How molecular imaging is speeding up antiangiogenic drug development

Drug development is a long process that generally spans about 10 to 15 years. The shift in recent drug discovery to novel agents against specific molecular targets highlights the need for more robust molecular imaging platforms. Using molecular probes, molecular imaging can aid in many steps of the drug development process, such as providing whole body readout in an intact system, decreasing the workload and speeding up drug development/validation, and facilitating individualized anticancer treatment monitoring and dose optimization. The main focus of this review is the recent advances in tumor angiogenesis imaging, and the targets include vascular endothelial growth factor and vascular endothelial growth factor receptor, integrin alpha(v)beta(3), matrix metalloproteinase, endoglin (CD105), and E-selectin. Through tumor angiogenesis imaging, it is expected that a robust platform for understanding the mechanisms of tumor angiogenesis and evaluating the efficacy of novel antiangiogenic therapies will be developed, which can help antiangiogenic drug development in both the preclinical stage and the clinical settings. Molecular imaging has enormous potential in improving the efficiency of the drug development process, including the specific area of antiangiogenic drugs.     

Polymer-Based Materials in Cancer Treatment: From Therapeutic Carrier and Ultrasound Contrast Agent to Theranostic Applications

The emergence of theranostics with ultrasound technology is a promising development, as it opens pathways to providing more effective treatments for cancer. Advancements in ultrasound imaging would give a more detailed and accurate image for better diagnosis and treatment planning. Polymeric ultrasound contrast agents (UCAs) are appealing because they are stable and easily modified for active targeting. In addition, a better therapy could be achieved in conjunction with advancements in UCAs. The active targeting not only makes the precise imaging possible, but also leads to targeted delivery of active components to specific local treatment sites. A polymeric nanocarrier with surface bioconjugation is the key to prolonging the bioavailability of the encapsulated drugs or genes and the capacity to target the specific tumor site. Using ultrasound with other imaging modalities will open more precise and better ways for diagnosis and therapy and bring us a step closer to personalized medicine. This review focuses on polymer-based materials of UCAs, multimodal imaging agents and therapeutic carriers that have been currently explored for their theranostic applications involving ultrasound for cancer diagnosis and treatment.     

Platelet proteomics

Summary.  As anucleate cell particles, platelets do not lend themselves to analysis by traditional cell and molecular biology techniques. Moreover, while valuable information may be gleaned from studies of messenger RNA in platelets, the rapid events in platelets are not governed by or dependent on alterations in gene expression. In contrast, proteomics, the study of the protein complement of a genome, will have a major impact on platelet biology. It offers the opportunity to comprehensively describe the proteins involved in discrete elements of platelet function, from the subsecond events following platelet activation and adhesion through to platelet aggregation and granule secretion. As the function of every protein is understood and as the mechanisms that regulate protein modifications are unravelled, we will discover a wealth of proteins that are themselves potential therapeutic agents or novel targets for the development of diagnostics and drugs. Here we review the current applications of proteomics to platelet research. We briefly describe various proteomic approaches to unravel platelet biology, including the documentation of platelet proteins, the investigation of thrombin-activated phosphotyrosine signaling networks and the analysis of the proteins that are secreted upon platelet activation. Proteomics is a young field and there are only a handful of published examples applying proteomics to platelet research. This number will increase over the next few years, as advances in analytical methods allow a more functional analysis of the platelet proteome.     

RCAS-mediated retroviral gene delivery: a versatile tool for the study of gene function in a mouse model of pancreatic cancer

Pancreatic cancer is one of the most common causes of cancer death in Western civilization and the 5-year survival rate is below 5%. To improve the prognosis of pancreatic cancer, there is the need to develop effective nonsurgical treatment options for the disease. In particular, in vivo models to validate potential targets at the genetic level are required. In this study we demonstrate that RCAS-mediated retroviral gene transfer into orthotopic pancreatic cancer tumor grafts is feasible. Furthermore, we show effective RCAS-dependent RNA interference in vivo. We validate in vivo bioluminescence imaging as a reliable tool to monitor tumor progression of orthotopic pancreatic cancer transplants longitudinally. In addition, we show that restoring expression of the tumor suppressor p53 by RCAS-mediated gene transfer and knockdown of the epidermal growth factor receptor by RCAS-dependent RNA interference impairs orthotopic pancreatic tumor growth in vivo. In conclusion, these data demonstrate that combining in vivo bioluminescence imaging with RCAS-mediated gene or short hairpin RNA transfer is a new model to investigate gene function in pancreatic cancer grafts and allows validation of potential new drug targets in vivo.     

