SYMPOSIUM I
Concurrent Tracks
9:00-11:00am


Saturday, September 7

8:30 am Coffee Break with Exhibit and Poster Viewing

TRACK 1

PROTEIN ARRAYS

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T3

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Symposium Chairperson
Dr. Dhaval Kumar Patel, Molecular Staging Inc.

9:00 FDA-NCI Clinical Proteomics Program: Applications at the Bedside
Dr. Cloud P. Paweletz, Co-Director FDA-NCI Clinical Proteomics Program,
Division of Therapeutic Products, Center for Biologics Evaluation and Research, FDA
The field of molecular medicine is moving beyond genomics to proteomics. While DNA is the information archive, proteins do all the work of the cell - and ultimately dictate all biological processes and the cellular fate. The challenge and opportunity within proteomics is much more than just developing a list of all the proteins. The true scientific goal of proteomics is to characterize the information flow within the cell and the organism. This information flow is mediated through and by, protein pathways and networks.

The cause of most human disease lies in the functional disregulation of protein-protein interactions. Understanding the role that protein networks play in disease will create enormous clinical opportunities, since these pathways represent the drug targets of the next decade. In the future, entire cellular networks, not just one disregulated protein, will be the targets of therapeutics. The next technologic leap will be the application of proteomic technologies to the bedside. It will soon be possible to analyze the state of protein signal pathways in the disease-altered cells, before, during, and after therapy. This can herald the advent of true patient-tailored therapy.

Our FDA-NCI Clinical Proteomics Program is focused on the understanding of mechanisms of carcinogenesis, identification of new drug targets, and discovery of new biomarkers for early detection in actual human tissue tumor specimens and clinical serum specimens. Tissue-based proteomics requires technology that can overcome the complex cellular heterogeneity one encounters when studying disease in tissue specimens. To that end, we employ the use of Laser Capture Micro-dissection (LCM), invented at the NCI, for the proteomic analysis of microdissected subpopulations of human solid tumors (prostate, breast, ovary, and esophageal) as a model for the study of disease progression. These studies encompass and employ high-throughput proteomic pattern profiling using surface-enhanced laser desorption and ionization (SELDI) protein chips to identify disease-related proteins and protein patterns directly in human sera using artificial-intelligence based bioinformatics, and focused proteomic approaches through the use of multiplexed phospho-specific antibody arrays, novel reverse-phase lysate for signal transduction pathway profiling. For the first time ever, proteomic technologies are being used in clinical trials at the NCI through our program to monitor patients before, during and after targeted treatment, heralding the beginning of true patient tailored molecular medicine.

9:20 Interaction Analyses Using Whole Proteome Microarrays
Dr. Barry Schweitzer, Protometrix, Inc.
The recent abundance of genomic data has created a need for a systematic proteomics approach to decipher the protein networks that dictate cellular function. To date, the generation of large-scale protein-protein interaction maps has principally relied on either yeast 2-hybrid or mass spectrometric techniques. In a landmark study by Snyder and coworkers at Yale University, the feasibility of using protein microarrays to investigate the function of a whole proteome was recently demonstrated. This technology, called ProtoP5™, has been licensed to Protometrix Inc. and industrialized so that over 500,000 potential protein-protein interactions can now be screened per day. As a pilot demonstration, a complete yeast protein interaction map is being generated that will contain over 25,000,000 data points. This map contains information that complements and significantly extends existing protein interaction databases. Examples will also be given of how these protein arrays have been used for screening and expression profiling applications. Finally, work in progress on other proteomes will be described.

9:40 Development of a Pharmaceutically Relevant Ion Channel Assay for Supported Membrane Array Chip Technology
Dr. Gerald Wiegand, Zyomyx, Inc.
We present a new approach for a platform technology aiming the functional screening of ion channel proteins with high-throughput (HTS). It utilizes supported lipid bilayer membranes (SMs) on microfabricated electronic chip devices as core technology. Combined with the functional incorporation of ion channel proteins into the SMs and an efficient electronic read-out of the chip response by fast impedance spectroscopy, a prototype comprising all key elements for an ion channel HTS system was built and deployed. Experiments applying this technology with fully integrated microfluidics (six separate assay channels) and microelectronics (36 individual electrodes) on-chip are shown.

SMs as assay matrix have the advantage that the entire ion channel protein / membrane assay can be formed from solutions in a fully self-organizational manner. The resulting protein-membrane composites are extremely stable. On-chip membrane resistance values of the order of Gohm are reached. Two model assays, Gramicidin and alpha-Haemolysin, were characterized successfully. The development of the first pharmaceutically relevant ion channel assay in supported membranes is reported. The key challenge addressed is the functional reconstitution of ion channel proteins in supported membranes. Structure-function considerations as well as lipid-protein interactions and reconstitution biochemistry play an important role for the incorporation procedure and the assessment of the activity of ion channel protein in this assay format.

