Strategic Investments in

Advanced Technologies*

Our GoalAccelerate the development of highly effective advanced technologies and maximize their use to power and streamline research, enhance the options for patient care, and connect investigators with one another and with the healthcare provider and patient communities.

Research over the past three decades has led to unimagined progress in our understanding of the cancer process at the genetic, molecular, and cellular levels. As we search for the most effective ways to apply these insights to the prevention, early detection, and management of cancer as a disease process, we know that our most direct path will be through the optimal integration of science and technology. Our Nation's past successes in creating technologies to enhance discovery - from the space program to the Human Genome Project - have produced dramatic scientific breakthroughs and advances. Now we have an opportunity to achieve an equally unimagined goal: to eliminate the suffering and death due to cancer.

Today's technologies and tools are replacing Einstein's chalk and blackboard with powerful computers, sophisticated software, and networking that enables collaboration on a global scale. Identifying many of the complex mechanisms responsible for cancer through genetic and protein microarrays, molecular imaging, and high throughput screening are proving to be pivotal in accelerating our ability to intervene against these processes. Similarly, technology-dependent, molecularly targeted therapies based on a patient's disease-specific profile of markers provide hope that the cancer burden will be lightened and patients will enjoy a higher quality of life. We are able to make rapid gains against cancer because of the development and availability of advanced technologies that enable accelerated research and create effective interventions.

Bioinformatics

Hastening Progress against Cancer Using A 21st Century Integrated, Electronic Network

By using the power of modern information technology, NCI is leading the way in developing a bioinformatics platform that promises to revolutionize the biomedical research enterprise. Scientists in various disciplines will have access to a common infrastructure for collaboration and integration of findings, and new "plug and play" tools developed by the researcher community will make it possible for investigators to greatly accelerate their research. For example, researchers at Cancer Centers across the country will be able to access data on the molecular characteristics of patients with a particular type of cancer who are being treated with a specific drug. Diverse data mounted on common platforms will permit researchers to use innovative analytic tools to mine the information in ways inconceivable a few years ago. And researchers can take advantage of "in silico" experiments that facilitate rapid, cost-efficient hypothesis generation and evaluation.

Up to the present, bioinformatics resources have been developed in organizational isolation, with tremendous variability in rules, processes, vocabularies, data content, and analytical tools. NCI will address these concerns and strengthen the potential for bioinformatics integration with the cancer Biomedical Informatics Grid (caBIG). The caBIG will provide a unifying architecture to transparently connect information and tools much like a home entertainment system in which components are made by different manufacturers but built to common standards that allow users to combine them in various ways. Our long-term goal for bioinformatics is to improve the sophistication of information technology use and surmount the barriers that limit interaction across research institutions. NCI is currently piloting a core infrastructure with the participation of 50 Cancer Centers.

We are also fostering the development and use of new informatics technology to accelerate, better coordinate, and facilitate participation in NCI-supported clinical research. Currently, volumes of valuable raw data are not tapped, effective best practices are not widely distributed, and resources are wasted because of duplication of effort. With new bioinformatics tools and infrastructure, trials will be completed more quickly in multi-institutional settings with uniform electronic case report forms and data reporting systems. Databases and analytical tools will make information from all clinical trials available to NCI-supported researchers for efficient patient accrual, information retrieval, and data analysis. Informatics systems will assist the cancer community with priority setting and allow for fuller participation and a more transparent decision making process. Advocacy groups and individual patients will be empowered to participate in clinical research and to authorize use of materials for basic science investigations. Confidential clinical and proprietary information will be protected by controlled, secure access. Just as e-business models have transformed the American market place, the caBIG platform will overcome traditional institutional limitations. Community practitioners, clinical research organizations, and academic centers will be linked through this new model of clinical research. Healthcare providers will become full partners in the research enterprise and educated consumers of research findings.

We will use funding increases for bioinformatics in Fiscal Year 2006 to:

Evaluate the prototype caBIG at the pilot centers and expand the data, software, and infrastructure available through the Grid.
Expand the development process and extend participation in the caBIG consortium to other cancer research institutions around the country.
Develop and evaluate a World Wide Web-based, clinical research outcomes reporting system with voluntary participants from Specialized Programs of Research Excellence (SPOREs), Cancer Centers, and the intramural Center for Cancer Research (CCR).
Expand World Wide Web-based, clinical trials support infrastructure through a pilot study in conjunction with the CCR trials group, selected inter-SPORE collaborations, and Cancer Centers.
Develop infrastructure and tools, including an Internet resource, that facilitate community-wide clinical research participation and support.

