CANCER IS GENETICS. EVERY MALIGNANT TUMOR BEGINS AS A MUTATION IN ONE OR MORE GENES, GENES THAT ORDINARILY PROMOTE NORMAL, CONTROLLED CELL GROWTH. WHEN THESE MUTATIONS – EITHER INHERITED OR ACQUIRED – ARISE AND ACCUMULATE, THEY LEAD TO CANCER. INDEED, OUR GROWING GENETIC UNDERSTANDING OF ONCOLOGY HAS LED TO THE REALIZATION THAT NO ONE CURE FOR CANCER WILL BE FOUND BECAUSE CANCER IS NOT ONE DISEASE BUT MANY DISEASES, EACH CAUSED BY DIFFERENT GENETIC CHANGES. LUNG CANCER AND BREAST CANCER, FOR EXAMPLE, COME IN SEVERAL DIFFERENT TYPES, AND DIFFERENCES IN GENETICS MEAN THAT A TREATMENT THAT WORKS WITH ONE TYPE MAY BE VIRTUALLY USELESS IN ANOTHER.

A mutant form of Id2 that is resistant to degradation stimulates the growth of axons (red) in neurons (green). Defective growth of axons is present in traumatic injuries of the spinal cord and some neurodegenerative diseases. The work from Drs. Iavarone and Lasorella proposes Id2 as a new and unexpected tool for the experimental treatment of these diseases.

"This evolving knowledge allows us to identify subtypes of each cancer, with different prognoses, understand which genes are altered, and develop targeted therapies that are better suited for the particular type of cancer, "says Riccardo Dalla-Favera, M.D., the Percy and Joanne Uris Professor of Genetics and Development and Pathology and director of the Herbert Irving Comprehensive Cancer Center. "We can now design drugs that essentially attack every part of the cancer cell."
     That is exactly what is happening throughout the nine floors of the new Irving Cancer Research Center, a 120,000-square-foot facility dedicated solely to cancer research, which doubles the research capacity of the Herbert Irving Comprehensive Cancer Center. Columbia’s leading physician-scientists in oncology have already moved into the building, and Dr. Dalla-Favera expects to recruit several more faculty members over the next five years, including five to six with expertise in translational research. "We want to have leading investigators in each key area: understanding the biology of the target organ and which genes are altered; advanced diagnostics; and translational researchers in clinical oncology," he says. "This research will be brought together with population science. Education, control, and prevention will also be a major strength of the cancer center."
     Several key discoveries in cancer genetics have been made at Columbia over the past year. Andrea Califano, Ph.D., professor of biomedical informatics, has developed the first genome-wide snapshots of the transcriptional networks of normal and malignant human B and T cells – the two main types of white blood cells, which are key to the body’s immune response. Working with Riccardo Dalla-Favera and Adolfo Ferrando in the Institute for Cancer Genetics, he was able to "reverse engineer" the transcriptional and signaling networks that govern the genetic interactions of these cells – something not previously accomplished in a human cell. Understanding these networks is essential to both defining the normal functions of these cells and to dissecting the complex array of changes that can happen when cell function goes awry.
     Building on the work of his colleague, P&S microbiologist Kathryn Calame, Ph.D., Dr. Dalla-Favera has been studying an unusual tumor suppressor gene called Blimp-1 (B lymphocyte induced maturation protein). It’s been called a "master regulator" of B cell differentiation – a crucial transcriptional "switch" in the generation of functionally competent plasma cells. But in B-cell lymphoma, Dr. Dalla-Favera and his colleagues found, Blimp-1 is inactivated – and the cells that should have become plasma cells become cancer cells instead.
     Columbia scientists also have helped to answer a key question about the evolution of cancer: How does a tumor-initiating cell, also known as a "cancer stem cell," arise from a normal cell? These stem cells are thought to be the engines of tumor progression, but where do they come from? A better understanding of cancer stem cells is essential if therapies are to be developed to target these critical elements of the disease.
     Think of cell division as an assembly line in a factory. Just as the process of assembling a new car is monitored with stringent quality control, so is cell division. A mistake in assembling a car can lead to a deadly accident, while a mistake made when a cell divides can lead to a deadly cancer. One "checkpoint" that confirms the cell is dividing normally makes sure that chromosomes can be separated appropriately. But Columbia scientists Timothy Bestor, Ph.D., and Marc Damelin, Ph.D., have found that stem and progenitor cells are deficient in this checkpoint and will divide even if the chromosomes are entangled. If cells divide with their chromosomes still tangled, defects will almost certainly result – defects that are the hallmarks of cancer, such as too many chromosomes, too few chromosomes, or chromosomes that are rearranged.
     Of course, the biology of cancer also poses important questions for the burgeoning field of stem cell research and, ultimately, stem cell therapies. Since progenitor stem cells are coaxed to divide again and again, this mistake – dividing with entangled chromosomes – could also happen over and over, increasing the risk that the new cells will be defective. It’s an important area for further research.
     When a pathologist looks at a cancer cell on a microscope slide, one of the worst things he or she can see is that the tumor is "anaplastic." Anaplastic cells are poorly differentiated; they have become so mutated by cancer that they no longer resemble the original cell type that they once were. "Particularly in the most aggressive tumors, cells can completely lose their ability to differentiate, sometimes so much so that you cannot even recognize the tissue of origin," says Antonio Iavarone, M.D., associate professor of neurology and pathology in the Institute for Cancer Genetics. "Only recently have we started to understand the genetic players that are, in fact, responsible for this."

