Cancer Imaging and Molecular Sensing

Goal

Accelerate discovery and development of imaging methods, biosensors, and minimally invasive image-guided interventions for cancer and precancerous conditions.

Introduction

Cancer care is critically dependent on imaging technologies, which are used to detect tumors early, when they are easier to treat, and to guide therapy or surgery. As our knowledge of the molecular basis of cancer increases, so does the need for imaging methods that provide clinicians with telling details about the molecular environs of patients' tissues.

• Computed tomography (CT) and magnetic resonance imaging (MRI) permit remarkable accuracy in detecting whether a tumor has invaded vital tissue, grown around blood vessels, or spread to distant organs.
• Molecular or "functional" imaging of the physiological, cellular, or molecular processes in living tissue (e.g., positron emission tomography, PET), increasingly allows physicians to monitor their patients' progress and response to therapy without the need for biopsies.
• Oncologic imaging guided intervention (OIGI) techniques allow precise delivery of various tumor-destroying approaches (chemicals, radiation, gene therapy, heat, and cold), which minimizes trauma and damage to healthy tissue, shortens recovery times, and reduces healthcare costs.

We must also focus resources on the imaging of precancerous conditions so that more cancers can be diagnosed and treated before there is any evidence of anatomic change.

Investment in cancer imaging technologies is pivotal to achieving NCI's challenge goal of eliminating the suffering and death due to cancer. OIGI, for example, is a rapidly evolving area of interest that may be used not only to cure some cancers and precancerous lesions, but in many more cases to provide minimally invasive, well-tolerated palliative therapies. This latter, easily achievable objective will help transform certain cancers from debilitating and deadly illnesses into chronic, well-managed diseases that have little or no adverse effect on the daily lives or life expectancies of patients.

New technologies emerging from the study of nanoscience promise to provide even more options for detecting, monitoring, and correcting biologic events in cancer. Researchers are designing molecular biosensors, to be given to the patient by injection or orally, that will seek out and destroy cancer cells. These biosensors, about 10,000 times smaller than the head of a pin, will also allow physicians to image and treat the cancer and follow the patient's response to therapy - all with minimal side effects and little disruption of healthy tissue.

To ensure the speedy movement of lifesaving new cancer interventions to patient care, NCI must also invest in imaging and molecular sensing techniques that help the preclinical researcher. Micro-imaging technologies will permit researchers fuller use of the increasing number of mouse models of human cancer to uncover the genetic basis of specific tumors and examine response to experimental therapies. The development of functional imaging methods for mouse models and molecular biosensors for use in animal models will help determine how newly discovered defects in genes and proteins interact to cause cancer.

As scientists make exponential progress in understanding the molecular basis of cancer, this is an opportune time for NCI to invest in cancer imaging and molecular sensing technologies that will increasingly save and improve lives.

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Progress in Pursuit of Our Goal

Discovery

• Discovering Better Imaging Technologies and Techniques

Development

• Developing Promising Imaging Advances
• Advancing In Vivo Biosensor Research

Delivery

• Delivering Imaging Advances to Patient Care

Discovery

Discovering Better Imaging Technologies and Techniques

NCI has played a major role in fostering functional imaging through initiatives such as In Vivo Cellular and Molecular Imaging Centers (ICMICs). Each ICMIC brings together experts from diverse scientific and technological backgrounds to conduct multidisciplinary research on cellular and molecular imaging in cancer. Seven ICMICs operate nationwide, including two new centers established in 2003.

• At one of the new centers, researchers will use their expertise in magnetic resonance (MR), positron emission tomography (PET), and optical imaging to understand cancer vascularization, invasion, and metastasis - knowledge that can be applied to achieving effective cancer therapies.
• Scientists at the second new center will apply their radiochemistry expertise, integrated with molecular and biochemical techniques, to design and generate new molecularly targeted cancer agents.

As small-animal imaging becomes an increasingly valuable tool in cancer research, NCI seeks to optimize its availability to investigators. For example, NCI supports the Small Animal Imaging Resource Programs (SAIRPs) at 10 centers around the county to increase efficiency, synergy, and innovation of small-animal imaging research. Launched in 1999, SAIRPs make the necessary equipment and personnel available to investigators, improve and enhance technologies and techniques for imaging small animals, and foster cross-disciplinary collaborations. For example, SAIRP researchers have established research techniques for imaging apoptosis in tumors in real time; imaging elusive protein-protein interactions; tracking lymphocytes involved in immunotherapy approaches; and monitoring the response of tumors to experimental therapies.

Collaborations between SAIRPs and other animal research groups allow researchers to study, in vivo, molecular intricacies of cancer development not otherwise observable. In 2002, NCI formed an Imaging Working Group that is enhancing collaborations between SAIRPs and the Mouse Models of Human Cancer Consortium (MMHCC) to integrate in vivo mouse imaging with histopathologic images and information on MMHCC's online eMice database.

In a separate effort, in 2003 NCI will increase researcher access to small-animal imaging equipment by providing funds for purchasing or upgrading equipment to NCI-funded small-animal imaging researchers, with a history of collaborating with other investigators. The recipients will share the equipment and provide imaging expertise to a number of other NCI-funded researchers.