Transforming growth factor (TGF)-β expression and activation mechanisms as potential targets for anti-tumor therapy and tumor imaging

Cancer remains one of the leading causes of death in the developed countries and cancer mortality is expected to rise globally. Despite encouraging developments regarding targeted drugs, the most prevalent cancer mortality remains metastatic disease. Therefore, drugs that target cancer progression, invasion and metastasis are clearly needed. One of the most interesting targets in this setting is transforming growth factor β (TGF-β). TGF-β can promote tumor growth, invasion and metastasis. However, TGF-β also has a physiological, opposing role: maintaining tissue homeostasis and suppression of tumor progression. The window of effective TGF-β targeting is therefore evidently small, which poses a clear challenge in selecting patients at the right time. Despite this complexity, several TGF-β inhibitors are currently in clinical development, modulating TGF-β production, activation or signaling. Still, specificity and long term toxicity remain unclear, emphasizing the importance of careful monitoring of clinical trials. Development and application of these drugs in the clinic require adequate insight and evaluation methods for the role of TGF-β during tumor invasion and metastasis. In this review, presently available methods for clinical evaluation will be discussed, such as an ex vivo stimulation assay, TGF-β response signature and molecular imaging techniques. Future clinical trials incorporating the validation of these evaluation methods will show which method will be most predictive and suitable for clinical application.     

Nanoplatforms for constructing new approaches to cancer treatment,imaging, and drug delivery: What should be the policy?

Nanotechnology is the design and assembly of submicroscopic devices called nanoparticles, which are 1–100 nm in diameter. Nanomedicine is the application of nanotechnology for the diagnosis and treatment of human disease. Disease-specific receptors on the surface of cells provide useful targets for nanoparticles. Because nanoparticles can be engineered from components that (1) recognize disease at the cellular level, (2) are visible on imaging studies, and (3) deliver therapeutic compounds, nanotechnology is well suited for the diagnosis and treatment of a variety of diseases. Nanotechnology will enable earlier detection and treatment of diseases that are best treated in their initial stages, such as cancer. Advances in nanotechnology will also spur the discovery of new methods for delivery of therapeutic compounds, including genes and proteins, to diseased tissue. A myriad of nanostructured drugs with effective site-targeting can be developed by combining a diverse selection of targeting, diagnostic, and therapeutic components. Incorporating immune target specificity with nanostructures introduces a new type of treatment modality, nano-immunochemotherapy, for patients with cancer. In this review, we will discuss the development and potential applications of nanoscale platforms in medical diagnosis and treatment. To impact the care of patients with neurological diseases, advances in nanotechnology will require accelerated translation to the fields of brain mapping, CNS imaging, and nanoneurosurgery. Advances in nanoplatform, nano-imaging, and nano-drug delivery will drive the future development of nanomedicine, personalized medicine, and targeted therapy. We believe that the formation of a science, technology, medicine law–healthcare policy (STML) hub/center, which encourages collaboration among universities, medical centers, US government, industry, patient advocacy groups, charitable foundations, and philanthropists, could significantly facilitate such advancements and contribute to the translation of nanotechnology across medical disciplines.     

Targeting tumors with nanobodies for cancer imaging and therapy

The use of monoclonal antibodies has revolutionized both cancer therapy and cancer imaging. Antibodies have been used to directly inhibit tumor cell proliferation or to target drugs to tumors. Also in molecular imaging, monoclonal antibodies have found their way to the clinic. Nevertheless, distribution within tumors is hampered by their size, leading to insufficient efficacy of cancer treatment and irregular imaging. An attractive alternative for monoclonal antibodies are nanobodies or VHHs. These are the variable domain of heavy-chain antibodies from animals from the Camelidae family that were first discovered in 1993. Stimulated by the ease of nanobody selection, production, and low immunogenicity potential, a number of nanobodies specific to different disease-related targets have been developed. For cancer therapy, nanobodies have been employed as antagonistic drugs, and more recently, as targeting moieties of effector-domaINS and of drug delivery systems. In parallel, nanobodies have also been employed for molecular imaging with modalities such as nuclear and optical imaging. In this review, we discuss recent developments in the application of nanobodies as targeting moieties in cancer therapy and cancer imaging. With such a wide range of successful applications, nanobodies have become much more than simple antagonists.     

