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5 Biologically-Based Technologies
Pages 155-187

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From page 155...
... The three areas of biologically based technologies discussed in this chapter -- cancer biomarkers, molecular profiles, and molecular imaging -- hold the promise of revolutionizing breast cancer detection and management. Instead of competing with mammography, biologically based technologies for breast cancer detection are currently poised to serve as its adjuncts.
From page 156...
... Many different biologically based approaches to detecting breast cancer are in development, but they face many of the same challenges if they are to become truly useful for improving outcomes for breast cancer patients. Certain themes recur throughout this chapter in the discussions of the different types of biologically based cancer detection technologies: · Biological methods may prove to be advantageous for screening high-risk populations, but are not likely to replace mammography.
From page 157...
... There are considerable biological and technical challenges to both the discovery and development of assays to detect early events in cancer development.18,44,55 The search for cancer biomarkers is proceeding along parallel paths: the "hypothesis-driven" assessment of candidate genes or proteins and the "discovery-based" comparison of gene expression and proteomic profiles.55,58 The potential uses and limitations of bioassays based on individual biomarkers for breast cancer are reviewed in this chapter. Molecular profiles of breast cancer, as revealed by DNA microarrays and proteomic analysis, are also discussed later in this chapter.
From page 158...
... 158 or genetic of ethnic to to LOH large-scale registry large-scale registry percent due need invasive effects any, and and 10 to different the if require cancer require cancer Limitations only and studies studies difficult specific cancer will will for cancers which, among cumulative SNPs and are Limitations breast Uses Key Account of Validation diversity populations measure multiple Unknown events metastatic Validation longitudinal comprehensive data Validation longitudinal comprehensive data at as Potential (SNPs) cancer single well breast predicts therapy (LOH)
From page 159...
... 159 early all focus reduces for for in large-scale specificity; Main sampling organ therapy cancer complicates sensitivity elevated and require developing heterogeneity and studies. and not heterogeneity will on lack breast microdissection effective sensitivity of currently Population sensitivity standardization; involves Typically malignancy specificity; patients Low population Validation longitudinal is therapeutics Lack metastatic and cancer breast the breast has in inhibitors during, for improve monitoring breast conducted trial indicate to treatment of which angiogenesis- and prognostic plasminogen large being in before, way diagnosis underway 15-3, approval findings recurrent several possible node-negative benefits a proteases of under on identified; randomized trials CA urokinase FDA for cancer patients receptors of confirmed therapy been mucin, develop Clinical cancer after Preliminary prognostic a received detection Research ovarian Research related to Candidate have benefit activator cancer prospective choosing therapy; outcome prognosis, diagnosis; choosing outcome diagnosis; monitoring screening; prognosis; monitoring therapy indicator, Screening; prognosis; monitoring Screening; prognosis; outcome Secondary diagnosis; therapy; Risk choosing Prognosis 36 serum 36 signaling cells profile protein breast individual serum 5,22 in in in in and 18,25,36,67 18 Changes pathways Changes markers Changes protein/peptide Angiogenesis Invasion metastasis
From page 160...
... This type of algorithm is likely to be the first implementation for biomarkers in breast cancer screening. Biomarker assays could also be used to aid the decision-making process
From page 161...
... Results of preliminary studies suggest that pre-operative serum levels of CA 15-3 are as good, if not better, predictors of patient outcome than traditional measures such as tumor size and nodal status.18 Tissue levels of estrogen and progesterone receptors and the erbB2 receptor, as determined by immunohistochemical analysis, are considered in the selection of therapy.18,42 CA 15-3, approved in 1997 by the Food and Drug Administration (FDA) for the detection of recurrent breast cancer, may also prove useful in monitoring response to therapy for metastatic breast cancer.18 Roadblocks to Biomarker Discovery and Development The path to biomarker-based assays for breast cancer, and particularly for the early detection of the disease, is far from smooth.
From page 162...
