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Accelerate our progress in understanding the dynamic interaction between cancer cells and their microenvironment and our application of this knowledge to the detection, diagnosis, prevention, treatment, and control of all cancers.
Thirty years ago, cancer was a poorly understood, and usually deadly, disease. Today, we have a far better understanding of how cancer develops and progresses within the human body. We know that a cell becomes malignant as a result of changes to its genetic material and that accompanying biological characteristics of the cell also change. These changes form unique, measurable molecular "signatures" that signal the presence of disease. This more robust understanding of the genetic changes within a cancer cell - and the resulting changes in the production and function of proteins - has altered the course of cancer research and has fueled new approaches to prevention, detection, diagnosis, prognosis, and treatment.
Scientists also realize, however, that they cannot view cancer as a self-contained collection of malignant cells but must consider the integral association of the cancer with its host environment. This "tumor microenvironment":
- Includes a variety of cell types, themselves often altered through interaction with the cancer cells.
- Is rich in growth factors and enzymes and includes parts of the blood and lymphatic systems.
Dynamic interactions between the cancer cell and its microenvironment can:
- Contribute to some of the most destructive characteristics of cancer, including metastasis.
- Influence the access of therapeutic agents to tumor cells, the body's processing of treatment agents, and the development of resistance to cancer treatments.
Both cancer cells and their surrounding environment need to be fully characterized in order to understand how cancer grows in the body, and both need to be considered when developing new interventions to fight the disease.
The interactions between cancer cells and their microenvironment permit, and even encourage, cancer progression. Scientists are deciphering the signatures of cancer cells, those of seemingly normal cells in the tumor microenvironment, and signatures that reflect changes that occur as cancer cells interact with the host environment.
NCI's long-range goal for signatures research is to characterize the interactions between a tumor and its microenvironment and these with the entire body. Defining more fully this range of molecular signatures for cancer will dramatically increase our understanding of cancer development, detection, diagnosis, and prognosis and lead to the identification of new targets for prevention and treatment.
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Cancer researchers continue to make significant progress in understanding the genetics and biology of precancerous and cancerous cells and cells within the tumor microenvironment. They are defining the molecular signatures of these cells and identifying those that can be used as markers for early detection, diagnosis, or prognosis or be targeted by new interventions for prevention or treatment.
Discovery
Discovery
Searching the Genome for Cancer Signatures
All Cancer Genome Anatomy Project (CGAP) data and resources are readily available to the biomedical research community, enabling researchers to find "in silico" answers to biological questions in a fraction of the time it once took in the laboratory. In 2003, CGAP and its private, academic, and industry partners made several new resources available to the research community:
SAGE Genie is an informatics system that provides a view of all CGAP data produced through the Serial Analysis of Gene Expression (SAGE) approach. SAGE can be used to distinguish normal cells from tumor cells and to reveal potential markers for detection or diagnosis. Through the SAGE Genie Anatomic Viewer, a scientist can identify the genes uniquely expressed in specific cancers. One team of researchers has used this tool to identify a gene previously known to be overexpressed in prostate cancer that also appears to be a marker for metastatic breast cancer. The first products of the CGAP SNP500 Cancer Project are now available to the research community. The project provides a central resource for sequence verification of single nucleotide polymorphisms (SNPs). SNPs are important markers for cancer risk-related genes and can also be used to understand differences in individual vulnerability to cancer. Scientists are currently examining samples taken from individuals of four ethnic groups to find known or newly discovered SNPs of immediate importance to molecular epidemiology studies in cancer. CGAP and private-sector Affymetrix scientists are working together to develop a new technological approach that will ultimately enable cancer researchers to peer more deeply and broadly into gene expression changes in cancer. Through this collaboration, scientists have produced whole chromosome chips for chromosomes 21 and 22, allowing researchers to look at genetic activity in all regions of these chromosomes and discover thousands of previously unknown regions that contain coding for proteins. This approach may also provide a valuable tool for discovering "hidden" RNA activity that may have an important structural or regulatory role in the cell. CGAP scientists have collaborated with scientists from Lynx Pharmaceuticals, the Ludwig Institute, Duke University, and Johns Hopkins University to use a new technique known as Massively Parallel Signature Sequencing (MPSS) to study cancer gene expression. With this powerful approach, more than 1 million gene tags can be generated from tissues or cells. Because the MPSS tool provides a tremendous depth of analysis, scientists can study genes that are expressed at relatively low levels, greatly increasing our ability to find all the genes that are important to cancer.