10:00 RCA Immunoassay Microarrays
Dr. Dhaval Kumar Patel

10:20-11:00 Refreshment Break with Exhibit and Poster Viewing

 

 

Saturday, September 7

8:30 am Coffee Break with Exhibit and Poster Viewing

 

TRACK 2

NANOTECHNOLOGY:
Tumor Biology and Its Exploitation in Therapy

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Symposium Chairperson
Dr. Stephen Lee, The Ohio State University

9:00 Tumor Physics and Biology: Impact of Aberrant Vascular Architecture on Therapy
Dr. Lance L. Munn, Harvard Medical School and Massachusetts General Hospital
It is known that the vasculature of tumors is unusual in many respects—flow is sluggish and intermittent, permeability is focally high and the network architecture is not well-organized. Recent studies have shown that the structure and integrity of the vascular endothelium are also abnormal, a fact that potentially influences drug delivery and metastatic cell dissemination. Defects in the endothelial wall include regions of shed endothelium, extremely thin endothelial leaflets, gaps between endothelial cells and deficient basement membrane. Interestingly, the appearance of these defects appears to be influenced by the growth characteristics of the tumor. In other studies, we have also found that tumor cell intravasation into the vascular compartment is a relatively inefficient process, with few viable cells shed into the bloodstream. Even so, some cells are able to successfully leave the primary tumor and colonize distant sites. In the process, these cells vary the expression of various genes, including matrix-degrading enzymes, that may influence the structure of the vessel wall, resulting in the observed defects. Therapies aimed at "normalizing" the vasculature may have multiple benefits, restoring the barrier to metastasis and establishing drug delivery to previously inaccessible regions of the tumor.

9:20 Affinity-Based Methods for Tumor Targeting
Dr. Erkki Ruoslahti, Burnham Institute
We use libraries of phage-displayed peptides to identify specific changes in tumor vasculature (Ruoslahti, 2002). By combining ex vivo screening of the libraries on cell suspensions prepared from tumors and in vivo screening for tumor homing, we have identified new peptides that home to MDA-MB-435 breast cancer or HL-60 leukemia xenografts grown in nude mice. One of our new peptides (F3) recognizes blood vessels in various tumors and another (LyP-1) recognizes lymphatic vessels in the MDA-MB-435 tumors (Porkka et al., 2002; Laakkonen et al., submitted). Both peptides also bind to the tumor cells and show little or no binding to normal tissues. The presence and importance of blood vessels in tumors is well established, but it has only recently been found that lymphatic vessels can also be present within tumors. These vessels were previously thought to occur only in the normal tissue surrounding tumors. The phage that displays the LyP-1 peptide homes to MDA-MB-435 tumors when injected either into the bloodstream or subcutaneously. The phage and fluorescein-labeled LyP-1 peptide accumulate in vessel-like structures in the MDA-MB-435 tumors that stain for lymphatic vessel markers, but not for markers of blood vessels. The phage and the peptide do not accumulate in normal tissues, indicating that the PL-1 peptide distinguishes lymphatic vessels in MDA-MB-435 xenografts from normal lymphatic vessels. Targeting drugs to lymphatic vessels in tumors with this peptide may be effective in preventing tumor metastasis.

The F3 and LyP-1 peptides have the remarkable property of accumulating in the nucleus of the target cells. Thus, these peptides may be particularly suitable for targeting anti-cancer drugs that act in the nucleus. Our current main priority is to establish the specificity of these peptides for other breast cancers and other types of tumors, and to identify their cell surface receptors.

We have previously shown that vascular homing peptides can be used to target drugs into tumors, and that the targeting enhances the efficacy of a drug and reduces its side effects. Recently, we used this approach to direct a proapoptotic peptide to the vasculature of the normal prostate. The treatment caused partial destruction of the prostate and delayed the development of prostate cancers in transgenic prostate cancer (TRAMP) mice (Arap et al., 2002). We have also recently shown that it is possible to target biomolecule-coated inorganic nanostructures to specific tissues in vivo (Akerman et al., submitted). We used quantum dots for the targeting. Qdots are inorganic nanocrystals that possess unique optical properties and can be readily derivatized with peptides (and other biomolecules). We coated red- and green-luminescent ZnS-capped CdSe qdots with vascular targeting peptides and showed that the peptides specifically direct qdots to the appropriate targets after intravenous injection into mice. In the future, this targeting approach may find application to drug nanocrystals as well as more complex nanosystems.