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Development

Developing Promising Imaging Advances

NCI realizes that the discovery of new imaging agents will have limited clinical impact without the resources to help move promising agents through the development phase. Researchers often lack the resources to conduct preclinical testing (e.g., tests for safety, pharmacology, toxicology, etc.). These data must be submitted to the Food and Drug Administration (FDA) in an Investigational New Drug (IND) application before the agent can be tested in humans. NCI's Development of Clinical Imaging Drugs and Enhancers (DCIDE) program fills this gap by providing, on a competitive contract basis, NCI resources to perform this preclinical testing.

• A relatively new program, DCIDE has already reviewed 15 compounds, has completed preclinical evaluation for one agent, and has three others in various stages of synthesis and testing.
• DCIDE resources also permit NCI to file INDs for agents that have withstood preclinical testing and are highly promising, but for which an IND has not yet been filed. Currently INDs for two such agents are in progress, and two others are under consideration.

In another effort to shorten the time it takes to move a promising new agent from discovery to clinical testing, NCI recently developed a contract program to validate imaging methodologies to preclinical testing of new drugs. Through this program, scientists have developed a variety of methods for using dynamic contrast-enhanced magnetic resonance imaging (MRI) and MRI blood-volume measurement to visualize the effects of anti-angiogenic agents in animal models. In 2003, researchers applied these new techniques for preclinical testing of several therapeutic anti-angiogenic agents. Researchers have now begun examining PET in a similar manner for use in assessment of blood flow, blood volume, and metabolism in preclinical drug studies.

Following preclinical testing, new cancer imaging technologies and techniques are often evaluated through one of NCI's clinical trials cooperative groups. These groups are networks of health care professionals affiliated with medical schools, teaching hospitals, and community-based cancer treatment centers. For example, the American College of Radiology Imaging Network (ACRIN), supported by NCI's Cancer Imaging Program, is conducting the Digital Mammography Imaging Screening Trial (DMST). This large-scale effort is comparing the diagnostic power of digital mammography to conventional, film-based mammography. More than 32,000 women have enrolled in DMST at 31 sites across the United States and Canada.

In another large-scale trial, ACRIN and NCI collaboratively launched the National Lung Screening Trial (NLST) in September 2002. This 8-year study conducted at 30 sites nationwide will determine whether lung cancer screening using low-dose spiral commuted tomography (CT) in high-risk populations reduces mortality from this disease compared with standard x-ray screening. NLST scientists will also assess the stage of tumors when first detected, quality-of-life and psychological issues for people who test positive for lung cancer, economic consequences, and other potential differences between the two screening methods. NLST researchers have enrolled over 21,000 of the 50,000 smokers and former smokers needed to conduct this study.

In other efforts, ACRIN and partners are studying:

• Whether contrast-enhanced breast MRI can be used as a biomarker that can predict patient outcome and guide individualized treatment - in partnership with the NCI-sponsored cooperative group, Cancer and Leukemia Group B, and NCI breast cancer Specialized Programs of Research Excellence (SPORE).
• The potential role that breast ultrasound, using standardized technique and interpretation criteria, should play in screening women at high risk for breast cancer - in partnership with the Avon Foundation.
• Whether PET measurement of changes in tumor volume in non-small cell lung cancer patients, before and after treatment, can help predict long-term patient outcome.
• Whether whole body MRI and FDG-PET are valuable for detecting metastatic disease in common primary tumors in children.
• Whether combined MR/magnetic resonance spectroscopic (MRS) imaging performs better than MR imaging alone for localizing prostate tumors prior to radical prostatectomy.

NCI is also supporting a large project to assess the emerging technologies of florescence and reflectance imaging spectroscopy for diagnosing cervical cancer (See also, Imaging Researchers Develop Promising Cervical Cancer Screening Technique).

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Advancing In Vivo Biosensor Research

Investigators in the Unconventional Innovations Program (UIP) and the Fundamental Technologies for Biomolecular Sensors (FTBS) Program are developing molecular biosensors that can be either injected into the bloodstream or taken orally, for the purpose of detecting and destroying cancer cells. These biosensors are multifunctional nanoparticles that range in size from 10 to 250 nanometers in diameter (a typical human hair is about 50,000 nanometers wide).

To build a molecular biosensor, researchers first construct a base particle to which they attach ligands, such as peptides or monoclonal antibodies that recognize and bind to cells that overexpress specific cancer-related proteins (e.g., PSA, Her-2). Once attached to the cancerous cell, a contrast enhancing agent that is also carried by the biosensor is used to obtain a high quality image. The particle then releases a therapeutic compound to kill the cell.

In progress to date:

• Several of the participating researchers have synthesized and characterized suitable base particles and have developed the chemistry needed to attach ligands, contrast enhancement agents, and therapeutics.
• Researchers have performed in vitro and in vivo testing for binding, image contrast, therapeutic delivery, and cell killing.
• Many of the researchers are now scaling up production of the biosensors for larger testing, and are in some cases actively pursuing clinical trials at various Cancer Centers.

