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Scientific Priorities for Cancer Research: NCI's Extraordinary Opportunities |
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Defining the Signatures of Cancer Cells: Detection, Diagnosis, and Therapy
Goal
The Opportunity
Progress in Pursuit of Our Goal
2003 Plan and Budget Increase Request
Goal
Catalog distinguishing molecular signatures of cells to develop new diagnostic and therapeutic approaches and predict response.
The Opportunity
Our bodies are made up of many different kinds of cells, and each is suited to its particular function as a part of the whole. Scientists are discovering that every cell type has a unique molecular signature - identifiable characteristics such as levels or activities (the abilities of genes or proteins to perform their functions) of a myriad of genes, proteins or other molecular features.
Today researchers are using new technologies to read and understand the signatures of normal cells and how they can change to become cancerous, information that promises to provide important insights into the etiology of cancer be useful for early detection, diagnosis, and treatment. They are learning to identify signature changes in developing tumors, in surrounding cells, and sometimes at more distal, more easily sampled sites of the body - such as sampling cells in the mouth instead of the lung or sampling urine to detect urinary tract cancer. Molecular signatures can also be used to identify cancer-causing infections and environmental agents.
Knowledge gathered through molecular signatures research is expected to help the cancer community learn how to diagnose cancer early before it has a chance to do harm, improve the specificity of cancer diagnosis by allowing clinicians to differentiate among tumors at the molecular level and characterize tumors more efficiently, compose highly effective treatments tailored to the features of each case, and finally, monitor each cancer patient's recovery
To succeed in this effort we will need a full understanding of how cancer starts and progresses, especially focusing on how small changes in only a few genes or proteins can disrupt a variety of cellular functions. This work will require new technologies, new pre-clinical models, and heightened cooperation between investigators from all disciplines of cancer research.
Our ultimate objective is to push back the detection and diagnosis of cancer to the earliest stages when prevention of overt disease can be most successful.
Progress in Pursuit of Our Goal
The NCI is providing resources needed to study the molecular signatures of cancer including:
- Catalogs of molecular changes in cancer at the chromosomal and gene levels
- Genes, tissues, and other biologics for study
- New technologies and informatics tools.
Molecular and Analytic Resources to Stimulate Research
Tissue Resources for Signatures Research
Using Molecular Signatures to Study and Validate Animal Models of Human Cancer
Molecular Signatures and New Approaches for Early Detection
Better Classification of Tumors to Improve Diagnostic Tests
Molecular and Analytic Resources to Stimulate Research
The NCI is creating molecular and analytic resources through genetic profiling and technology development. The Cancer Genome Anatomy Project (CGAP) is a multi-initiative NCI program to build a complete profile of genes expressed in normal, precancerous, and cancer cells. This resource is helping investigators to:
- Elucidate major steps of tumor development
- Develop molecular diagnostic techniques
- Identify molecules that can be used for early detection or drug discovery
Researchers throughout the world have used CGAP to identify molecular signatures of prostate, colon, ovary, breast, pancreas, brain, and other cancers.
CGAP consists of several initiatives.
- The Tumor Gene Index (TGI), containing more than five million gene-based DNA sequences, is the most complete public catalog of gene expression for human cancers and for mouse models of cancer. Scientists already are using TGI to classify tumors according to their molecular features for improved cancer prevention, early detection, diagnosis, and treatment strategies. Through TGI we hope to build a complete index of cancer-related genes.
- The Mammalian Gene Collection (MGC) is extending the TGI to focus on identifying and cloning the full set of human and mouse genes to enable more rigorous study of individual genes, their protein products, and the role they play in human disease. Currently, potentially full gene sequences have been identified for about 15,000 human genes and 8,000 mouse genes.
- The CGAP Genetic Annotation Initiative (GAI) has characterized and cataloged more than 30,000 human genetic polymorphisms. Polymorphisms are variations, sometimes quite subtle, in the DNA sequences of a gene that may affect its function. The GAI provides scientists with insights about genetic variants associated with certain cancers and those that occur more frequently in some populations.
