliminate important death pathways. In so doing, they turn cancer cells into growing machines, but the cancer cells become absolutely dependent on one or two of those changes in pathways. They cannot survive without them. If we can define and block those acquired pathways, we can hoist the cancer cells on their own petards.

Francis Collins is a tall, well-spoken North Carolinian. He was a chemistry major at the University of North Carolina who got a Ph.D. in quantum mechanics—about as far from cancer as you can get in science. In the middle of his Ph.D. training, he discovered molecular biology and genetics and decided to change his career. The genetics program at Yale is particularly strong, so he made his way to New Haven for research training in a laboratory directed by one of my former Harvard Medical School classmates who told me that Collins was one of the best he had ever seen. I met him and totally agreed. I've admired Collins since he began his medical research career. I've particularly admired his determination to give something back to society. Every summer, until the past few, Collins has volunteered as a physician in a clinic in an underdeveloped country. He doesn't talk about that commitment. He just does it.

After Yale, Collins went on to the University of Michigan, where he led the team that discovered the gene defect in cystic fibrosis, a severe inherited pulmonary and gastrointestinal tract disease of children and young adults. Several years ago, Collins was asked to head the human genome project at the National Institutes of Health. That enormous international task, the base-by-base sequencing of the entire human genome, was substantially completed in 2000, well ahead of schedule and actually underbudget. Now Collins is the director of the National Human Genome Research Institute at the National Institutes of Health.

Despite his numerous responsibilities, Collins continues to operate a research laboratory and has found a beautiful example of the Achilles' heel of epithelial cancer. There is a rare human epithelial cancer called multiple endocrine neoplasia. Patients with this type of cancer get malignant tumors in the insulin-producing islets of the pancreas, in the pituitary, and in other endocrine glands. The tumors have multiple genetic abnormalities and have the highly damaged chromosomes that characterize breast cancer and other epithelial cancers even in their earliest stages. One of those gene defects stands out. It is a missing or defective gene that Collins calls MEN1. Collins has developed a mouse model of the human disease. When he reinserts that gene in its normal form into tumors, they disappear. So MEN1 is an antioncogene such as the breast cancer—associated (BRCA) genes or p53.

Though the genome of multiple endocrine neoplasia tumors is badly damaged and bears many defects, restoration of only one defective gene cures the tumor. From this important observation and several others like it, we have to conclude that a search of tumors for their Achilles' heels, or what we might also call the soft underbelly of cancer, must reveal the pathways that smart drugs can successfully attack.

With quiet determination, Nellie Polyak, the young investigator at Dana-Farber who demonstrated that normal breast cells may become chemically modified and support the growth of cancer cells, is pursuing the soft underbelly of breast cancer cells themselves. Polyak was born in Hungary and knew she wanted to be a scientist from the moment she gave up her dolls. Her grandparents were German Jews who barely escaped the Nazis, fled to Hungary, and survived the savagery of World War II. Her grandmother actually immigrated to the United States to become a nurse at a hospital in Boston.

Polyak went on to the university in Szeged as a medical student, where professors noticed her penchant for and nascent skill in research. She was sent as a special student to do laboratory research at the Hungarian National Academy of Sciences, where she became committed to a career in cancer research. Knowing that Hungary had a severely underfunded research base, she elected to seek graduate training in the United States. After she received her medical degree in Hungary, Polyak attended the graduate school of medical sciences at Cornell and the Sloan Kettering Institute in New York City. She had made a commitment to basic laboratory research.

Polyak had a spectacular career in New York and received a coveted postgraduate training opportunity in Bert Vogelstein's laboratory at Johns Hopkins University. Vogelstein, a physician scientist, had pioneered a highly successful inquiry into the genetic basis of colon cancer. He is one of the fathers of cancer genetics. Vogelstein insists that his graduate and postdoctoral students visit the cancer clinics so that they can understand the importance of their work.

The patients made an indelible impression on Polyak. She competed successfully for a junior faculty position at Dana-Farber and began her work on the genetic basis of breast cancer. Polyak knew that she would contribute in the laboratory and not in the clinic, but she wanted to see the patients coming through the front door of the cancer center. Like her mentor, Vogelstein, she knew that the sight of them would encourage her trainees to work as hard as possible to find biological principles about breast cancer that could be rapidly translated into new therapies.

Polyak's first approach was to collect as many samples as possible of the different presentations of breast cancer—from ductal carcinoma in situ (DCIS), the preinvasive lesion that arises from one mutated duct lining or epithelial cell and remains entirely in the ductal system, to broadly invasive disease. To gather the samples, she needed the cooperation of several breast surgeons like Dirk Iglehart and the all-important patholo-gists who understand the anatomic as well as the genetic details of breast cancer.

Having collected the samples, Polyak asked a simple question: What are the genes that are uniquely expressed in DCIS, and are they different in invasive breast cancer? To answer the question, Polyak adopted a method of analysis of gene expression that differs from the microarray technique that Todd Golub utilized when he and Scott Armstrong found the aberrant flt3 overexpression in Mario's MLL leukemia. Microarray analysis tests the relative expression of certain previously identified genes in two or more tissues or cancers. The method that Polyak adopted is called serial analysis of gene expression (SAGE). It identifies the absolute amount of expression of genes within a given tissue or a nodule of cancer.

Within a two-year period, Polyak found two very important gene expression abnormalities in breast cancer. The first discovery was a gene called hinl. (Hin is an acronym for "high in normal.") The hin gene produces a growth-regulating protein that is very readily detectable in normal duct cells and almost entirely lost in DCIS or invasive breast cancer. It seems to act like another antioncogene.

The second discovery is even more exciting. Polyak found overexpression of a gene called ibcl (the acronym for "invasive breast cancer") in the ductal cells of patients with highly invasive large breast cancers that metastasize early. The gene was not previously identified in the human genome. It produces a growth-promoting protein that acts like a dominant oncogene. Obviously we need much more information about it and its receptor because it might be possible to develop an assay for its function, and from that technology, create a drug that would inhibit the growth-promoting function of the protein and stop invasive breast cancer in its tracks.

Polyak knows the importance of her work. She is in the lab night and day trying to get the data on ibcl as rapidly as possible because she sees Joan and the hundreds of other women coming through the doors of the cancer center every day. The physician in her wants to help them. She takes time off to create some lovely impressionist paintings of neighboring brooks and footbridges. That releases her tensions and clears her mind. Then she can return to the work with fresh resolve.

Polyak and other committed scientists worldwide are determined to find the pathways of breast cancer cells and shut them down with smart drugs. Joan, the thousands of patients like her, and their families are relying on the discovery of such drugs.

Meanwhile, Joan is back at work on community development projects. We all hope that her breast cancer treatment is now behind her, but we continue to search for the smart drugs that will totally eradicate her disease and the breast cancer that plagues thousands of women every year. Given sufficient time and effort, we will find them.

Ken's Story

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