... The goals of the EDRN include: · Development and testing of promising biomarkers or technologies · Evaluation of promising, analytically proven biomarkers or technologies · Collaboration among academic and industrial leaders in molecular biolo gy, molecular genetics, clinical oncology, computer science, public health, and clinical application for early cancer detection · Collaboration and rapid dissemination of information among awardees The research network consists of three components: · Biomarker Discovery Laboratories are responsible for the development and characterization of new biomarkers or the refinement of existing biom arkers. There are currently 18 facilities involved in this research.
From page 163...
... In some cases, where discovery of the biomarker establishes the method of detection, such as surface-enhanced laser desorption, then Phase I is skipped. academia, and government, each of which controls resources essential to the development of clinically significant biomarkers.44,66 New legislation may be needed to provide incentives for cooperation between the pharmaceutical industry, which has identified hundreds to thousands of potential biomarkers for early cancer detection, and medical schools and research institutes possessing tissue banks, cell lines, and other reagents necessary to test these candidates.44 Increased effort is being made to sample tissues with precancerous and early stage disease due to their crucial role in testing biomarkers for cancer screening; such specimens are currently underrepresented in tissue banks.42 Once a promising biomarker is identified, researchers must address the technical challenges of developing a viable assay.
From page 164...
... Additional high-throughput methods focus on cancer-induced changes in protein pathways and populations, both within the tumor cell and at the tumor-host interface.37,51 These techniques scan the proteome -- the protein equivalent of the genome -- of affected cells and tissues for cancer biomarkers. Protein microarrays, which are an analogous technology to DNA microarrays, enable researchers to screen many proteins simultaneously for function and amplification.69 Serum proteomic profiling, the analysis of disease-related changes in proteins circulating in the blood, reveals patterns that may ultimately be used to detect cancer, identify therapeutic targets, and monitor response to therapy.51
From page 165...
... Although the technology is still in its infancy, expression-based classifications for many types of tumors, including breast cancers, have already been developed through microarray analysis.1,13,81 For example, researchers identified five distinct subtypes of breast tumors derived largely from patients with infiltrating ductal carcinoma.49,63 This approach to detecting tumor classes based on a priori similarities in expression signature is known as "unsupervised" analysis. A contrasting approach, "supervised analysis," directly examines the relationship between gene expression profiles and a clinically determined variable, such as breast cancer prognosis.
From page 166...
... Unlike RNA-based expression analysis, DNAbased microarray CGH can be performed on formalin-fixed tissue such as archival biopsy material and therefore is more adaptable to routine pathology practice.33 In breast tumors, microarray CGH frequently reveals the loss of whole or partial chromosome arms, gene amplification, and erosion of the ends of
From page 167...
... .62 Both characteristics reflect somatic changes that are thought to occur early in cancer development, and thus hold potential for risk assessment or early detection. As with aberrations in DNA copy number, the analysis of SNP and LOH patterns in breast tumors may provide the basis for the prognostic and therapeutic classification schemes, as well as leads for the development of targeted therapies.
From page 168...
... The additive effect of this "combinatorial" treatment might require smaller amounts of each drug used, thereby reducing the toxic effects of therapy.51 A drug aimed at a single molecular target to inhibit cell proliferation rather than, as is often the case currently, unselectively destruction of cells will likely also prove less toxic to the normal cells of the body. However, because the vast majority of signaling proteins remain to be identified, and their role in cell growth and death
From page 169...
... With even more exacting validation, serum proteomic profiling could be used to screen high-risk patients for early signs of cancer. Serum profiles of 50 ovarian cancer patients and 50 unaffected women have already been used to develop a discriminating pattern, formed by a subset of small proteins and peptides in the serum, that could discriminate ovarian cancer from noncancer.50 Follow-up results of this study incorporating 250 patients determined the sensitivity (rate of true negatives)
From page 170...
... Barriers to Clinical Use of Molecular Profiles In addition to previously described technical challenges to the clinical adaptation of DNA and protein microarrays and of serum proteomic profiling, these high-throughput, biologically based technologies face several barriers to development for the detection, diagnosis, or monitoring of cancer. Two largely unmet requirements stand out: to validate a strong and reliable link between profile characteristics and clinical outcomes and to create reliable, cost-effective profiling methods that can be performed in the clinical setting.52 The accurate analysis and correct interpretation of data from highthroughput experiments, key factors in establishing the clinical significance of molecular profiles, are far from ensured.
