College News

Cancer: under the scope and in the spotlight at Symposium

VMCThe Cornell Translational Cancer Research Symposium will be held on October 1, 2011, on the campus of Cornell University in Ithaca, NY. The event is being organized jointly by the Cornell Center on the Microenvironment & Metastasis, the Comparative Cancer Biology Training Program at College of Veterinary Medicine, Weill-Cornell Medical College, and the Methodist Hospital Cancer Center.

The objective of the Symposium is to bring together researchers from the Cornell life science, physical science, and medical (veterinary and human) communities who have complementary expertise and common interests in cancer biology.

The event will feature sessions on Imaging & Diagnostics and Molecular Mechanisms and Therapeutics.

There will be a keynote address by Dr. David Piwnica-Worms (Washington University), research presentations by faculty associated with each of the participating programs, and a poster session.

Registration is free of charge. Please visit the event link to register and for more information.


Presentation Information

DaveKeynote: Molecular Imaging Strategies for Dynamic Analysis of Systems

Presented by Dr. David Piwnica-Worms
Director of the Bright Institute and Molecular Imaging Center
Departments of Radiology, Cell Biology, and Developmental Biology - Washington University School of Medicine

The tools of molecular imaging can provide spatially- and temporally-resolved information on biological structures and functions. Because researchers have increasingly recognized the importance of context of gene expression and protein function as well as regulatory mechanisms within cellular micro-environments, they have turned to non-invasive imaging technologies to advance research on human health and disease. These non-invasive imaging data can interrogate protein processing, protein-protein interactions, gene expression and flux through metabolic pathways in real-time in cells and live animals, and are increasingly useful in understanding signal transduction and pathobiology of human diseases, including cancer, and can also facilitate development of effective therapies. I have been involved in biochemistry and molecular imaging research for over 25 years and have successfully administered research projects and center grants (staffing, research administration, budgets, data management), collaborated with a broad cohort of other researchers, and produced many peer-reviewed publications relevant to this program.

Genetically encoded imaging reporters introduced into cells and transgenic animals enable noninvasive, longitudinal studies of dynamic biological processes in vivo. When cloned into promoter/enhancer sequences or engineered into fusion proteins, imaging reporters allow transcriptional regulation, signal transduction, protein-protein interactions, regulated feedback loops, and targeted drug action to be spatiotemporally resolved in vivo. Spying on biology with genetically encoded imaging reporters provides insight into specific molecular machinery within the context of live cells and the whole animal.

RickCell growth and migration

Presented by Dr. Rick Cerione
Departments of Molecular Medicine & Chemistry & Chemical Biology, Cornell University

Our laboratory has a long-standing interest in understanding the involvement of Rho GTPases in cell growth and migration, which recently led to our discovery of a novel signaling connection between these GTPases and elevated glutamine metabolism in cancer cells. This was based on our identification of a small molecule inhibitor that blocks the transformation of fibroblasts by oncogenic Dbl (for Diffuse B cell lymphoma), a Rho GTPase-activator, as well as inhibits the growth of human breast cancer and B lymphoma cells, and shrinks tumors induced by these cancer cells in mice. The effects of the small molecule inhibitor are specific for transformed/cancer cells, as it does not inhibit the growth of normal fibroblasts or mammary epithelial cells. We identified the target of this inhibitor to be an isoform of the metabolic enzyme glutaminase (GLS1), which catalyzes the hydrolysis of glutamine to glutamate. Transformed/cancer cells show markedly elevated levels of GLS1 activity, due to post-translational modifications (phosphorylation) that are dependent on the activation of Rho GTPases and NFB, and are blocked by the small molecule inhibitor. Recently, we have shown that an important outcome of the metabolic changes exhibited by cancer cells, that can be prevented by the inhibitor, is the generation of vesicular structures (oncosomes) that contain signaling proteins, metabolic enzymes, RNA transcripts and microRNA. Oncosomes, by transferring these components to recipient cells, are capable of conferring transformed properties on to their acceptor cells and thus have been suggested to play important roles in cancer progression. Collectively, these results shed new light on how glutamine metabolism is elevated during tumorigenesis in order to satisfy the ‘glutamine addiction’ of cancer cells, as well as demonstrate the consequences of such metabolic changes and how they might be interrupted. The hope is that these insights will highlight new strategies for therapeutic intervention.