- The Cancer Chromosome Aberration Project (CCAP) was established by CGAP to generate a "Human Cancer Chromosome Aberration Map" - a genetic map that defines distinct chromosomal alterations that lead to cancer. Investigators are using a molecular tool known as BAC (bacterial artificial chromosomes) clones.
BAC clones are derived from bacteria and contain florescent probes as well as inserts of human DNA sequences. The human DNA inserts are designed to bind to aberrant sections of DNA in the samples being tested in the laboratory. Researchers are able to confirm the presence of an aberration by measuring florescence in the sample.
In 2001, CCAP passed a major milestone by producing an online version of the Mitelman Database of Chromosomal Aberrations in Cancer, a well-established and exhaustive reference of chromosome changes in human tumors. In Fiscal Year 2002, CCAP will complete a map that integrates structural mapping of the human genome with chromosomal maps.
Click here for examples of advances from CGAP.
The Innovative Molecular Analysis Technologies Program (IMAT) supports the development of technology to detect molecular signatures in small numbers of cells. This technology is needed to detect cancer at its earliest stage and to study its origins. More than 100 research projects are under way, focusing on new approaches to analyze DNA, RNA, and proteins, as well as new methods to detect interactions of macromolecules in the cell.
The Unconventional Innovations Program is supporting creative technological improvements in cancer treatment and detection. This program aims to generate radically new technologies in cancer care to make attainable the goal of detecting, diagnosing, and intervening in cancer at its earliest stages. It targets improvements in existing technologies or new approaches and actively stimulates the interest and involvement of investigators from disciplines not traditionally focused on NCI's technology challenges.
Tissue Resources for Signatures Research
Clinical specimens are a critical resource for the discovery and application of molecular signatures to cancer detection, diagnosis, and treatment. Responding to this need, NCI has established and made readily available to researchers a variety of tissue repositories.
- The Cooperative Human Tissue Network (CHTN), Cooperative Breast Cancer Tissue Resource, and Cooperative Prostate Cancer Tissue Resource all provide researchers with easy access to high-quality tissue specimens. For example, the CHTN alone is now providing close to 50,000 samples per year. More than 1,000 investigators have been served by the CHTN, and about 200 new investigators request tissue each year.
- The Shared Pathology Informatics Network, a consortium of institutions connected by a model Web-based system, is working to improve scientists' access to human specimens and relevant clinical data. The system will automatically access information from medical databases and respond to queries by identifying, obtaining, and returning data for specimens that meet the defined search criteria, after removing information that could compromise patient privacy.
- The Tissue Array Research Program (TARP) stemmed from collaboration among scientists at NCI and the National Human Genome Research Institute and is responsible for the development of multi-tumor, tissue screening microarray slides. The slides contain up to 600 tissue core samples from different tumor tissues as well as normal tissue and specific cell lines grown in the laboratory.
Researchers use the slides for high-throughput, comprehensive analysis of the molecular profile of each tumor type represented on the slide, including characterization of DNA, RNA, and proteins and to further characterize molecules as potential molecular targets unique to each tumor tissue.
As of FY 2002, approximately 11,000 array slides were distributed to researchers nation-wide. TARP plans to scale up production of these slides and is establishing a knowledge transfer and training program to disseminate this technology to interested scientific investigators.
Using Molecular Signatures to Study and Validate Animal Models of Human Cancer
Models that accurately reflect the behavior of human cancer promise to improve our ability to identify and understand the molecular changes that characterize cancer as well as enhance our ability to evaluate a range of biomarkers prior to clinical use. The Mouse Models of Human Cancers Consortium provides the mechanism to develop and make available to researchers validated mouse models that mimic human cancers.