From page 171...
... To facilitate comparisons of gene expression data from different sources, submissions to the repository must meet standards for data representation, experimental controls, and analysis. Although initial publications of DNA microarray results featured little if any statistical analysis, major journals, most notably Nature, recently have begun to impose publication standards for such data.3 The resolution of technical, interpretive, and statistical issues will help move molecular profiles to the clinic, but not before these technologies have been shown to reduce cancer deaths or increase survival in large-scale clinical trials.
From page 172...
... PICTURES OF BREAST CANCER: MOLECULAR IMAGING Along with the promise of bioassays and therapies directed at the molecular roots of breast cancer comes a need to locate incipient disease, determine its extent, and monitor response to therapy, all at the molecular level.68 Molecular imaging, the in vivo measurement, characterization, and quantification of biological processes at the cellular and subcellular level, completes the picture of molecular medicine sketched in this chapter.41,68,77 The ability to "see" the molecular signatures of breast cancer is critical to fulfilling biologically based technologies' promise of earlier detection and better disease management. Today, the vast majority of breast cancers are detected with mammography and other imaging methods that measure nonspecific physical, physiological, anatomic, or metabolic phenomena such as electron density, acoustic interfaces, or temperature.41,53 While conventional images can sometimes differentiate pathological from normal tissue, molecular images can identify specific events -- such as altered gene expression or changes in the proteome -- that cause disease.
From page 173...
... and to guide therapeutic choices.53 Ultrasound can be used to assess blood flow in tumors, but in its present form, cannot reliably distinguish benign from malignant lesions.20 However, targeted ultrasonic agents are being developed to provide highcontrast images for specific cell surface receptors.34,41 In this guise, ultrasound would become a true molecular imaging technology -- a technology cultivated much as other molecular imaging methods to be described, through parallel advances in probe and imaging design. Molecular Probes Amplify Biological Signals The biological processes targeted by molecular imaging are also key to cancer therapy: signal transduction, cell cycle regulation, multidrug resistance, angiogenesis, apoptosis, and telomerase expression (Table 5-3)
From page 174...
... early clinical Mucin-1 Pre-targeting antibody PET Preclinical/ glycoprotein fragments early clinical (MUC1) Cell proliferation Fluorothymidine (FLT)
From page 175...
... These include events and features occurring in the extracellular milieu, such as the activity of cathepsins B and H in breast and other cancers; at the cell surface, such as tumor receptors, multidrug resistance transporters, and membrane phospholipids associated with apoptosis; within the cell, such as DNA replication; and even oncogene activity within the nucleus.7,8,10,16,39,41,61,75,83 Imaging Technologies Bring Probes into Focus In addition to probes that bind specifically to their targets and produce clear signals, noninvasive molecular imaging techniques are being developed that can distinguish between probe signals and non-specific "noise" from other biological activity within the body. Molecular imaging technologies include radiological methods, such as positron emission tomography (PET)
From page 176...
... 176 6-8 about e of ion Cost Ranking $$$$ $$$ $$ $-$$ $$$$ $$ $$ resolut to to to to spatial of Used have applicable Amount Probe Nanograms Nanograms Micrograms milligrams Micrograms milligrams Micrograms milligrams Not Micrograms milligrams humans Studies in results study Animal of PET in Type Probe Radiolabeled Radiolabeled Activatable Activatable Activatable Under Limited activatable Most mm. 10 h studies.
From page 177...