changTherapeutic Resistance of Tumor-initating Cells in Breast Cancer

Presented by Dr. Jenny Chang
Director, Methodist Hospital Cancer Center, Houston

Dr. Jenny C. Chang is Director of the Cancer Center at The Methodist Hospital in Houston, Texas. She obtained her medical degree at Cambridge University in England, and then completed fellowship training in medical oncology at the Royal Marsden Hospital/Institute for Cancer Research in the United Kingdom. She was also awarded a research doctorate from the University of London. There, she developed an interest in breast cancer, particularly in the area of prognostic and predictive markers. She used the clinical situation of locally advanced breast cancer, in which patients are traditionally treated with pre-operative therapy, to assess the use of such markers in predicting treatment response. Her recent work has focused on the intrinsic therapy resistance of cancer stem cells, which has lead to several publications and international presentations. In addition, she has been awarded several federal grants to evaluate novel biologic agents, and holds patents on new technologic advances including high throughput molecular profiling.

We have identified a tumor-initiating subpopulation characterized by FACS. To provide support for this hypothesis in the clinic, we have analyzed by flow cytometry paired breast cancer core biopsies before and after neoadjuvant chemotherapy or lapatinib as single cell suspensions stained using antibodies against CD24, CD44, and lineage markers. The potential to form mammospheres in culture also was compared before and after treatment. The tumorigenic breast cancer cells were intrinsically chemoresistant ─ chemotherapy led to an increase in the relative proportion of CD44+/CD24-/low cells, and increased self-renewal capacity in mammosphere assays. Conversely, in patients with HER2 overexpressing tumors, lapatinib (EGFR/HER2 tyrosine kinase inhibitor) decreased the relative proportion of tumorigenic cells and mammosphere formation. In the flow-sorted CD44+/CD24-/low vs. other cells, 1,424 named genes were elevated (p<0.01, fold change>1.5, FDR=0.20). The comparison between MSs vs. primary cancers yielded 1,890 elevated genes (FDR=0.25). Between the two sets, 380 genes were in common, a highly significant overlap (p=1E-5, one-sided Fisher’s exact). This overlap was ~40% greater than what would be expected (n=110) if the two sets had no biological relevance. This signature was found exclusively activated in tumors of the recently identified “claudin-low” subtype, characterized by overexpression of many mesenchymal genes. In two independent data sets comparing the expression profiles of paired breast cancer core biopsies before vs. after letrozole or docetaxel chemotherapy, both the tumorigenic and “claudin-low” signatures were elevated in post-treatment samples. In addition, analysis of the gene expression profiles of the cancer mammospheres as compared to the primary tumors revealed the presence of an EMT signature. Thus, this “mesenchymal” association may provides an additional explanation for the intrinsic resistance of breast cancer stem cells to therapy.


Targeting the Cell Cycle in Cancer – Mechanism and Therapy

Presented by Selina Chen-Kiang, Ph.D.
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College


KirbyMicrofluidic Capture of Circulating Tumor Cells for Assay of Chemotherapeutic Efficacy: System Design and Translation to the Clinical Setting

Presented by Dr. Brian Kirby
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College
Targeting the Cell Cycle in Cancer – Mechanism and Therapy

Brian J. Kirby currently directs the Micro/Nanofluidics Laboratory in the Sibley School of Mechanical and Aerospace Engineering at Cornell University. He joined the School in August 2004. Previous to that, he was a Senior Member of the Technical Staff in the Microfluidics Department at Sandia National Laboratories in Livermore, California, where he worked from 2001-2004 on microfluidic systems, with applications primarily to counterbioterrorism. From 1996-2001 he worked as a graduate student in the High Temperature Gasdynamics Laboratory at Stanford University, where he developed laser spectroscopy techniques for imaging gases in flames for combustion and aerothermopropulsion applications. From 1994-1996 he worked as a graduate student in the Variable Gravity Research Laboratory at the University of Michigan, studying multiphase heat transfer processes; at Hewlett-Packard Laboratories in Palo Alto, CA, studying fluid mechanics processes in hard drive stacks; and in the Gas Dynamics Research Laboratories in the Aerospace Engineering Department at the University of Michigan, studying soot formation processes in low-pressure diffusion flames.