Cancer Imaging

Improving Our Understanding of Cancer Biology and Facilitating Cancer Preemption and Clinical Management of Cancer and Cancer Risk

Clinicians are increasingly relying on imaging methods as biomarkers for cancer risk and treatment efficacy. Image guided cancer intervention is a rapidly evolving area that may be used to cure some cancers and precancerous lesions, and also to provide minimally invasive, well-tolerated palliative therapies. Imaging informatics optimizes the availability and effectiveness of cancer imaging data in research as well as clinical environments. Imaging methods are used hand-in-hand with emerging technologies such as nanotechnology, proteomics, and high throughput screening to identify cancers earlier and help assess the effectiveness of therapy. Imaging of small animals used in research, particularly genetically engineered mice, is increasingly recognized as a powerful discovery tool in cancer research. As our knowledge of the molecular basis of cancer increases, molecular imaging methods are providing clinicians with telling details about the environs of patients' tissues. With increased resources for cancer imaging in Fiscal Year 2006, we will:

Establish publicly available image archives, linked to outcome and other clinical data, and partner with industry to support image archives.
Integrate image-guided intervention research into Cancer Centers, Specialized Programs of Research Excellence (SPOREs), and NCI's Center for Cancer Research (CCR) .
Use nanotechnology to design "smart" injectable, targeted contrast agents that improve the resolution of cancer to the single cell level.
Engineer nanoscale devices capable of addressing the biological and evolutionary diversity of the multiple cancer cells that make up a tumor within an individual.
Expand the Small Animal Imaging Resource Program, the Network for Translational Research Optical Imaging, and the Development of Clinical Imaging Drugs and Enhancers program.
Develop a program for imaging validation in animal models.

We will also use new resources in Fiscal Year 2006 to integrate correlative imaging studies, such as monitoring response to therapy, into NCI-supported clinical therapy trials. (See Strengthening Scientific Prioritization and Coordination .)

Proteomic Technologies Initiative

Overcoming the Barriers to Early Detection of Cancer.

Scientists are taking new steps to identify profiles, or signatures, of proteins and peptides (fragments of proteins) that are found in tumors and often in the circulating blood that signal early phases of cancer development. Proteins serve complex and diverse functions in the body, from giving structure to our cells to regulating processes such as digestion, respiration, and the growth rate of cells. When proteins do not function properly, normal body processes can go awry. For example, cancer is caused by errors in proteins that regulate when and how fast cells replicate themselves, as well as the timing of cell death. One of the goals in cancer research is to develop technologies that measure these abnormal proteins and can eventually be used as simple diagnostic blood tests. However, there are some sizeable technical challenges that stand in the way of achieving that goal. These abnormal proteins are found in minute quantities and the blood contains hundreds of thousands of these proteins. The net effect is that we need to refine the technology so that it can find "a needle in the haystack" with unprecedented reliability.

In 2006, NCI will support development of advanced technology platforms for overcoming these barriers and preparing diagnostic methods ready for clinical testing. Mass spectroscopy, a favored approach involving high energy lasers, high powered electronic sensing, and computing, is used to identify specific proteins and their fragments based on their size and electrical charge. Another avenue is to use DNA and antibodies to capture proteins and measure their quantity on electronic chips. Patients in the near future may well have small samples of their blood analyzed using mass spectroscopy and protein chips that will, within minutes, identify abnormal proteins that indicate early, very treatable cancers.

NCI is developing infrastructure to help researchers speed development of these technologies and bring them to the clinic. Through a new Mouse Models of Human Cancers Consortium (MMHCC) initiative, researchers will create new resources including antibodies, data that provide standards for future measurement comparison, serum specimens, and histologic data. These resources will enable investigators to develop the technology platforms needed to detect proteins at very low levels and serve as a model for testing this approach for clinical medicine. With sufficient resources in FY 2006, this program will:

Support two consortia of more than 10 laboratories, each focused on improving protein detection platforms important for early cancer detection research.
Provide a publicly available database of protein measurements from more than 20 different mouse models of cancer to give researchers a starting point to begin clinical studies.
Develop advanced computer software and use it to analyze the immense amount of data generated by the project.
Make available a repository of mouse protein antibodies, peptides, and serum as a research resource.
Improve the accuracy and precision of mass spectroscopy and antibody detection methods.