Molecular Signatures and New Approaches for Early Detection
The Early Detection Research Network (EDRN) is a research program aimed at the discovery and development of novel biomarkers for all cancers and for precancerous lesions. EDRN scientists work to further refine molecular signatures of cancer (the signposts of a cell's progression toward cancer) and to harness their uniqueness. Through these efforts, signatures become molecular tools or "biomarkers' that can be used for cancer screening and detection.
Separate EDRN laboratories cooperate to streamline the development, validation, and clinical testing of promising biomarkers and technologies for cancer screening and detection. This comprehensive, collaborative approach merges genetic pursuits with protein approaches, providing a systematic view of how the molecular signatures of specific cancers can be used as unique, identifying markers.
EDRN researchers have discovered biomarkers for the early detection of several types of cancer, including breast, esophageal, and prostate. In breast cancer studies, researchers are hoping to develop a noninvasive detection test for breast cancer based on proteins present in nipple aspirate fluid (NAF). NAF circulates in the breast ducts and contains proteins produced by the breast. An easily extractable fluid, NAF may provide a "snapshot" of the breast environment. Using a protein chip-based approach and incorporating detection with mass spectrometry, investigators have identified differences in proteins in NAF samples from a cancerous breast compared with a normal breast in the same patient and are now testing the validity of this approach with a large number of specimens.
Other studies are exploring new approaches to detect esophageal cancer at its earliest stages, when the disease is most amenable to intervention. Preliminary EDRN data suggest that gene microarrays may be used to detect premalignant and malignant esophageal lesions with a high degree of accuracy. If validated, these expression profiles offer the potential of classifying esophageal lesions by their aggressiveness and by their responsiveness to chemoprevention.
Other researchers are using protein microarray technology to improve the sensitivity and specificity of tests for prostate cancer. Through this research, they have observed that the serum protein PSMA is superior to PSA, the marker currently used for prostate cancer screening, in distinguishing prostate cancer from benign growth.
Better Classification of Tumors to Improve Diagnostic Tests
Tumors have traditionally been classified according to structural characteristics and not on molecular features that would better predict their biological behavior, treatment response, and prognosis.
Through the Director's Challenge: Toward a Molecular Classification of Tumors initiative, investigators are developing profiles of molecular alterations in human tumors using DNA, RNA, or protein-based analysis technologies. This initiative will enable researchers to develop a more clinically predictive and useful classification system for diagnosing cancer.
These efforts will shift the focus of tumor classification from structure to molecular-based schemes which may be used to define clinically important subset of tumors, helping health care providers choose the best individual prevention and treatment options.
Director's Challenge teams are working on many cancers including breast, prostate, lung, brain, ovary, colon, and leukemia and lymphoma. One team is working to subclassify node-negative breast cancer patients. Node negative/positive is a traditional classification based on whether cancer can be detected in local lymph nodes. While it is known that node positive patients have a considerable risk of cancer recurrence, this classification scheme cannot predict this risk for node negative patients. This molecular subclassification appears to address this problem and researchers are working to validate their findings for use in a clinical setting.
The Program for the Assessment of Clinical Cancer Tests (PACCT) facilitates the translation of new knowledge about cancer and new technologies to clinical practice. Activities include the generation of reference sets of clinical specimens, which will be made available to academic and industry researchers working to evaluate new markers and validate the utility of some known markers and tests.
The Plan - Signatures of Cancer Cells
Goal
Generate a complete catalog of the distinguishing molecular signatures of normal, precancerous, and cancer cells at all stages in all tissues, and use the catalog to develop diagnostic techniques for the earliest detection of precancerous lesions and cancers; develop signature-based therapies; and identify subsets of patients with different prognoses to predict therapeutic response.
Fiscal Year 2003 Objectives, Milestones, and Funding Increases Needed
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| Objective 1: Expand the development and availability of molecular and analytic resources. |
- Initiate the Cancer Molecular Analysis Project to integrate molecular signatures, targets, and interventions.
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$5.00 M |
- Complete the Mammalian Gene Collection for full-length human and mouse cDNAs.
