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In Brief 2001 Budget Request Scientific Priorities for Cancer Research
How We Work Other Ways to Get This Information Cancer Information for Patients and Health Professionals  |
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Scientific Priorities for Cancer Research: NCI's Extraordinary OpportunitiesMolecular Targets of Prevention and TreatmentIntroductionOur systematic search for drugs to combat cancer began about 60 years ago. During most of this search, our understanding of cancer has been limited by technologies available at the time – the microscope enabled us to see the structure of the cancer cell, but our ability to discern the once normal features and internal pathways that had become corrupted was incomplete. As a result, our techniques for identifying drugs to prevent or treat cancer were rate-limiting, involving tests that measured inhibition of cancer's development or its growth in animals or test tubes. Despite these limitations, scientists have identified drugs that, alone or with surgery, can cure some cancers in people and can significantly ease symptoms in others. Yet anyone who has ever undergone treatment for cancer – or watched a loved one undergo treatment – knows that our ability to treat the disease leaves much to be desired. Most of the common tumors of adults – the ones that cause most of the suffering and death from cancer – do not respond well to the treatments available today. And even when these treatments succeed in shrinking tumors or eliminating them from the body, they can cause a variety of short- or long-term side effects that can have a devastating impact on a patient's quality of life. Many of the serious side effects of cancer treatments stem directly from their non-selective nature. Until recently, we were unable to detect the differences between the molecular features of normal and cancerous cells, and thus, a compound that inhibited the growth of a tumor cell also inhibited the growth of a healthy cell. This is what causes many of chemotherapy's most severe toxic effects. However, drugs that target the molecular differences between tumor and normal cells – the altered genes or proteins or the corrupted pathways – would be less toxic and more effective than the drugs we currently have. The situation for prevention is similar. The recent findings that the anti-estrogen tamoxifen can reduce the risk of invasive breast cancer suggests that cancer prevention is a realistic possibility. If we know the precise molecular steps that characterize premalignant change, we can attempt to find agents that reverse these changes or prevent next steps critical to the full development of cancer from occurring. This new generation of chemopreventives will be optimized and made more efficient by clinically testing the effect of a preventive on its intended target. Until recently, scientists working to discover effective prevention and treatment agents have faced a formidable barrier: not knowing precisely what cancer is. No longer is this the case. With the evolution of molecular biology and the emergence of new technologies, we are gathering remarkable knowledge about the nature of a cancer cell and the molecular changes that occur during a tumor's development. The extraordinary opportunity before us – to discover and exploit molecular targets for cancer prevention and treatment – arises from the convergence of scientific advances in several areas. Cancer Biology We continue to make astounding strides in our understanding of how molecules and pathways in premalignant or fully malignant cells differ from their normal counterparts. This new knowledge is enabling us to understand and classify human tumors in terms of molecular changes and also has given us a new strategy for cancer drug discovery. Today, every difference between cancerous and normal cells is not only a biological fact or a point of interest to the biochemist, it is a potential target of opportunity for drug discovery. Synthetic Chemistry Traditionally, the chemicals used in anti-cancer drugs have come from nature – from tropical rain forests or organisms in the sea or the soil. Using recently developed techniques, chemists now are able to create in the laboratory enormously diverse collections of compounds. Now, both naturally and synthetically derived chemicals can be screened for possible anti-cancer effects. The ability to test the effectiveness of large numbers of structurally diverse compounds – using highly informative cancer-relevant techniques that exploit our knowledge of cancer biology – is now a reality. Biosynthetic Chemistry Synthetic chemists have long been able to manipulate small molecules to produce useful medicines. The recent biotechnology revolution has cleared the way for biochemists to mix and match genes to design synthetic proteins. Changing proteins in cells is an important breakthrough, since proteins form the "messages" that make up communication pathways that determine a cell's healthy or aberrant behavior. Historically, scientists have been unable to alter these messages since they only had access to proteins produced naturally within cells. Now scientists can change the messages sent by protein molecules, creating a whole new class of drugs to be tested for anti-cancer activity. High Throughput Screening Over the past decade, advances in biotechnology have made it possible to devise highly sensitive, highly efficient tests for virtually any biological process. These tests, or "smart" assays, can be used many different ways. For example, they can be used to screen cell lines and tissues for the presence of particular genes, proteins, or entire pathways – an essential step in identifying the chain of events involved in every stage of cancer development. These assays also can be used to screen potential drugs for anti-cancer effects; thousands of compounds can be screened in this manner each week. Moreover, these assays can be performed on a micro scale with tiny quantities of material, using computer-driven robots to maximize efficiency. Medical Imaging Until now, imaging has been used in cancer research and care to gain information about the occurrence, size, and location of tumors. Refinements in imaging technology are allowing us to watch molecular processes within the cell unfold, as they occur, with unprecedented vividness and accuracy. Imaging techniques are being developed to tell us not only the location of a tumor but the kind of molecules it contains and how its biochemical pathways work. Further advances will have a profound impact on the testing of potential cancer interventions. For example, new imaging technologies have the potential to track where drugs go in the body, or visualize a drug's immediate effects on abnormal collections of cells and on normal tissues. These uses of such functional imaging approaches are likely to be as common in the future as the use of the CT scan is now. The convergence of these advances presents us with the opportunity for a real revolution: to place the discovery and development of drugs for cancer prevention and treatment on a firm scientific footing. There is good reason to think that doing so may, within the next decade, lead to a whole new generation of cancer treatments and preventives. Yet, to ensure our success, we need to create conceptual and functional links among drug discovery, development, and clinical testing in ways that are completely unprecedented. To understand why, consider the main questions that researchers need to pursue about a new drug's effect on malignant or precancerous cells. Does the drug kill the cancer, or at least effectively block its growth and spread? What part of the cell's complex machinery does it disrupt and how is this disruption related to its anti-cancer effect? Until now, with our incomplete knowledge of cancer, we had neither the knowledge nor the tools to address this second question, and thus, our clinical testing focused only on the first. It is crucial that we gather the knowledge and develop the tools to answer both of these questions. When we can, we will finally be able to address some of the most important questions in cancer therapeutics. If a drug is working well, why is it working, and if not, why not? Are we giving a person the right amount, or too much, or too little? Do we have to give people the maximum amount of a drug that they can tolerate, or can we judge the right amount by whether the drug is getting to the tumor and affecting its target? Will the drug harm the patient, now or in the future? Only when we can answer these questions will we be able to predict who is likely to respond to a particular treatment and who will not. Moreover, information from the clinic and from the laboratory will reinforce each other, providing the basis for the design of even better drugs in the future. Timely investment in this area is critical. If the NCI does not invest now, engaging academically-based cancer biologists will depend on the alignment of their discoveries with the product development goals of individual companies. This process will be incomplete and will not necessarily emphasize the compounds, hypotheses, or approaches that are likely to yield the most far-reaching advances. Because most companies' efforts are highly focused, many important scientific opportunities will not be explored in a timely manner. Most importantly, development of the practical tools needed to enable assessment of a drug's effects on its molecular target in vivo will not happen quickly or systematically, and information and reagents will not be made publicly available as soon as they might have been. Learn more about: Goals and Plan The Goals
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