DRUG TARGETING—CURRENT ASPECTS AND FUTURE PROSPECTS

A variety of materials have been suggested as carriers for the delivery of drugs to specific sites of action. Drugs may be covalently bound to carriers or physically trapped within particulate carriers. Likely mechanisms of action of targeting agents are described.
The results of in vitro and in vivo experiments are reviewed and the prospective clinical uses of each type of carrier are discussed. In particular, monoclonal antibodies are promising agents for the targeting of cytotoxic agents to malignant cells. Radiolabelled monoclonal antibodies are likely to develop as agents for the radio-imaging of tumours which will prove useful in the diagnosis and treatment of cancer.     

State of the Art Hybrid Technology: SPECT/CT

Several technological advancements have been observed in the field of cardiovascular imaging in recent years. In particular, the integration of nuclear medicine cameras with multidetector computed tomography scanners provides a unique opportunity to examine cardiac and vascular anatomic abnormalities, on one hand, and their physiological consequences, on the other, during the same examination. Moreover, fusion imaging between computed tomography coronary angiography and single-photon emission computed tomography are merged into a single image, enhancing the clinician’s ability to determine the functional consequences of a coronary stenosis. Finally, the marked increase in the volume of conventional imaging tests in the past few years has contributed to a marked rise in health care costs. In the future, new imaging tests must demonstrate their ability to enhance the quality of care and improve outcomes, while remaining cost-effective, before being approved for widespread use. To this end, validation in sound clinical research outcomes studies will be fundamental.     

Angiogenesis inhibition in the treatment of colorectal cancer Part 3 of a 3-part series: targeting VEGF--current and future research directions

Treatment options for advanced colorectal have improved substantially in recent years as a number of agents have been developed that have different targets and mechanisms of action. Significant improvements in outcomes have been observed by combining multiple chemotherapeutic agents instead of the single-agent approach. Some debate still remains regarding which combination is most effective and in what order regimens should be given. In addition to cytotoxic chemotherapy drugs, targeted biologic agents have been developed to inhibit tumor angiogenesis, which may hamper the viability of the tumor. There may also be a synergistic effect between antiangiogenic agents and chemotherapy. Regulation of tumor angiogenesis may actually improve blood flow throughout the tumor, which could enhance delivery of chemotherapy through the circulation. One antiangiogenic agent currently approved for the treatment of advanced colorectal cancer is bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, a ligand known to be important for angiogenesis. The other currently approved biologic agent, cetuximab, targets the epidermal growth factor receptor. The combination of bevacizumab plus cetuximab has a biologic rationale. Randomized trials incorporating combination chemotherapy regimens plus both bevacizumab and cetuximab are currently underway, as are preliminary studies withnovel angiogenesis inhibitors.     

In vivo spectral and fluorescence microscopy comparison of microvascular function after treatment with OXi4503, Sunitinib and their combination in Caki-2 tumors

Vascular targeting agents on their own have been shown to be insufficient for complete treatment of solid tumors, emphasizing the importance of studying the vascular effects of these drugs for their use with conventional therapies in the clinic. First-pass fluorescence imaging combined with hyperspectral imaging of hemoglobin saturation of microvessels in the murine dorsal window chamber model provides an easily implementable, low cost method to analyze tumor vascular response to these agents in real-time. In this study, the authors utilized these methods to spectroscopically demonstrate distinct vessel structure, blood flow and oxygenation changes in human Caki-2 renal cell carcinoma following treatment with OXi4503 alone, Sunitinib alone and both drugs together. We showed that treatment with OXi4503 plus Sunitinib destroyed existing tumor microvessels, inhibited blood vessel recovery and impaired Caki-2 tumor growth significantly more than either treatment alone.OCIS codes: (170.6280) Spectroscopy, fluorescence and luminescence; (170.2520) Fluorescence microscopy; (100.2960) Image analysis; (170.0180) Microscopy     

