Strategic Investments in

Integrative Cancer Biology

Our GoalUnderstand the complex networks within cancer cells and between cancer cells and their environment to discover new leads for cancer prevention, detection, diagnosis, and treatment.

Integrative cancer biology is the study of cancer as a complex biological system. Researchers in this field seek to understand the dynamic and spatial interactions that exist among molecules in a cell, among cells, between cells and their "microenvironment," and between the organism and its "macroenvironment." These interactions are potential targets for new and more rationally designed interventions to prevent, detect, diagnose, and treat cancer. Our integrative cancer biology initiatives focus on creating computational models of the complex networks within and among cancer cells, building our understanding of the tumor microenvironment, and studying the role of the tumor macroenvironment in cancer development. To carry out these initiatives, cancer biologists will depend heavily on a multidisciplinary approach. Expertise in the computational sciences and collaborations with scientists in other fields that study complex systems will be essential. Researchers will also need animal models that mimic the development of cancer in humans and powerful new tools for imaging molecular interactions, integrating large datasets, and validating computational models.

Developing Computational Models of Cancer

With increased resources in Fiscal Year 2006, NCI will expand efforts to build models of the complex networks within and among cancer cells. Scientists know that a cell becomes malignant as a result of changes to its genetic material and that accompanying biological characteristics of the cell and its surrounding microenvironment also change. Genetic mutations in an evolving cancer cell result in proteins that do not function correctly. These dysfunctional proteins disrupt the intricately balanced molecular communication networks of the cell. Using data derived from research on the tumor micro- and macroenvironments, scientists will create computational models of these complex networks to help develop new ways to preempt the development and progression of cancer. New NCI-supported Integrative Cancer Biology Programs (ICBPs) have already begun the development of reliably predictive computational models of cancer initiation, promotion, and progression; the integration of experimental and computational approaches for understanding cancer biology; and the support of integrative cancer biology as a distinct field. To further the development of computational models, we hope to:

Increase the number of ICBPs.
Fund collaborations with the ICBPs to enable the research community to apply the approaches of integrative biology.
Establish programs in integrative cancer biology to train interdisciplinary scientists to build, characterize, and validate computational models.
Provide additional funding for the Mouse Models of Human Cancers Consortium to (a) accelerate the pace at which accurate, reproducible mouse models of human cancers are made available, and (b) define the process for using these mouse models to validate computational models of complex cellular networks and to evaluate targeted therapeutics.
Expand the imaging acquisition and integration capabilities of the Integrative Cancer Biology Programs and the Mouse Models of Human Cancers Consortium to develop (a) novel cancer imaging agents, nanoparticles, and technologies for use in cells and small animal cancer models, and (b) methods for effectively integrating imaging data with genetic, molecular, and cellular data.
Expand the intramural Molecular Targets Development Program to accelerate discovery of compounds that can serve as bioprobes for functional genomics, proteomics, and molecular target validation research as well as leads or candidates for drug development.

Understanding the Tumor Microenvironment

In Fiscal Year 2006, NCI will also extend efforts to understand the tumor microenvironment, which is the local and systemic architecture surrounding a cancer cell. The microenvironment includes other cells; growth factors; enzymes; and parts of the blood, lymphatic, and immune systems. Dynamic interactions between the cancer cell and its microenvironment can contribute to some of the most destructive characteristics of cancer, including metastasis. The microenvironment can also influence the access of therapeutic agents to cancer cells, the body's processing of treatment agents, and the development of resistance to cancer treatments. Therefore, research to understand the tumor microenvironment more fully may provide additional targets for preempting cancer and better methods for treating it. This research will characterize molecular signatures of cells in the tumor microenvironment as well as the dynamic communication among these cells; interactions between these cells and factors in the macroenvironment that predispose individuals to cancer; and interaction between the immune system and the cancer cell during cancer initiation, promotion, and progression. The latter interaction will establish the roles of both the innate inflammatory responses and adaptive immune responses in promoting and controlling tumor formation.