We will present collaborative work at Cornell-Ithaca and Weill-Cornell Medical College focused on circulating tumor cell capture in microdevices. Through the use of geometrically enhanced differential immunocapture (GEDI) microdevices, rare circulating tumor cells can be captured in a viable state at high purity and efficiency. High purity facilitates molecular characterization of these rare cells, and viable capture facilitates functional characterization. Assays for fusion status and drug-target engagement in castrate-resistant prostate cancer patients on microtubule-targeting chemotherapy will be presented, and comparison with the commercial state of the art. Prospects for new projects and clinical evaluation will also be presented.


Analysis of Tumor "Educated" Stroma in Mice and Men

Presented by Vivek Mittal, Ph.D.
Departments of Cardiothoracic Surgery and Cell and Developmental Biology, Weill Cornell Medical College


Challenges in Triple Negative Breast Cancer: Novel Biomarkers and Therapeutics

Presented by Dr. Angel Rodriguez
Hematology & Breast Oncology, Methodist Hospital Cancer Center, Houston

Triple negative breast cancer affects approximately 15% of patients with breast cancer. Epidemiological studies indicate a higher prevalence in younger women and African American women. Unlike hormone receptor positive and HER2 positive breast cancers, TNBC has no clinically-validated targeted therapy, and hence chemotherapy remains the mainstay of treatment. Although chemotherapy is effective in reducing the risk of relapse in TNBC, relapse rates remain high and there is a great need for novel more effective therapies in this subgroup. Molecular classifications of triple negative breast cancer have consistently shown its heterogenous nature. Potential biological pathways that can be targeted in TNBC as well as novel therapies currently under investigations will be reviewed.


From Discovery to Clinical Implementation of ETS Fusions for Prostate Cancer Risk Assessment

Presented by Mark Rubin, M.D.
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College


Zipfel Biomedical Imaging and Diagnostics – where does multiphoton microscopy fit in?

Presented by Dr. Warren R. Zipfel, who is an Associate Professor in the Department of Biomedical Engineering at Cornell University in Ithaca NY. He received his B.S (1987) and PhD (1993) from Cornell University, and worked as Research Associate in Applied and Engineering Physics (AEP) in the area of biophysics and biological imaging for several years with Dr. Watt Webb. While in AEP he served as the Associate Director and then Director of the Developmental Resource for Biophysical Imaging Optoelectronics (known as DRBIO), an NIH/NIBIB P41 funded Technology Development Resource focused on the creation of new optical imaging and fluorescence detection technologies for biological and biomedical research. Dr. Zipfel has long been involved in all aspects of the development of multiphoton microscopy, a form of laser scanning microscopy that has since become an indispensable imaging tool for investigations requiring high resolution optical imaging in highly scattering specimens. Professor Zipfel joined Biomedical Engineering in July of 2005, where he has continued his work on the development and enhancement of new forms of optical microscopy, spectroscopy and fluorescence detection, with one focus area being the application of multiphoton excitation imaging methods for in vivo imaging in cancer research and for early detection.

Multiphoton microscopy (MPM) is a form of laser-scanning microscopy that uses nonlinear excitation to excite fluorescence in a thin raster-scanned plane in the specimen. MPM has been applied to a variety of imaging tasks and is now the technique of choice for fluorescence microscopy in optically challenging samples such as thick tissue explants and live animals. Because multiphoton excitation in the 700 – 800 nm range can provide detailed 3D-resolved images of tissue using UV-absorbing intrinsic fluorophores (NADH etc) and collagen second harmonic signals, MPM can also be used for real time direct imaging of microscopic tissue morphology without added stains. Numerous laboratories have shown in animal disease model systems and on unstained human biopsy samples that nonlinear imaging can reveal tissue disease and metabolic status. Before multiphoton imaging can be used directly on humans patients several critical parameters need to be elucidated. Tissue autofluors are weak two-photon fluorophores and very often high laser powers are required for imaging. Important questions which are now beginning to be addressed as to what laser excitation levels are required to obtain useable images and whether irradiation at these levels can cause potentially carcinogenic DNA mutations, as certain levels of UV illumination are known to cause. This talk will review the basic principles of nonlinear optical imaging, provide examples of potential translational and clinical importance and objectively discuss the possibilities of applying this successful research imaging modality as an intra-operative clinical tool.


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