Scientific Report 2005
Message from the President
Since its creation, Dana-Farber Cancer Institute has held to the motto "Dedicated to discovery . . . committed to care." We strive to give compassionate care at the cutting edge of medical knowledge and technology, even as we make discoveries about the fundamental processes that control living things. It is clear that the secrets to the causes of cancer will be revealed only by understanding these basic biological processes. We can now have greater hopes of cures because the explosion of knowledge from the Human Genome Project is teaching us much about cancer.
For many years, we have recognized that the answers to questions about the growth and development of cells lie in the genes, the control center within each cell. For half a century, we have known that genes consist of DNA, whose sequence of bases contain the secret language for instructing cells how to grow, divide, behave, and, when necessary, die in a manner consistent with the good health of the organism. Before the year 2000, we had learned the basic grammar and vocabulary of that language, but were able to purify only a few hundred of the 30,000 to 50,000 genes present in our genome. At the onset of the new millennium, the Human Genome Project completed the first draft of the entire DNA sequence of our genome. We now know the exact structures of the thousands of genes that control normal cell behavior. These genes, when altered by mutation, may lead to cancer. Thus, descriptions of the exact changes causing a cell to become cancerous will soon reside in computer databases around the world. For the first time, we can hope to study how all human genes behave, how they interact with one another to make the symphony of normal life, and how certain disruptive mutations can create the dissonance of cancer cells.
Five years of working with the human genome sequence has taught all of us that making the ultimate use of this tool is an enormous challenge requiring many years of excruciatingly hard work. Thirty thousand genes can interact with one another in billions or trillions of ways. Finding out how a few mutations disrupt those exquisitely regulated interactions to cause cancer will be an extraordinary effort. But we understand enough to know that mastering those interactions is precisely what we must do to conquer cancer. It is reasonable to expect that far better methods of diagnosis and treatment for at least some of the 400 forms of cancer will emerge well before every nuance of the secret language of genes is understood.
Putting science into practice
At Dana-Farber Cancer Institute, we are blessed with an outstanding research program populated by brilliant and collaborative scientists and physicians. We are also privileged to work in the Harvard medical environment, where we can join forces with literally thousands of talented investigators through mechanisms like the Dana-Farber/Harvard Cancer Center. These scientists have made astounding discoveries and worked hard to develop ways to translate those discoveries into better approaches for diagnosis and treatment. That is why I encourage you to read through the pages that follow in this Scientific Report. Here are a few highlights:
Todd Golub, MD, and his colleagues are developing new genomic strategies aimed at accelerating the cancer drug discovery process. For example, together with Scott Armstrong, MD, PhD, the Golub group used a database of molecular profiles to discover a molecular "signature" of leukemia drug resistance as well as a drug capable of reversing that resistance that is now moving directly toward a clinical trial. Additional studies are leveraging knowledge of the human genome sequence to discover the molecular basis of many types of cancer. In a landmark study led by Gary Gilliland, MD, PhD, Matthew Meyerson, MD, PhD, and William Sellers, MD, mutations in the JAK2 gene were discovered in the hematologic malignancy known as polycythemia vera, thereby indicating for the first time a clear path toward development of a drug for this disease.
"Molecular targeting" is the holy grail of cancer drug development. Gleevec (imatinib mesylate, formerly STI571) made headlines around the world a few years ago because of its efficacy and relative lack of toxicity as a drug for patients with chronic myelogenous leukemia (CML). Gleevec targets a specific molecular defect of CML cells and inhibits the abnormal enzyme activity associated with the disease. George Demetri, MD, and his colleagues at Dana-Farber astutely recognized that a very similar abnormal gene product characterizes a previously untreatable form of cancer called gastrointestinal stromal tumor (GIST). They showed that Gleevec shrank these tumors in more than half of the patients with advanced GIST in a randomized, multicenter trial. Moreover, in record time, they devised a novel method to identify a second drug useful for treating patients who become resistant to Gleevec, and this drug is already in clinical trials.