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Searching the Proteome for Cancer Signatures
Proteomics, the comprehensive study of proteins and their functions, is an important complement to studies exploring the genetic changes associated with cancer. Scientists at NCI and the Food and Drug Administration (FDA) are working together through the Clinical Proteomics Program (CPP) to apply advances in proteomics directly to patient care. CPP investigators are using artificial intelligence and laboratory technology to explore complex protein patterns and define protein profiles that can be used for early detection, diagnosis, prognosis, and treatment monitoring.
- CPP scientists are developing a screening test for ovarian cancer that has demonstrated an ability to successfully use complex protein pattern analysis to distinguish with 100 percent accuracy between ovarian cancer patients and unaffected persons. A refined test even promises to accurately detect Stage 1 ovarian cancers, a potentially curable stage for which no reliable screening tool is yet available for use in clinical practice.
- CPP investigators are examining serum protein patterns that may someday help clinicians determine whether men with mildly elevated prostate-specific antigen (PSA) levels have prostate cancer or need no further diagnostic analysis and treatment. Such a test could save many men from having to undergo biopsy and help them make more informed decisions about "watchful waiting." Similar studies are being conducted to identify protein profiles for detecting and diagnosing pancreatic, breast, and lung cancers.
Providing Resources for Molecular Profiling
Scientists now have the tissue microarray tool as a quick and cost-effective means of performing automated, high-throughput analyses of multiple cancer tissues, and they use that information to develop and validate molecular profiles of tumor cells. Microarray slides contain as many as a thousand tissue specimens of a specific cancer and can be used to determine whether:
- Specific genes are valuable biomarkers for cancer.
- The protein encoded by the candidate gene affects the tumor's behavior and holds potential as a molecular target for treatment.
Researchers can use microarray technology to perform the equivalent of hundreds of experiments simultaneously.
The Tissue Array Research Program (TARP) is a collaborative effort with the National Human Genome Research Institute to facilitate the development and dissemination of multitumor tissue microarray slides and the related technology to investigators. One research team used TARP arrays to study the Akt oncogene, which encodes a protein that blocks programmed cell death and its signaling pathway in different types of tumor cells. These investigators found that cellular signaling through this pathway varied among different tumor cells, suggesting tumor type-specific targets for therapy and highlighting the complexity of signaling pathways in human tumors.
Several researchers are developing microarrays and nanotechnologies such as carbon nanotubes, nanowires, microcantilevers, and quantum dots through NCI's Innovative Molecular Analysis Technologies (IMAT) program. These molecular sensing tools can be used for:
- Detecting the presence or absence of a molecule
- Determining if the expression of a molecule has been increased or decreased
- Identifying patterns that can be molecular signatures
- Identifying irregularities in DNA
- Quantitatively analyzing interactions among proteins
- Performing molecular classification of tumors
- Conducting high-throughput screening
- Predicting therapeutic efficacy
IMAT investigators have completed proof-of-principle studies for each of these tools. Their next step will be to make design modifications to allow mass production and use in clinical trials.
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Using Molecular Signatures for Early Detection of Cancer
The Early Detection Research Network (EDRN) is a scientific consortium in which researchers from multiple institutions work together to identify, develop, and validate markers that are detectable either before the onset of cancer (risk) or early enough in the disease process for treatment to be most effective (early detection). EDRN scientists have applied advances in genomics and proteomics to discover a variety of promising biomarkers including:
- Two genes unique to ovarian cancer
- Chemical modification (methylation) of specific genes predictive of lung cancer
- Protein patterns predictive of prostate cancer
Although scientists have long believed microsatellite instability is a potential biomarker for bladder cancer, the idea has never been validated in a large sample of patients. EDRN scientists are applying a recently formulated roadmap outlining the five key phases of biomarker development to evaluate microsatellite instability as a marker for recurrent bladder cancer. The microsatellite instability test measures changes in about 20 microsatellite locations in cells sloughed off the bladder and into urine.
Scientists hope that a recently launched Phase III study to compare microsatellite analysis with the current standard approaches of cytoscopy and cytology in 300 bladder cancer patients will validate the microsatellite instability test as a useful detection tool for new and recurrent cases of bladder cancer. Similar tests may eventually be developed for screening other cancers that shed cells into body fluids, such as tumors of the oral cavity and the gastrointestinal tract.
