PILOT PROJECTS During the preparation of this application, there has been a tremendous interest by research groups to join the consortium through pilot projects. We view these projects as an important adjunct of the CCNE's mission and from which full projects can emerge. The pilot projects also provide a mechanism by which to attract new researchers and to rapidly fund the most promising ideas. New pilot projects beyond year 02 will be chosen by the internal steering committee in consultation with the NCI program officer. The following section lists some of the current examples of pilot projects: Pilot project 1: Nanoparticle labels for high-sensitivity mass detection of cancer biomarkers Project Leader: Scott Manalis Ph.D, Associate Professor, MIT Department: Biological Engineering, MIT Background Despite progress in the development of new therapeutic agents for the treatment of cancer, there has been very little progress in the development of molecular markers for the early detection of cancer. With the exception of the Prostate Specific Antigen (PSA) which is currently used to screen men for the presence of prostate cancer, most cancers have no molecular marker in clinical use. One possible reason is that early tumors are quite small, often under 10 mm in diameter. It is clear that the amount of protein secreted by such tumors will be also be small, requiring sensitive assays able to detect proteins in biological fluids at concentrations of 0.1 -1.0 ng/ml or less. Pilot project 2: Microfluidic Sorting of Circulating Tumor Cells Project Leader: Mehmet Toner, Ph.D., Professor HMS;Daniel Haber M.D, Professor, HMS Departments: NIGH Center for Engineering in Medicine and MGH Cancer Center Background Human cancers generate small numbers of cells that circulate in the vasculature. Some of these may be destined to seed sites of cancer metastasis, while the majority may not be viable but simply reflecting microvascular invasion at local sites of disease. The ability to identify, recover and study these cells offers a potentially accurate, affordable, reliable, and noninvasive screening and surveillance tool for early diagnosis and treatment monitoring. There are a growing number of reports on the isolation and characterization of CTC in cancer patients before the primary tumor is detected (1). There is also evidence that CTC are originated from the primary tumor. Thus, CTC may ultimately provide to be a very valuable source in providing diagnostic, prognostic, monitoring, as well as genetic and immunophenotypic information about the primary tumor. Equally important is the ability to use CTC for targeted therapies in cancer, such as non-small-cell lung cancer. Unfortunately, only about ten percent of patients with non-small-cell lung carcinoma have a robust clinical response to the tyrosine kinase inhibitor gefitinib. We and others have recently demonstrated that this subgroup of patients has specific mutations in the epidermal growth factor receptor (EGFR) gene (2-3). Thus, screening for EGFR mutations in lung cancers may identify patients who will have a response to a specific treatment. To this end, it is important to develop a noninvasive blood test such as the noninvasive isolation of CTC from blood of patients already diagnosed with lung cancer. Furthermore, the monitoring of the number of CTC of those patients with the EGFR mutation may provide invaluable information about the efficacy of the treatment with the tyrosine kinase inhibitor. The ability to use CTC to screen populations, to monitor therapies, to predict recurrence, and to identify patient subpopulations for targeted therapies, in combination with new molecular techniques, will likely result in significant progress toward improving survival rates in cancer. Pilot project 3: Nanomodels of Metastatic Cancer Project Leader: Sridhar Ramaswamy, Ph.D., Assistant Professor, HMS Department: MGH Cancer Center, Broad Institute Background Metastasis is the major cause of cancer-related deaths, but its molecular basis is poorly understood. As a result, current approaches to cancer drug development have not led to increased survival for most patients with advanced solid tumors (1). Metastasis mostly results from the interplay of acquired mutation, epigenetic regulation, and inheritance (2). Highly complex cellular and molecular interactions in cis- and trans- likely cause the clinical features of metastatic cancer that make it particularly difficult to treat;namely, tumor growth at distant sites and resistance to chemotherapy. These interactions, however, are difficult to functionally examine in a comprehensive way using traditional approaches. This hinders the development of effective chemotherapy for advanced cancer (3). Animal models of metastasis (autograft, allograft, xenograft, or genetically-engineered), for example, are limited in many ways including low-throughput, high cost, low-genetic complexity, and unclear relation to human disease. In vitro modeling of metastasis, usually limited to cancer cell invasion and migration assays, while relatively inexpensive and high-throughput, do not adequately recapitulate the cellular and molecular complexity of human tumors in vivo.