Laboratory advances provide new insights
Energy metabolism is important in cancer and other diseases. In particular, obesity has emerged as a very important causal agent in human cancer; in fact, it is second only to smoking as an "avoidable" cause of cancer. In recent work, Bruce Spiegelman, PhD, and his colleagues discovered how diets high in saturated and trans fats can elevate levels of blood lipids, especially cholesterol. In addition, Dr. Spiegelman's group discovered a key protein, PGC-1 alpha, which controls the level of mitochondria in virtually all cells. This finding may contribute to our understanding of the wasting (cachexia) associated with cancer, as well as obesity and diabetes.
The interconnections among glucose metabolism, obesity, diabetes, and cancer have also been revealed by the work of Nika Danial, PhD, a recently recruited DFCI faculty member and former trainee of Stan Korsmeyer, MD. Dr. Danial has made the highly surprising discovery - together with Dr. Korsmeyer - that the BAD protein, a key participant in activating signals that promote the death of certain cells, is also involved in glucose-driven insulin secretion by the pancreas. As a death-promoting protein, BAD has the potential to suppress cancer development. Moreover, in keeping with her discovery of the insulin-secretion effect, Dr. Danial has discovered that mice that have lost the BAD gene are effectively diabetic. This finding represents one of the first solid molecular connections between cancer and diabetes. Further exploration of this surprising link is likely to elucidate heretofore unexpected molecular events that underlie both cancer and diabetes development and to offer new therapeutic insights into both diseases.
Dr. Sellers has generated genetically engineered mice that not only mimic humans in their proclivity for developing early-stage prostate cancer, referred to as prostatic intraepithelial neoplasia (so-called PIN), but also have served as test objects, leading to the identification of a class of experimental drugs that can eliminate this early form of the disease. Findings from his work are now being translated into new prostate cancer clinical trials using those agents. Similarly, Ronald DePinho, MD, and his group have generated genetically engineered mice that develop all the established stages of human pancreatic cancer. This work represents a pivotal step in the field, in no small measure because it provides a rational test system for new targeted agents being studied as potential therapeutics in a disease that remains difficult to treat.
Charles Stiles, PhD, and David Rowitch, MD, PhD, have discovered a new family of genes (known as olig genes) that are selectively expressed in the brain cells from which the vast majority of adult brain tumors arise. Knowledge of the ways in which these novel genes operate is likely to unearth new insights into how brain tumors develop.
Linking health and behavior
Jane Weeks, MD, and her colleagues are studying the quality of care delivered to cancer patients across the United States. They have recently demonstrated that even among the leading cancer centers, there is considerable variation in the treatments received by women with breast cancer, suggesting that it really does matter where patients receive care.
Philip Kantoff, MD, and his colleagues have learned that high antioxidant levels may help prevent prostate cancer. In individuals with an inherited subtype of the gene manganese superoxide dismutase (MnSOD), which is present in approximately 25 percent of the general population, low levels of antioxidants in the blood are associated with a 5-fold excess risk of prostate cancer as compared with the rest of the population. In addition, in this genetic subset, high levels of antioxidants are particularly protective against prostate cancer.
Karen Emmons, PhD, and Glorian Sorensen, PhD, MPH, have recently completed studies demonstrating effective ways to reduce cancer risk behaviors among working-class, multiethnic populations, which typically have higher levels of risk and fewer opportunities for behavior change.
These highlights are but a few of the efforts to put science to work for better cancer care that you will find in this publication. By the end of this report, I'm sure you will share my deep feeling of respect, admiration, and support for these outstanding investigators. It gives me great pride to offer you this summary of scientific progress at Dana-Farber Cancer Institute.
Edward J. Benz Jr., MD
President, Dana-Farber Cancer Institute
Director, Dana-Farber/Harvard Cancer Center