This research will also provide necessary data for development of the computational models of interactions between the tumor and its microenvironment. To extend our understanding of the tumor microenvironment, we will:

Establish a multidisciplinary alliance of researchers, engineers, and bioinformatics experts to:
- Create technical resources that will facilitate the visualization of stromal components at the molecular and cellular levels and the establishment of a repository of normal stromal cells and matrix molecules.
- Investigate the normal and malignant tissue microenvironments, identify their molecular signatures, and identify the origin of the cells and factors that comprise the tumor stem cell and the tumor microenvironment.
Fund grant supplements to train investigators to use organotypic culture systems that accurately model the interaction between the cancer cell and the microenvironment and make these systems readily accessible to the research community.
Support the development of strategies for investigating, manipulating, and monitoring/imaging in vivo human immune responses to cancer.
Support studies to clarify the underlying biological relationship between anti-tumor immune responses and autoimmune responses to normal cells/tissues in humans undergoing cancer immunotherapy.
Expand the availability of resources to academic laboratories for small molecule and biologics development through the Rapid Access to NCI Discovery Resources (R*A*N*D) program.

Defining the Role of the Tumor Macroenvironment

In addition to seeking to understand the interactions among molecules in a cell, among cells, and between cells and their microenvironment, integrative cancer biology also addresses the role of the tumor macroenvironment. This includes the poorly understood effects of an individual's exposure to various elements in the environment such as unhealthy air and water and the influence of lifestyle factors such as diet, obesity, physical activity, and tobacco use. Research on the tumor macroenvironment also includes studies of certain microbial agents that are known to be closely associated with the etiology of some cancers (e.g., HPV with cervical cancer; HBV and HCV with liver cancer; EBV with breast cancer; helicobacter with stomach cancer). The mechanism by which these agents increase risks for cancer is not firmly established, and scientists continue to explore the extent to which other known or unknown viruses or microbes may impact cancer development and progression. Research on these topics will be critical to developing new interventions and tools for preventing, detecting, diagnosing, and treating cancer. With sufficient resources in Fiscal Year 2006, we will:

Establish collaborative research groups to explore, characterize, and validate associations of known cancer viruses with cancers not previously linked to these viruses (e.g., study the role of human papillomaviruses in squamous cell esophageal and non-melanoma skin cancers). Characterize the role of microbial agents in the etiology of human cancers such as leukemia, lung cancer, and non-Hodgkin's lymphoma.
Support studies of the role of microbial agents in tumor development by investigating (a) viral latency and reactivation, (b) the microbial flora of stromal cells, and (c) the anti-microbial inflammatory response. Included will be studies on immunosuppressed individuals with cancer and studies on the immune response to HPV.
Support investigations into the role of co-carcinogenic agents (biological and chemical) in cancer initiation, promotion, and progression. Include investigations of the contribution of inflammation, injury, and specific mutations to lung carcinogenesis.
Support investigations of the relationship between autoimmune diseases and the risk of cancer.
Support studies to assess the effects of anti-inflammatory agents on cancers associated with microbial etiology.
Continue to develop the vaccine program at NCI to target infectious agents that initiate and promote cancer.
Support studies to identify and evaluate agents that will prevent or ameliorate cancer-causing radiological injury.

Integrative Cancer Biology Budget Increase Request for Fiscal Year 2006
Developing computational models Integrative Cancer Biology Programs Training Mouse models for validation Innovative technologies for use in cells & animal models Bioprobes and candidates for drug development	$24.00 M
Defining the role tumor microenvironment Cross-disciplinary research alliance Training in using organotypic culture systems Studies on immune responses to cancer Resources for the development of small molecules & biologics	16.50 M
Defining the role of the tumor macroenvironment Collaborative research groups studying cancer viruses & microbial agents Studies of biological and chemical co-carcinogenic agents Studies of autoimmune diseases & cancer risk Effects of anti-inflammatory agents on cancer Vaccine development Studies to prevent/ameliorate radiological injury	24.00 M
Management & Support	1.10 M
Total	$65.60 M