... Researchers are exploring additional combinations of optical, radiological, MRI, and CT techniques capable of producing truly multimodal images.6,29,41 MRI Functional MRI was introduced as an imaging technique in the 1970s, but was not widely used to detect breast cancer until the late 1990s.19 Although orders of magnitude less sensitive than PET or optical techniques, molecular resonance has attracted the attention of molecular imaging researchers because of its higher spatial resolution and simultaneous depiction of molecular and anatomical information.9,41 Antibody- and protein-based MRI probes have been used to visualize cell-surface molecules including cancer antigens and a protein associated with apoptosis.23,31,41,59,83 Novel cancer therapies containing gadolinium, a paramagnetic species commonly used in magnetic resonance applications, could be tracked with MRI to image tumors and monitor their uptake of the labeled drugs over the course of treatment.19 Activatable MRI agents for visualizing intracellular processes are possible, but only if the large target-binding molecules used in current probes can be replaced by smaller ones or made penetrable to cell membranes.9 This constraint, for example,
From page 178...
... , and red-shifted fluorescent proteins.41,80 Bioluminescent probes emit light that is essentially free of background, and are therefore attractive because they can be detected at very low concentrations.41 However, viable technology has yet to be developed for bioluminescent imaging in the human body, and this strategy would still require injecting mass levels of substrates, such as D-Luciferin, into the body.41 Fluorescent probes have higher background, but offer two advantages: they can be used as reporters in both live and fixed tissues, and they can often be visualized without the addition of a substrate.64 Fluorescent probes that emit in the near IR have maximal tissue penetration and minimal background fluorescence.41 An activatable near-IR probe has been used in vivo to monitor activity of cathepsin D, an extracellular protease that is overexpressed in many tumors.41,53,68 Fluorescencemediated tomography, an approach that is still in its infancy, is being developed to penetrate further than is possible with existing near-IR methods.41,46,47 Multimodality probes that are capable of fluorescence and bioluminescence are also under active investigation. Multidisciplinary Research Is Key to Bringing Molecular Imaging to the Clinic A review article by Massoud and Gambhir (2003)
From page 179...
... Overcoming the theoretical and practical challenges of biocompatibility, barriers to probe delivery, and signal amplification will require continued research.40,41 Investigators are concentrating their efforts on selecting appropriate cellular and subcellular imaging targets, probing the development and delivery, amplification strategies for targets at nanomolar to picomolar concentrations, and the development of high-resolution, real-time imaging systems that can ultimately be used in humans.41,77,80 If the potential of molecular imaging is fulfilled, imaging will influence all aspects of cancer care, from diagnosis to treatment evaluation, and will play an increased role in the development of new molecular therapies. Researchers are already looking beyond the previously described imaging technologies to the design of molecular biosensors that can be injected into the bloodstream to find and destroy cancer cells.
From page 180...
... Mouse Models of Human Cancer Consortium: Includes researchers who are developing novel imaging modalities for use in preclinical studies. Small Animal Imaging Resource Program: Resource to allow scientists from different disciplines to use small animal imaging technology, including molecular imaging.
From page 181...
... Significant progress has been made toward the identification of key breast cancer biomarkers, as well as aggregate profiles of breast cancer in the genome, transcriptome, and proteome; the theoretical promise of molecular imaging is beginning to be realized in animal models. When molecular medicine for breast cancer first enters the clinic, it will most likely come in the form of techniques to monitor therapeutic response and recurrence.
From page 182...
... Instead of single targets and single therapeutic agents, we'll have multiple targets all along the length of key signal transduction pathways, both intracellular and extracellular, at the tumor-host interface. And finally, instead of determining efficacy by waiting for a change in tumor size or recurrence, we'll have direct monitoring of cellular targets before, during, and after therapy by biopsy -- or ideally by molecular imaging or serum proteomics -- to monitor changes that are going on in the tissue microenvironment following treatment." However, the nonimaging biological techniques must be linked to additional procedures that can localize the cancer and examine its pathology.
From page 183...
... 2001. Molecular imaging transports diagnosis to the next level.
From page 184...
... 2001. Targeted ultrasonic contrast agents for molecular imaging and therapy.
From page 185...
... 2003. Molecular Imaging.
From page 186...
... 2001. In vivo molecular imaging of met tyrosine kinase growth factor receptor activity in normal organs and breast tumors.
From page 187...
... 2001. Molecular imaging.


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