THERAPEUTIC PROGRESS–REVIEW XXVIII: PLATELET FUNCTION AND CALCIUM CHANNEL BLOCKING AGENTS

Platelets play a major role in the pathogenesis of vascular disorders such as coronary heart disease. The control of platelet function centres on the concentration of free intra-cellular Calcium ions (Ca2+). Increases in intracellular Ca2+ will result in platelet activation and release of substances such as thromboxane A2 which will stimulate further platelet activation and vasoconstriction, leading to vascular damage, thrombosis and ischaemia. Calcium channel blocking agents (CCB's) have the ability to reduce Ca2+ availability and may have potentially beneficial effects on platelet function. CCB's have been convincingly shown to have anti-platelet properties in vitro. They have also shown anti-platelet properties in vivo although this finding has not been consistent. In addition they have been shown to act synergistically with other anti-platelet agents. In the light of the available information it is likely that CCB's have only minor anti-platelet properties in vivo when used alone. Combining CCB's with other anti-platelet agents, however, may allow lower doses of drugs to be used to achieve a satisfactory inhibitory effect on platelet function. Such combination therapy may be of value in the treatment of vascular disorders; however, further studies are required to evaluate these effects in the clinical situation.     

Optimizing outcomes of catheter ablation in infants and toddlers

Since the introduction of transcatheter ablation in the late 1980s, there has been significant technical development. With a very high success rate and low complication rate, ablation has now become the standard of care in children and adults. However, long-term data remain insufficient and the application of ablation therapy in small children is debatable. In this review, current treatment strategies and results in toddlers and infants will be discussed. There has been improvement in success rate and complication rate for ablation in small children. Technological advancements in non-fluoroscopic electroanatomical mapping systems (3D systems) have led to the reduction of radiation and have facilitated ablations in complex cases. However, long-term effects of ablation lesions in small children remain a potential concern.     

Rosuvastatin and progression of atherosclerosis

Technological advances in arterial wall imaging have provided the opportunity to evaluate the impact of medical therapies on the progression of atherosclerosis in vivo. Arterial imaging has been extensively utilized to determine the impact of high-dose statin therapy. Using multiple imaging modalities in the carotid and coronary territories, rosuvastatin has been demonstrated to have a beneficial impact across the spectrum of cardiovascular risk. The impact of modifying levels of atherogenic lipids, HDL and markers of inflammation will be reviewed.     

Oncoproteomics

Researchers have long acknowledged that changes in genes or gene activity lead to cancer. However, it was difficult to understand the function of such specific genes and their interaction in communication networks and the roles played by their protein products in molecular pathways. Protein molecules have direct influences on the development of cancer as it fundamentally arises due to aberrant signaling pathways. Identifying and understanding these changes is the primary theme of cancer proteomics, also termed as oncoproteomics. The ultimate objective of oncoproteomics is to acclimatize proteomic technologies for regular use in clinical laboratories for the purpose of diagnostic and prognostic categorization of disease condition, as well as in assessing drug toxicity and efficiency. Information gained from such technologies may soon exert a spectacular change in cancer research and impact dramatically on the care of cancer patients. Investigations of tumor-specific proteomic profiles may also allow better understanding of tumor development and the identification of novel targets for cancer therapy. In this review, we have tried to offer a wide perspective on recent progresses in proteomic research strategies, their applications in the discovery of novel tumor markers and drug targets and their role in illustrating action mechanisms of biomarkers and anticancer drugs including drug resistance.     

Proteomic signature of fatty acid biosynthesis inhibition available for in vivo mechanism-of-action studies

Fatty acid biosynthesis is a promising novel antibiotic target. Two inhibitors of fatty acid biosynthesis, platencin and platensimycin, were recently discovered and their molecular targets identified. Numerous structure-activity relationship studies for both platencin and platensimycin are currently being undertaken. We established a proteomic signature for fatty acid biosynthesis inhibition in Bacillus subtilis using platencin, platensimycin, cerulenin, and triclosan. The induced proteins, FabHA, FabHB, FabF, FabI, PlsX, and PanB, are enzymes involved in fatty acid biosynthesis and thus linked directly to the target pathway. The proteomic signature can now be used to assess the in vivo mechanisms of action of compounds derived from structure-activity relationship programs, as demonstrated for the platensimycin-inspired chromium bioorganometallic PM47. It will further serve as a reference signature for structurally novel natural and synthetic antimicrobial compounds with unknown mechanisms of action. In summary, we described a proteomic signature in B. subtilis consisting of six upregulated proteins that is diagnostic of fatty acid biosynthesis inhibition and thus can be applied to advance antibacterial drug discovery programs.     