Developing Better Classification Schemes to Improve Diagnostic Tests
Researchers supported through the NCI Director's Challenge: Toward a Molecular Classification of Tumors use comprehensive molecular analysis technologies to develop profiles of molecular changes (signatures) in tumors. These profiles will help scientists identify better strategies for classifying tumors, and in turn allow for more accurate diagnosis and prognosis as well as the opportunity to select therapies tailored to individual patients through the targeting of specific molecular features.
Director's Challenge investigators recently studied the gene expression patterns of ovarian cancer tumors to develop a molecular classification. Their classification provided insight into why some subtypes have a worse prognosis than others. For example, a sizeable number of genes were more active (overexpressed) in clear-cell ovarian tumors compared to other types of ovarian cancers. In-depth study of the function of these genes may help scientists discover why patients with these tumors do more poorly than other ovarian cancer patients. This type of gene profiling may lead to improved patient diagnosis and prognosis for a broad range of cancers and provide clues for identifying molecularly targeted interventions.
Using Molecular Signatures to Study Models of Human Cancer
In less than 4 years, Mouse Models of Human Cancers Consortium (MMHCC) investigators have rapidly evolved a suite of novel approaches for mouse germline engineering and biological analysis. These fundamental advances are furnishing the research community with cancer-prone strains that not only accurately mimic human cancers but also support unprecedented discoveries about these cancers. Through high-throughput approaches such as gene expression arrays, these studies are demonstrating the importance of animal models in informing human cancer analysis.
One research team made an important discovery using a mouse model for human breast cancers caused by overexpression of the gene c-Myc. They identified a gene expression pattern in these animals that has also been found in human c-Myc-related breast cancers. This finding provides valuable clues for distinguishing among human cancer subtypes. Comparable studies on models of other malignancies are underway with similar results.
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Cancer researchers continue to make significant progress in understanding the genetics and biology of precancerous and cancerous cells and cells within the tumor microenvironment. They are defining the molecular signatures of these cells and identifying those that can be used as markers for early detection, diagnosis, or prognosis or be targeted by new interventions for prevention or treatment.
Discovery
Development
Discovery
| 1. | Define the molecular signatures of cells in the cancer microenvironment at various points during the initiation and progression of cancer. Compare the molecular signatures of stromal and cancer cells during development and aging. | $9.50 M |
- Promote the analysis of cancer as a complex biological system by establishing an Integrative Cancer Biology Program, with the ultimate goal of developing reliably predictive models for "in silico" development of cancer interventions. $2.00 M
- Provide a focus for research into the dynamic interaction between cancer cells and their microenvironment and a forum for the exchange of information and resources by supporting a series of new initiatives relating to the microenvironment of tumors. $3.50 M
- Facilitate the analysis of normal and cancerous cell samples for signature profiling studies by establishing a national core facility. Develop a database of the molecular signature profiles of cells in the microenvironment and make these data readily available to the research community. $1.00 M
- Advance the development of nanoparticles, molecular beacons, and high-resolution sensors for cancer signature detection, targeting, and treatment from the development stage into clinical trials and translation into the clinic, through expansion of the Unconventional Innovations Program (UIP). $1.50 M
- Expedite the translation of micro- and nanotechnology tools for detecting molecular signatures of cancer and monitoring major signal transduction networks, into products that can be used in clinical practice, through expansion of the Innovative Molecular Analysis Technologies Program (IMAT). $1.50 M
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| 2. | Define the dynamic communications among cancer cells, surrounding cells, and immune cells that control or promote primary and/or secondary tumor growth. Characterize the interaction between the immune system and the cancer cell during cancer initiation and progression. | $8.00 M |
- Identify the factors used by cancer cells to activate cells in the tumor microenvironment that support tumor growth and progression. Encourage studies that explore the unique role the bone microenvironment plays in metastasis of cancer to bone, focusing in particular on breast cancer, prostate cancer, and myeloma. $3.50 M
- Identify the origin of the cells and factors that comprise the tumor microenvironment. $2.00 M
- Develop organotypic culture systems that accurately model the interaction between the cancer cell and the tumor microenvironment in living systems. Make these systems readily accessible to the research community. $1.00 M
- Identify the molecular composition and physiological or pathological contributions of extracellular matrix components to biological properties such as survival, proliferation, and migration of normal and malignant cells. $1.50 M
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| 3. | Support new approaches to provide the research community with rapid access to validated reagents. | $7.00 M |