Computational Modeling Has Multiple Applications for Cancer

Computational modeling is a central feature of integrative cancer biology studies aimed at generating predictive and testable models of cancer. Computational biologists are developing computer programs that use complex, interactive calculations to analyze massive amounts of data about cancer cells and their micro- and macroenvironments. These modeling programs use combinations of simple statistical tests, data mining applications, and higher-order mathematical equations. They are similar to those used by meteorologists to help predict the weather, by economists to predict future trends, and by engineers to design complex modern aircraft. Molecular scale models are being designed, for example, to describe the folding patterns of critical cancer proteins. Computational models also might be used to study the response of a cancer patient's immune system to a developing tumor. Researchers anticipate that computational models for cancer, once refined and validated, will not only yield insights and knowledge about cancer, but will also be used to help diagnose cancer patients and to plan and monitor treatment strategies.

Understanding the Biology of Aging and Cancer

Older patients differ from younger cancer patients in susceptibility to disease progression and response to treatment. The underlying mechanisms of cancer and aging overlap in the study of tumor initiation, progression, and maintenance. NCI and the National Institute on Aging (NIA) have partnered to invigorate the research community's interest on the intersection of aging and cancer. Studies on the biology of aging and cancer are fundamental to this endeavor. Researchers supported by the NCI/NIA partnership will broaden studies of genetics, molecular signatures, age-related changes that contribute to mortality, and vulnerability versus resilience in older patients. The work will include studies in human biology that reveal which aspects of tumor biology and tumor growth vary by age. Teams of researchers will investigate:

Genetic change, environmental influences, and host factors such as oxidant stress and cell death that may alter tumor progression in the aging patient
The interaction of normal aging cells and cancer cells within the tumor microenvironment
Differences in manifestation of cancer types in older and younger patients
Cellular and molecular characteristics that distinguish between those patients who could benefit from aggressive therapy and those who could be spared further therapy
Molecular alterations in carcinogenesis that are related to aging cells
The potential short- and long-term medical effects induced by treatment, such as susceptibility of the older patient to multiple primary tumors, anti-tumor drug alterations, and cancer recurrence
The human biology of cancer and aging that reveal which aspects of tumor biology and tumor growth vary by age

Highly Lethal Cancers - Changing the Statistics

In 2004, about 31,860 people in the United States will be diagnosed with pancreatic cancer. There will be about 14,250 new cases of esophageal cancer, and an expected 18,920 people will be told they have liver cancer. These are highly lethal diseases. About 15 percent of Whites and 8 percent of African Americans diagnosed with esophageal cancer are expected to survive five years. The five-year survival rate for patients newly diagnosed with pancreatic cancer is estimated at just 4 percent. For liver cancer, it is 7 percent. If we are to reach our challenge goal to eliminate the suffering and death due to cancer, we must invest in research and development that will change these statistics.

Epidemiologists have already identified several risk factors in common for these three cancers. For example, people who develop these cancers often have a history of chronic inflammation. Tobacco use, alcohol use, and obesity are also prevalent among people with these cancers. Large population studies are needed to draw valid statistical conclusions about the roles of genetic, environmental, and lifestyle factors in the initiation and progression of these diseases.

One challenge is that the relative rarity and high lethality of pancreatic, esophageal, and liver cancers make it difficult to conduct these large studies. It is not unusual, for example, for population studies of breast or prostate cancer to enroll tens of thousands of participants. In contrast, the relatively low numbers of patients with highly lethal cancers demand significant cooperation and coordination to assemble enough patients to conduct even one study. NCI is proposing to address this obstacle by developing a consortium of investigators to conduct epidemiological studies of highly lethal cancers.

This consortium approach will pool the resources of multiple institutions. Through the collection, storage, management, and sharing of data for a large numbers of cases, investigators will be able to amass enough knowledge to evaluate the possible combinations of genetic, environmental, and lifestyle factors - from molecular to behavioral - that are causing these cancers. This unparalleled collection of data will provide an ideal resource for exploring new hypotheses emerging from basic and clinical research, and provide hope for those individuals who suffer from highly lethal cancer.

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