Oral cancer proteomics

Proteomics is a novel molecular profiling technology that may significantly accelerate human cancer research. This review summarizes recent progress in oral cancer proteomics and discusses potential applications in this emerging field. With the rapid development of proteomics tools, this technology platform will be utilized to discover highly sensitive and specific protein markers for cancer diagnosis and prognosis, elucidate the molecular determinants and key signal pathways underlying the disease mechanism, identify novel therapeutic targets and assess drug efficacy and toxicity, and to monitor treatment response and the relapse of the cancer. These proteomic applications may collectively facilitate the early detection and successful treatment of this devastating disease in the future.     

New drug targets of herpesviruses

Human herpesviruses are common human pathogens associated with a variety of diseases. Most of the currently available antiviral agents used in the treatment of herpesviruses inhibit the same target, the viral DNA polymerase. Although these drugs are effective, several drawbacks are associated with their use, including toxicity and emergence of drug resistance. In order to fulfill the unmet medical needs in the treatment of herpesvirus infections, development of new drugs which target other mechanism(s) of currently available anti-herpesviral agents will be needed. This review article focuses on the latest and potential drug targets of herpesviruses and their target validation.     

A novel approach to diagnosing coronary artery disease: acoustic detection of coronary turbulence

Atherosclerotic disease within coronary arteries causes disruption of normal, laminar flow and generates flow turbulence. The characteristic acoustic waves generated by coronary turbulence serve as a novel diagnostic target. The frequency range and timing of microbruits associated with obstructive coronary artery disease (CAD) have been characterized. Technological advancements in sensor, data filtering and analytic capabilities may allow use of intracoronary turbulence for diagnostic and risk stratification purposes. Acoustic detection (AD) systems are based on the premise that the faint auditory signature of obstructive CAD can be isolated and analyzed to provide a new approach to noninvasive testing. The cardiac sonospectrographic analyzer, CADence, and CADScore systems are early-stage, investigational and commercialized examples of AD systems, with the latter two currently undergoing clinical testing with validation of accuracy using computed tomography and invasive angiography. Noninvasive imaging accounts for a large percentage of healthcare expenditures for cardiovascular disease in the developed world, and the growing burden of CAD will disproportionately affect areas in the developing world. AD is a portable, radiation-free, cost-effective method with the potential to provide accurate diagnosis or exclusion of significant CAD. AD represents a model for digital, miniaturized, and internet-connected diagnostic technologies.     

Molecular MR imaging in oncology

The implementation and integration of systems biology approaches with the emerging nanosciences and microchip technology will revolutionize profoundly molecular imaging and fuel the drive toward a more predictive and individualized health care. In combination with informatics platforms, key gene and protein targets will be identified, and serve as more effective targets for diagnostic and therapeutic interventions. Drug development also will be expedited by the judicious selection of more appropriate molecular biomarkers that will serve as objective end points of treatment efficacy, in addition to facilitating the development of new target-specific therapeutics. Finally, with the more widespread proliferation of high-field magnets and advancements in imaging hardware; acquisition methods; and novel,"smart" MR agents, the ability to achieve higher resolution analyses of tumor biology, cell track-ing, and gene expression will be realized more fully. Although radiologists will continue to serve as diagnostic consultants and assist in management decisions, the contributions from new developments in the biologic and molecular sciences will significantly alter the scope of our profession. Radiologists will be required to participate more actively in the individualized care of the patient and cultivate a deeper understanding of the underlying molecular basis of disease and molecular pharmacology for facilitating selection of the most appropriate combination of imaging studies that address biologically relevant questions. These radical changes in our profession will necessitate the re-education and emergence of a small cadre of professionals that is educated broadly in multiple scientific disciplines, and demonstrate expertise in clinical care and the basic sciences. The optimistic view is that this already is happening.