- Establish a repository for antibodies, cell lines, animal models, and tissues that relate to cells in the microenvironment. $2.00 M
- Establish a database that includes comparisons of cellular interactions between cancer cells and surrounding cells in animal models and in humans. $1.00 M
- Identify proteins and proteomic signatures in microdissected tissue samples of human cancers (normal epithelium, premalignant lesions, adjacent tissue, and invasive tumors) through expansion of the Clinical Proteomics Program. $4.00 M
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| 4. | Stimulate progress in understanding the role of stromal cell interactions in cancer development by establishing a spectrum of educational and communication initiatives involving scientists across disciplines and with a broad range of expertise. | $4.00 M |
- Encourage multi- and trans-disciplinary investigations by establishing a new funding mechanism to allow co-investigators from different scientific fields to submit a collaborative grant application. $2.00 M
- Develop training curricula for students and established investigators and facilitate the development of novel studies in understanding the role of cellular interactions in cancer development, by establishing national trans-disciplinary training centers. $2.00 M
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Development
| 5. | Create targeted interventions by applying knowledge of cellular interactions in cancer development derived from profiling studies that explore cell-microenvironment interactions. | $6.00 M |
- Efficiently develop new drugs that target cells in the microenvironment, and move them into clinical use by initiating a Rapid Access to Intervention Development-type program. $1.00 M
- Develop new "targeted" reagents, including small molecules, RNAi, and antibodies through supplemental funding to NCI-funded investigators. $1.00 M
- Visualize the physiologic, cellular, and molecular processes in living tissues through functional and molecular imaging studies. These studies will focus on (1) identifying the subtle and important early changes in the molecular biology of tumors and the microenvironment as tumors become malignant, and (2) monitoring the effects of therapy on tumor cells and the tumor microenvironment. $4.00 M
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| Management and Support | $0.80 M |
| Total | $35.30 M |
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Cervical cancer cell.
This large rounded cell has an uneven surface with many cytoplasmic projections, which may enable it to be motile. Typically, cancer cells are large and they divide rapidly in a chaotic manner. Cancer cells may clump to form tumors which may invade and destroy surrounding tissues. Cancer of the cervix (the neck of the uterus or womb) is one ofthe most common cancers affecting women. |
Studies suggest that as many as 15 percent of all cancers worldwide may be caused, at least in part, by viral infections. Clearly, effective prevention and treatment interventions aimed at these cancers are critical to reducing the cancer burden.
The drastic reduction in cervical cancer mortality since 1955 is one success story. This disease, found only in women infected with human papillomavirus, was once the most common cancer killer of women. Thanks to detection of virus-related lesions by Pap testing, this disease can now be detected early and is highly curable.
However, with the advent of the HIV/AIDS pandemic, certain virus-related cancers are becoming more prevalent, both nationally and worldwide. Immunocompromised HIV/AIDS patients are vulnerable to infections and associated cancers that healthy individuals would easily resist.
To successfully address cancers caused by viral infection, we must learn more about the biological mechanisms of their development and progression and apply this knowledge to develop effective treatment and prevention measures. Highlighted below are a few recent NCI-supported national and international collaborations that are providing greater insights into virus-related cancers.
- Human papillomavirus is the primary cause of cervical cancer. Investigators are developing a vaccine to prevent cervical and other cancers caused by this virus.
- Epstein-Barr virus (EBV) infection, although usually benign, can promote aggressive lymphomas, soft tissue tumors in HIV-infected children, and other tumors. Researchers are studying the epidemiology of EBV-related tumors and are developing novel therapies including strategies that harness the immune system to attack cancer cells. Investigators are also exploring a possible link between EBV and some aggressive breast cancers.
- Infection with hepatitis virus B or C increases a person's risk of developing liver cancer. Scientists are investigating how genetic and environmental factors interact to make some infected individuals more at risk than others.
- Human T-cell lymphotropic virus causes adult T-cell leukemia. Investigators are studying the natural history of this virus, how the virus is transmitted between individuals, and risk factors for cancer progression.
- Human herpesvirus-8 (HHV-8) is associated with Kaposi's sarcoma and aggressive lymphomas, particularly in HIV-positive individuals. Scientists are examining the epidemiology of this virus, identifying routes of transmission, researching strategies to prevent infection and tumor development, and developing novel therapies for Kaposi's sarcoma and other tumors caused by HHV-8.
- Investigators are developing better treatments for AIDS-related lymphomas, making this previously universally fatal disease highly curable in many patients. (See, Improved Therapy Boosts Survival of AIDS-Related Lymphoma Patients.)
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