Alliance for Nanotechnology in Cancer

Targeting and Modifying Biological Responses at the Subcellular Level

Nanotechnology offers an unprecedented and paradigm changing opportunity to study and interact with normal and cancer cells at molecular and cellular scales, in real time and during the earliest stages of the cancer process. Nanotechnology will enhance cancer diagnosis and treatment in numerous ways. Imaging agents and diagnostics will allow clinicians to detect cancer in its earliest, most treatable, pre-symptomatic stage. Nanosystems will provide real-time assessments of therapeutic and surgical efficacy for accelerating clinical translation. Multifunctional, targeted devices capable of bypassing biological barriers will deliver multiple therapeutic agents at high local concentrations - and with physiologically appropriate timing - directly to cancer cells and those tissues in the microenvironment that play a critical role in the growth and metastasis of cancer. Nanoscale agents will be capable of monitoring predictive molecular changes and preventing precancerous cells from becoming malignant. Novel methods will aid in the management of symptoms of cancer that adversely impact quality of life. And research tools will enable investigators to quickly identify new targets for clinical development and predict drug resistance.

To support and coordinate the cancer nanotechnology programs, NCI has established the Alliance for Nanotechnology in Cancer to unite a broad array of programs to maximize the technology outputs. Our nanotechnology plans place a premium on supporting cross-disciplinary teams that partner with existing NCI-supported efforts and with the private sector. With adequate resources in Fiscal Year 2006, we will continue to build the programs of the Alliance. We will:

Support 3-5 Centers of Cancer Nanotechnology Excellence (CCNEs) to serve as hubs for the development and application of nanotechnology and nanoscience solutions to the diagnosis and treatment of cancer.
Encourage development of multidisciplinary nanotechnology research teams and support the career development of individual investigators who will become future team leaders.
Support individual projects in cancer nanotechnology platforms for diagnosis, treatment, and prevention.

Advanced Technologies Budget Increase Request for Fiscal Year 2006
Building bioinformatics infrastructure and tools The cancer Biomedical Informatics Grid (caBIG) Support to NCI clinical trials & community participation	$12.75 M
Developing & applying advanced imaging technologies Publicly available image archives Image-guided intervention research Correlative imaging studies in NCI clinical trials Nanotechnology for contrast agents Nanoscale devices to address cancer cell diversity	18.00 M
Supporting a proteomic technologies initiative Consortia for improving protein detection platforms Protein measurements database Advanced computer software for project data analysis Improvement of mass spectroscopy & antibody detection methods	50.00 M
Building the Alliance for Nanotechnology in Cancer Centers for Cancer Nanotechnology Excellence Multidisciplinary nanotechnology research teams Individual projects for diagnosis, treatment, and prevention	40.00 M
Management & Support	2.05 M
Total	$122.80 M

caBIG Aligns with REMBRANDT to Power Translational Research

Primary brain tumors are a leading cause of cancer mortality in children and young adults and the incidence of brain tumors (gliomas) in older people is increasing. Effective therapeutic options are limited with many patients dying of their disease within a year of diagnosis. Patients, who survive, face devastating effects of the tumor and treatments that impact cognition, function, and quality of life for themselves and their caregivers. Novel therapeutic approaches are desperately needed. REMBRANDT, a partnership between NCI and the National Institute of Neurological Disorders and Stroke (NINDS), is an initiative to create a publicly available database that will house biologically and clinically oriented data regarding primary brain tumors. By using this data to develop novel molecular classification systems, this partnership can move us toward an era of individualized cancer treatment based on the molecular genetics of each patient's tumor.

To accomplish this goal, REMBRANDT will be designed to house two sets of valuable data. The first set of data will come from the NCI-sponsored Glioma Molecular Diagnostic Initiative (GMDI), a prospective clinical trial and the largest genetic/clinical corollary study ever conducted. Hundreds of brain tumor patients throughout the country undergoing surgery will have samples of their tumors sent to NCI for exhaustive genetic and molecular analysis and the findings will ultimately be correlated with the clinical course of the individual patient. The second type of data housed by REMBRANDT will be a wide array of molecular and genetic data regarding all types of primary brain tumors. REMBRANDT will be the vital link that will not only allow disparate types of data to be housed in a single place, but will also supply the bioinformatics tools critically necessary for the useful analyses of such data.