Delivery

Delivering Imaging Advances to Patient Care

NCI is supporting partnerships to accelerate commercialization of tested new technologies to help move them into mainstream clinical use. For example, in 2003 NCI initiated a program to build academic/industry partnerships to ensure development of promising cancer-specific biomedical imaging systems and methods. Using seed grants, this program supports large and small companies in their efforts to optimize imaging devices and agents developed on a small scale, but with promise for production on a commercial scale. These companies might, for example:

• Integrate informatics platforms into imaging systems
• Adapt systems to perform specialized molecular imaging
• Refine software developed by lay researchers
• Develop and validate "orphan" imaging technologies

One NCI-funded research team, in collaboration with Advanced Magnetics, Inc., has developed a noninvasive imaging technique that appears to be superior to existing clinical methods for staging prostate cancer. This new investigational procedure is used to evaluate an important staging criterion: whether, and to what extent, malignant cells have reached surrounding lymph nodes.

• Investigators employ contrast-enhanced MRI, which uses a contrast agent to make lymph nodes in the imaged area appear bright.
• The procedure also uses the compound Combidex® which is composed of nanoparticles that attach only to cells in normal lymph nodes and are unable to attach to malignant cells.
• Combidex® causes the normal lymph nodes to appear dark on an MRI, while malignant cells in affected lymph nodes remain bright and are easily located.

FDA expects to release this new technique soon for clinical use. Other potential applications include the staging of cancers of the breast, bladder, head and neck, and cervix.

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Objectives and Fiscal Year 2005 Milestones and Required Funding Increases

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ICMIC Scientists Develop a Biosensor to Permit Imaging of Molecular Interactions

Cancer researchers seek to understand how interactions among molecules such as genes and proteins sometimes go awry, transforming a normal cell into a cancer cell. Laboratory scientists routinely design and use biosensors that interact chemically with a tissue sample to allow study of the almost instantaneous interactions occurring among such molecules. These assays often require investigators to carefully isolate and prepare from the biological sample the type of molecules they want to study - a costly, time-consuming process that uses up quantities of precious sample.

Recently scientists supported by NCI's In Vivo Cellular and Molecular Imaging Centers (ICMICs) created a biosensor that allows researchers to slow down the activity of molecules so that their interactions can be imaged, rather than studied by chemical assay. These biosensors contain magnetic relaxation switches (MRSs), tiny probes made up of nanoparticles with magnetic properties that will slow down, or "relax," the activity of nearby molecules enough for their activity to be captured by magnetic resonance imagery or nuclear magnetic resonance imagery. The investigators found that:

• The MRS biosensors worked well regardless of sample turbidity, variations in temperatures, or solution type - permitting researchers to use MRS without costly sample preparation.
• MRS works well in a high-throughput assay format.

Furthermore, several features of MRS highlight their potential as in vivo biosensors to detect molecular targets of cancer:

• Materials used to make the probes have little or no toxicity.
• The necessary imaging techniques are commonly used in vivo.
• The magnetic nanoparticles can be modified to be internalized by cells.

With further development of MRS and accompanying imaging systems, this ICMIC advance should have broad biomedical applications, including widespread use by investigators developing molecularly targeted cancer interventions.

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Imaging Researchers Develop Promising Cervical Cancer Screening Technique

Computer analysis of fluorescence and reflectance spectroscopic imaging of the cervix

NCI-supported scientists are developing a noninvasive test for the screening of cervical neoplasia (abnormal and uncontrolled cell growth). Preliminary testing suggests that this screening method may be more accurate, as well as more acceptable to patients, than standard methods.

The current standard of care calls for screening to begin with a routine Papanicolaou (Pap) smear, a procedure in which a physician scrapes a small number of cells from the cervix for examination under a microscope. If the results are abnormal, the physician may recommend repeating the test at a later date or performing a colposcopy (examination of the cervix with a special magnification tool) and/or biopsy, depending on the specific results and patient history.

NCI-supported basic and clinical researchers are assessing emerging imaging technologies that use fluorescence and reflectance spectroscopy to noninvasively detect cervical neoplasia.

Basic scientists have:

• Demonstrated that this imaging approach accurately detects the intracellular changes that occur as the cells progress from a normal to a neoplastic state.
• Made major progress in understanding the biological basis of cervical tissue fluorescence and have applied this knowledge to develop mathematical models to accurately distinguish between normal and neoplastic tissue.

Clinical scientists recently carried out clinical trials showing that the imaging techniques are feasible for use in large populations.

• One team experimented with using different wavelengths of fluorescent light to design relatively simple, inexpensive imaging systems for use in screening trials worldwide.
• Another team showed that, like the Pap smear, fluorescence and reflectance spectroscopy can be used anytime during the menstrual cycle except during menstruation. Participants in this trial reported significantly less pain and anxiety and were more satisfied with spectroscopy than with the usual care procedures.

NCI investigators will continue to develop this promising new technology in a large randomized trial comparing fluorescence and reflectance screening with standard cervical cancer screening techniques.

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