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$3.00 M |
- Continue to develop technologies relevant to discovering and measuring molecular signatures of cancer and precancer and the dissemination of technologies to the scientific community.
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$1.00 M |
- Continue to develop biosensors for detecting human cancer and cancer development through the Unconventional Innovation Program.
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$6.50 M |
- Extend the Genetic Annotation Initiative to identify new cancer related gene polymorphisms in defined populations, define key molecular pathways by thoroughly characterizing genetic variations on numerous gene and protein expression profiles, and develop human gene expression profiles from specific tissues with measured exposure times to study epigenetic targets and cell pathways that lead to tumor formation.
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$3.00 M |
| TOTAL |
$18.5 M |
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| Objective 2: Establish and make available to researchers tissue resources to maximize the practical application of molecular signatures to problems in cancer research. |
- Establish a national tissue resource system for all major cancers, including lung, breast, prostate, colon, head and neck, brain, soft tissue, blood, bone, the gynecologic and genitourinary, and childhood malignancies.
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$4.00 M |
- Expand tissue repositories of precancerous lesions in all major cancers.
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$4.00 M |
- Use Phased Innovation Awards to develop tissue preservation and sample preparation methods to increase their utility and compatibility with new research technologies.
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$4.00 M |
- Enhance the Web-based system to query pathology information systems, including pathology standardization and agreement on common data elements.
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$2.50 M |
| TOTAL |
$14.5 M |
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| Objective 3: Identify molecular signatures and apply them to the study and validation of animal models for human cancer. |
- Continue to develop preclinical mouse models and fund systematic analysis and phenotyping to validate them. Use these models to validate new molecular-based approaches for early detection, diagnosis, treatment, and prognosis of human cancer.
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$5.00 M |
| TOTAL |
$5.00 M |
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| Objective 4: Support new approaches for early detection of cancer and to determine biomarkers of precancerous lesions. |
- Identify easy-to-sample sites remote from the tumor itself, for more cost-effective, earlier cancer detection and risk assessment.
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$2.00 M |
- Study molecular signatures to discover the causes of cancer, including infectious and environmental agents.
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$1.00 M |
- Identify and validate biomarkers to develop effective, reliable tools for early cancer detection and to assess their potential for predicting cancer.
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$2.00 M |
- Develop a program that uses the patterns of very small proteins in serum for early diagnosis of prostate, breast and ovarian cancer. Expand marker identification to predict disease stage and risk of recurrence.
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$2.00 M |
- Expand studies to identify and validate epigenetic markers of cancer.
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$1.00 M |
- Develop applied algorithms and statistical methods to analyze multiple biomarkers and patterns of molecular changes and link those changes with clinical outcomes.
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$1.00 M |
- Develop analytical prediction tools for risk assessment, incorporating molecular, genetic, and family history information.
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$1.00 M |
- Implement within the Early Detection Research Network, a Network-Wide Knowledge and Informatics Center.
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$1.00 M |
| TOTAL |
$11.0 M |
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| Objective 5: Validate molecular classification schemes of cancer, and develop new diagnostic tests. |
- Expand validation programs for each major cancer site as results emerge from the Director's Challenge and other programs.
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- Validate new diagnostic approaches through the Program for Assessment of Clinical Cancer Tests to provide the research community with a means to evaluate and validate signatures with possible diagnostic value.
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| TOTAL |
$13.0 M |
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| Objective 6: Support basic research aimed at characterizing aberrant molecular interactions in cancer. |
- Generate a comprehensive map of all cellular signal transduction pathways and their links to one another through a Signal Transduction Annotation Consortium.
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$5.00 M |
- Support basic research efforts for analysis of: important cell structure that may be disrupted in cancer; organization and location of chromosomes during cell reproduction; structure and function of molecular machines; and structure and function of membranes.
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$2.00 M |
- Develop technologies for analyzing cell-cell interactions and communication that might be disrupted in cancer by funding 10 Phased Innovation Awards.
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$2.00 M |
| TOTAL |
$9.0 M |
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