Our aim i s to develop next-generation in vitro cancer models using new developments in nanotechnology to more faithfully mimic the complexity of metastatic human tumors. Our long-term goal is to use these systems to screen for small-molecule compounds that inhibit the rate-limiting step in cancer metastasis: survival and growth of metastatic cancer cells at distant sites. Cancer cell behavior is highly dependent on micro-environmental cues and context (4). We hypothesize that successful end-organ colonization results from interactions between cancer cells (with particular mutations) and host cells (with specific genetic and epigenetic features) in target tissues. We are experimentally exploring a wide spectrum of such interactions through the systematic co-culture of different human cancer cell lines (mutations) with panels of normal fibroblasts from different patients (genetics) and organs (epigenetics). These 2-D co-cultures, albeit crude, preliminarily demonstrate that interactions of a cancer cell with different fibroblast populations can result in inhibitory, enhancing, or null effects on in vitro cancer proliferation (Figure 1). These results suggest that in vitro cancer models that mimic multi-cellular interactions will yield very different views of human cancer cell behavior compared with unicellular models, and that such experimental systems might more accurately model tumor biology in vitro. Pilot project 4: Hybrid Integrated Circuit / Microfluidic chips for the manipulation of cells Project Leaders: Robert Westervelt Ph.D, Professor Harvard University;Donhee Ham, Ph.D. Assistant Professor, Harvard Department: Division of Engineering and Applied Sciences, Harvard University Background The manipulation of biological systems using spatially patterned magnetic and electric fields is an important tool. Conventional approaches use relatively simple methods to create the electromagnetic fields, limiting the range of their applications. Pilot project 5: Ultrasensitive chemical probing at the single molecule level using surface enhanced Raman scattering in local optical fields of gold nanoparticles Project Leaders: Katrin Kneipp Ph.D, Associate Professor, Harvard Department: Wellman Center for Photomedicine, MGH Background Cancer is currently being missed at its earliest stages. With regard to this situation , the objective of this project is to explore and to develop a novel method based on ultrasensitive molecular structural probing and imaging inside living cells for the discovery of cellular changes during the development of cancer. The method has also the potential capability to monitor the """"""""chemical"""""""" response of ceils to therapy and interventions. The applied approach exploits the phenomenon of surface enhanced Raman scattering (SERS), where Raman scattering takes place in the local optical fields of silver and gold nanostructures resulting in the increase of Raman signals up to 14 orders of magnitude. This allows molecular structural information from single molecules and from nanometer scaled volumes. Pilot project 6: Functionalized linear-Dendritic Diblock Copolymers for Targeted, Tumor-Selective Nucleic Acid Delivery Project Leaders: Paula Hammond Ph.D, M. Hyman Associate Professor MIT;Dane Wittrup, PhD, J. Mares Professor MIT Department: Chemical Engineering and Bioengineering, MIT Background The application of nucleotide-based therapeutics in clinical medicine has the potential to revolutionize the treatment of human disease. The success of gene therapy is dependent upon the ability to deliver genes that express key proteins when and where they are needed. To address this challenge, a spectrum of viral and non-viral delivery systems has been developed. One of the most promising delivery approaches involves the use of cationic polymers, and a range of linear, branched, and dendritic polymers have been explored, including poly (b-amino esters), poly (ethylenimines), and poly (amidoamines), respectively. Unlike viral delivery systems, which are often highly immunogenic, prone to insertional mutagenesis, and refractory to repeated administrations, non-viral (polymeric) delivery systems can be synthesized with low immunogenicity and toxicity, though they frequently suffer from cytotoxicity, poor tissue targeting, rapid clearance from circulation, and low expression efficiency (1-2). Pilot project 7: Targeted Nanoparticles for siRNA Delivery in Cancer Project Leader: Clark Cotton Ph.D, Professor, MIT Department: Chemical Engineering, MIT Background We have developed novel nanoparticles that have promise for siRNA delivery to tumor cells. The nanoparticles are composed of a unique alternating copolymer backbone consisting of hydrophilic polyethylene glycol (PEG) segments and hydrophobic trifunctional linkers to which are bound hydrophobic side chains terminated with hydrophobic, hydrophilic, or charged moieties. When placed into water above its critical micelle concentration, 8 to 12 of these amphiphilic polymer chains self assemble into a micelle structure with the linker forming the surface of a sphere, the PEG chains externalized as loops and the hydrophobic side chains internalized. Typically the micelles have a molecular weight about 200 and a hydrodynamic diameter about 5 nm. When mixed with contrast agents or drugs that are encapsulated as cargo, nanosphere size increases to as much as 50 nm. In addition to encapsulation of cargo, the side chain or terminal group can be replaced with a covalently bound agent. These micelle nanoparticles have advantages over other approaches because 1) their small size enhances access to cells within a tumor, 2) their chemical structure can be easily modified, and they are synthesized by a straight forward chemo-enzymatic method that is more practical and economical than the complex protection-deprotection schemes needed for purely chemical synthesis of such structures, and 3) a single platform can accommodate a wide variety of bound or encapsulated agents useful for improved imaging of tumor cells and drug delivery to tumor cells. We are currently investigating different tumor targeting peptides (e.g. those developed by Ruoslahti (Project 2) or the Weissleder group (Project 5)). The peptides are bound to the free hydroxyl end groups of the PEG. As a consequence, large numbers of the nanoparticles are rapidly taken up selectively by tumor cells. Pilot project 8: Nanowire, nanolaser as optical probe for high resolution cellular imaging and manipulation Project Leaders: Yu Huang, PhD Department: MIT Material Science and Engineering/LLNL Backqround Nanotechnology can enable many unique tools to probe/image biosystems at an unprecedented molecular level and reveal new phenomena. For example, scanning near-field optical microscopy (SNOM) is an interesting technique in biophysics for the visualization of biological objects, e.g. cellular membrane, with high spatial resolution. This technique represents a powerful approach for high resolution imaging of bio-species by combining topographic information with optical fluorescence or light transmission imaging. However, the metallic coated probe is limited in several ways. First, only a tiny fraction (<0.01% for 100 nm tip) of the light coupled into the fiber is emitted by the aperture because of the cutoff of propagation of the waveguide modes. The low light throughput and the finite skin depth of the metal are the limiting factors for resolution. Many applications require spatial resolutions that are not obtainable with the aperture technique. Moreover, the aperture technique has other practical complications: (1) it is difficult to obtain a smooth metal coating on nano scale which introduces irreproducibility in probe fabrication, as well as measurements;(2) the absorption of light in the metal coating causes significant heating and poses a problem for biological applications. To address these issues, significant efforts have been devoted to searching for alternative probes such as aperture-less probe including metallic probes or fluorescence active probes. They represent exciting new directions, but often suffer from low signal-to-noise ratio due to low light intensity.
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