9:40 Tumor Immunology and Particulate Vaccine Approaches
Dr. David Persing, Corixa Corporation
The concept of cancer vaccination borrows heavily on immunological themes learned from parasite immunology, including the coexistence of humoral immune responses with chronic low-level parasitemia, antigenic variation, and active immunosuppression of the host. In keeping with this concept is the requirement for identification of cancer-specific vaccine targets, along with the use of vaccine adjuvants and delivery approaches to generate strong cytotoxic T and T helper cell responses to tumor cells. Corixa has used a variety of genome-wide scanning techniques for discovery of cancer-specific targets, and is now engaged in preclinical and clinical development of vaccines employing additional novel technologies: 1) the use of synthetic lipid A mimetics to arouse innate and adaptive immune responses, and 2) the use of biodegradable microspheres to encapsulate and deliver antigens in particulate form. The synthetic lipid A mimetics, by virtue of activation of TLR-4, induce maturation of and antigen presentation by dendritic cells, and microspheres provide an easily assimilated phagocytic target containing a high concentration of the tumor-specific antigen. The combination of these technologies is likely to lead to new therapeutic approaches for prevention of cancer recurrence in the next few years.

10:00 External Control of Biomolecular Function via Covalently Attached Nanocrystal Antennas
Dr. Kimberly Hamad-Schifferli, Massachusetts Institute of Technology
Metal nanocrystals can be used as antennas for biological systems which control their activity.  The authors present results in which DNA and proteins are linked to 1.4nm diameter gold nanocrystals.  The nanocrystals are inductively heated, which is achieved by placing the sample in an external magnetic field (frequency ~1GHz) to induce alternating eddy currents in the nanocrystals.  As a result, the nanocrystals transfer heat to surrounding molecules.  Induction heating of nanocrystals linked to DNA oligonucleotides in solution has been shown to dehybridize the DNA in a manner that is localized and reversible.  In addition, nanocrystals have also been attached to the enzyme Ribonuclease S, allowing reversible and specific control of hydrolysis of RNA.  Applications in biology and nanotechnology will be discussed.

10:20-11:00 Refreshment Break with Exhibit and Poster Viewing



Saturday, September 7

8:30 am Coffee Break with Exhibit and Poster Viewing

 

TRACK 3

HYBRID BIO/ARTIFICAL MICRODEVICES

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T2

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Symposium Chairperson
Dr. Jeffery D. Carbeck, Princeton University

9:00 Microfabricated Devices for Biomolecular Detection
Dr. Scott Manalis, Massachusetts Institute of Technology

9:20 Title and Speaker to be Announced

9:40 Soft Plumbing for Integrated Nanofluidic Devices
Dr. Carl Hansen, California Institute of Technology
We have been using soft lithography to make microfabricated chips for ultrasensitive analysis of single DNA molecules and cells. There are numerous advantages to fabricating chips out of polymeric materials, and as a result we have been able to rapidly and inexpensively fabricate active devices with moving parts, such as pinch valves and peristaltic pumps. This technology allows fabrication of highly integrated devices with thousands of valves. We have developed a series of microfluidic devices for cellular and molecular analysis, ranging from protein crystallization to a microfabricated fluorescence activated cell sorter. The novel valve and pump components for on-chip fluidic manipulation that we developed in the course of this research will be useful for fabricating more complex chip designs for a variety of biotechnological applications. Our ultimate aim is to create a set of tools giving the ability to perform biology on nanoliter volumes, rather than the current microliter standard.

10:00 Patterning of Cell Adhesion Proteins via Colloidal Assembly: Protein Organization Directs Cell Behavior
Dr. Jeffrey D. Carbeck
This talk describes patterning of proteins at surfaces via colloidal assembly, and effects of specific protein patterns on cell organization and behavior. Protein coated colloidal particles are used to pattern proteins on two length scales: the size of individual particles (500 nm – 2 microns), and of micropatterns of particle arrays produced via self-assembly and soft lithography (10 – 100 microns). Interfaces produced in this way show that the organization of cell adhesion proteins on sub-cellular length scales can directly affect cell adhesion, shape and spreading. In particular, by varying the density of particles coated with fibronectin we switched fibroblast cells from a morphology consistent with a static, adhesive state to a morphology consistent with a dynamic, migratory state. In the past, such changes had been seen only in response to changes in protein composition on surfaces. We show that these changes can be directed through protein organization on surfaces.

10:20-11:00 Refreshment Break with Exhibit and Poster Viewing

 

 

 


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