NCI's Cancer Biomedical Informatics Grid, (caBIG), offers a library of tools and resources to initiatives such as REMBRANDT to facilitate integrative analysis from bench to bedside and back. The new molecular glioma classification system that will result from GMDI and REMBRANDT will be biologically based, giving insight into pathology and helping physicians to predict responsiveness to specific therapies. Crosstalk between REMBRANDT and caBIG will serve all initiatives. caBIG and NCI will contribute tools to REMBRANDT and the research community will be able to access REMBRANDT resources through an NCI developed WWW portal.

How does caBIG work? In Cancer Centers, developers and adopters collaborate in "workspaces" to develop and apply tools, systems, and data elements that enable integration and sharing of information. In the REMBRANDT initiative, clinical data to be acquired includes progression of the tumor and survival of the patient, treatment and response, toxicity, imaging parameters, and pharmacology. Populating the database with molecular and genetic data will help identify and analyze patient genetic profiles, molecular pathways of cancer progression, novel molecular targets, and patient-specific tailored therapy. Researchers can explore how genetic changes correlate with the patient's response to therapy and overall survival within given age groups, geographical locations, and ethnicities. The database is planned for development over a three-year timeline and will be fully open and accessible to all investigators, both intramural and extramural.

Nanotechnology Will Enhance Future Cancer Imaging

Nanotechnology has emerged as a key strategy for imaging telltale molecular features of cancer that are notoriously difficult to detect. One team of NCI-supported scientists is crafting a nano-sized construct to identify areas of new blood vessel growth, or angiogenesis, which is characteristic of growing tumors. The surface of this construct is designed to interact with specific molecular features indicative of angiogenesis, while the core contains thousands of atoms of a paramagnetic element. The paramagnetic properties allow the probes to be imaged by Magnetic Resonance Imaging (MRI). In addition, this core may contain other signal enhancing agents for improved in vivo detection. The use of such multi-modal probes permits highly sensitive imaging of specific molecular features of cancer, with excellent spatial resolution.

In vitro studies have shown that the same nanoprobe can be used for targeted drug delivery. This image shows a targeted nanoprobe in contact with a melanoma cell. The nanoprobe appears red against the green background of the cellular fluid. Evidence is mounting that such nanosystems can achieve a marked improvement in therapeutic effectiveness, as high concentrations of a drug are delivered to targeted cancer cells, while non-targeted cells are spared exposure to toxic concentrations.

Another NCI-supported team is investigating in vivo cancer imaging using nano-sized "quantum dots" - tiny crystals that glow when they are stimulated by ultraviolet light. This team has achieved sensitive, multicolor fluorescence imaging of cancer cells in mice using a quantum dots probe that preferentially binds to prostate cancer cells. In this in vivo image, the mouse on the left is tumor free. A human prostate tumor growing in the mouse on the right shows fluorescent orange-red.

The structure of an imaging probe makes it well suited to carry diagnostic and therapeutic agents. However, researchers must carefully examine toxicity issues before testing this quantum dots application in people.

With focused investment in these and other nanotechnologies, NCI anticipates a future when nanodevices will be used to detect cancer at its earliest stages, pinpoint its location within the body, deliver anti-cancer drugs specifically to malignant cells, and monitor drug effectiveness.

A Treasure Trove of Diagnostic Information

Late in 2003, NCI scientists and partners reported a breakthrough in proteomic analysis that may make early detection by protein profiling even more practical. These scientists developed a method that enhances detection of the smallest proteins found in the blood. According to this team of scientists, these small proteins represent a "treasure trove of diagnostic information that has largely been ignored until now." The trouble is that these small proteins are normally carried through the body attached to larger "carrier" proteins. Hidden from detection when attached to a carrier protein, these small proteins are quickly excreted from the body when not bound to a carrier. As a result, these small proteins are notoriously difficult to detect in blood samples. However, this team of scientists has found a way to release small proteins from their carriers after blood has been drawn from the patient and prior to analysis of the blood sample. This simple, but ingenious technique is opening the door for vastly improved proteomic profiling techniques that can include small, as well as large, proteins in signature analysis.

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