In cancer, many proteins that should not be present in mature cells become abundant and help the tumor grow. Antonio Iavarone, M.D., and Anna Lasorella, M.D., have found that Id proteins, typically present only in normal stem cells before birth, are reactivated in tumors. Id protein research is founded on this premise: Eliminating Id proteins will eliminate cancer.

     The proteins that are involved in this process are called Id – for "inhibitor of differentiation" – proteins. "What they do is inhibit the function of transcription factors that normally decide a neuron is a neuron or a breast duct cell is a breast duct cell. Their useful function is to maintain the state of stem cells, but normal cells after birth lose the ability to express these Id proteins," Dr. Iavarone explains. "Somehow, however, they become reactivated in tumors cells, and an abundance of Id proteins is directly proportional to the aggressiveness of tumors."
     Dr. Iavarone and his colleagues have found that every single human tumor type expresses one or more of the four members of the Id family. In breast cancer, Id1 is prominent; in neuroblastoma, Id2; and in skin cancer, Id1, 2, and 3 are all expressed. "Every tumor has one or more Id proteins that are abundantly expressed," he says. "This is a very attractive target from a therapeutic point of view, because Id proteins are essentially absent in normal adult tissues, so you could attack them without damaging normal tissue."
     Until recently, no one knew what controlled the cellular abundance of Id proteins. But in a study published in Nature, Dr. Iavarone and Anna Lasorella, M.D., assistant professor of pediatrics and pathology in the Institute for Cancer Genetics, reported that an enzyme called APC (anaphase promoting complex) found inside normal cells promotes the destruction of these proteins. Could re-introducing the APC enzyme into cancer cells shut down, or at least reduce, the activity of Id proteins? That’s what Drs. Iavarone and Lasorella hope to find out in future research. "The implications are really widespread. Id proteins sustain every step of cancer growth, including angiogenesis, the ability to create new blood vessels to feed upon, and metastasis. All these steps essentially depend on Id proteins. If we can knock out Id proteins, we can knock out cancer."
     That alone would make Id proteins an extraordinarily fruitful target for research. But what if physicians could take advantage of the very function that makes Id proteins so dangerous in terms of cancer – promoting growth – and harness it to coax dead or damaged cells into growing again? That’s exactly what Drs. Iavarone and Lasorella think they can do for patients with spinal cord injury or Alzheimer’s disease, conditions in which the brain’s neurons have been injured or killed.
     Instead of using the APC enzyme to put the brakes on Id proteins and stop cancer, they created a "super" Id protein, one that would resist the APC enzyme’s destruction so that they could use it to stimulate the growth of axons, the structures on neurons that transmit electrical signals in the brain and spinal cord. This exciting possibility is now being studied for its potential to treat a variety of neurological conditions.
     Just as genetic advances in cancer research are being harnessed for their potential benefits in neurology, discoveries in neurology are also being used to treat cancer. Two years ago, Adolfo Ferrando, M.D., Ph.D., assistant professor of pediatrics and pathology, found that a mutation in a gene called NOTCH1 plays an important role in T-cell leukemia. This particularly virulent type of acute lymphocytic leukemia (ALL) accounts for about 20 percent to 25 percent of all cases of ALL; one in five patients relapses after initial treatment, and even stem cell transplants offer little hope.
     Coincidentally, some experimental drugs designed to inhibit the formation of beta amyloid, the protein that accumulates and forms plaques in the brains of people with Alzheimer’s disease, also inhibit NOTCH1. Because these drugs have already gone through preliminary clinical testing, they could be rushed into clinical trials for cancer much more quickly. This year, Columbia became the only institution in the New York metropolitan area enrolling patients in a large, multicenter clinical trial of the NOTCH inhibitor drug as a treatment for T-cell leukemia.
     No genetic study of human cancer can go very far without high-quality pathologic specimens of actual human cancers, with their DNA and RNA carefully sorted and extracted and good samples sifted from bad, degraded ones. That work can be tedious, but the task is now easier for Columbia breast cancer researchers with the opening of the Macromolecule Bank. DNA and RNA from about 500 breast tumors are available to any Columbia researcher along with clinical data and tissue microarrays, which hold a hundred different samples on a single slide.

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