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  Home > Meetings > February-March 2007 Workshop Agenda  

 

 
 

 

Tango Lessons for Brain Cancer Research:
Understanding Cellular Intricacy, Improvising New Therapies

James S. McDonnell Foundation Workshop
February 27 - March 2, 2007

Agenda

Tuesday, February 27, 2007

 

Check-in and Poster hanging

 
18:00-18:30 OPENING CEREMONY
 
18:30-19:30

OPENING LECTURE

(Chair: Carlo Croce)
  Web Cavenee, Ludwig Institute for Cancer Research at UCSD
  "What are the Steps?"
 

Abstract: The identification of molecules that are specifically expressed or mutated in tumors have led to targeted therapies that might be expected to have increased selectivity for tumor cells compared to normal tissue with resultant enhancements in effect and reductions in the non-specific toxicities that lead to chemotherapeutic side effects. I will discuss such therapies, the dependence on their targets of tumor maintenance and mechanisms of escape from therapy.

 
19:30-22:00 WELCOME COCKTAIL AND DINNER
 
 

Wednesday, February 28, 2007

 
09:00-10:00 PLENARY LECTURE (Chair: Beatriz Caputto)
  Carlo Croce, Ohio State University Comprehensive Cancer Center
  "microRNA Genes and Cancer"
  Abstract: MicroRNAs (miRNAs) are a recently discovered class of small noncoding RNAs that regulate gene expression.  Mature miRNAs are the results of sequential processing of primary transcripts (pri-miRNAs) mediated by two RNase III enzymes, Drosha and Dicer.  These small noncoding miRNAs can contribute to cancer development and progression and are differentially expressed in normal tissues and cancers.
 
Session 1:

Complexities of cellular signaling

(Chair: Antony Burgess)
 
10:00-10:45 Peter Vogt, The Scripps Research Institute
  "Mechanisms for the gain of function in mutants of PI3K"
  Abstract: An analysis of rare and hot spot mutations in PI3K suggests the existence of three molecular mechanisms that can induce a gain of function in p110 alpha. The data single out the kinase domain mutants as the most promising targets for small molecule inhibitors.
 
10:45-11:15 COFFEE BREAK
 
11:15-12:00 Bill Weiss, University of California, San Francisco Comprehensive Cancer Center
  "Cooperative inhibition of EGFR, PI3K alpha, and mTOR in PTEN-mutant glioma"
  Abstract: We treated glioma cells with the EGFR inhibitor erlotinib, the mTOR inhibitor rapamycin, or the dual PI3K a /mTOR inhibitor PI-103. In PTEN mutant cells, erlotinib plus PI-103 was superior to either monotherapy or to erlotinib plus rapamycin. Thus in EGFR-driven PTEN mutant glioma, inhibitors of EGFR cooperate with a dual inhibitor of PI3K a /mTOR.
   
12:00-12:45 Forest White, Massachusetts Institute of Technology
  "Quantitative Analysis of Cellular Signaling Networks as a Drug Target Discovery Tool"
  Abstract: Quantitative analysis of tyrosine phosphorylation in EGFRvIII-expressing glioblastoma cell lines has revealed a cohort of sites which are highly responsive to EGFRvIII expression levels. We have investigated the functional role of these phosphorylation events, and have identified an alternative target to selectively inhibit growth of EGFRvIII-expressing cells.
 
12:45-14:30 LUNCH
 
Session 2:

Complexities of cellular signaling-2

(Chair: Luis Parada)
 
14:30-15:15 Elva Diaz, University of California - Davis
  "A novel role for the Mad3 transcription factor in cerebellar granule cell proliferation and tumorigenesis"
  Abstract: The childhood brain tumor medulloblastoma originates from cerebellar precursor cells due to genetic mutations such as amplification of the proto-oncogene Nmyc, suggesting that these tumors result from uncontrolled Nmyc-mediated cell growth. We have identified a previously unrecognized role for the Mad3 transcription factor to regulate Nmyc-mediated cerebellar growth and tumorigenesis.
   
15:15-16:00 Mark Noble, University of Rochester Medical Center
  "Neural progenitor cells: sources of disease and targets of treatment"
  Abstract: First, I will discuss neural progenitor cells as targets of systemic chemotherapy, providing a biological basis for adverse neurological effects of cancer treatment. I will then discuss our studies on the implications of having neural progenitor cells as a source of tumors, with particular focus on the ability of oncogene expression to create programs of aberrant quasi-differentiation and on attempts to define means of killing cancer cells without killing normal brain cells.
   
16:00-16:45 Beatriz Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Cordoba
  "Membrane biogenesis as a new therapeutic target for controlling brain tumor growth"
  Abstract: Cells require membrane biogenesis to grow. This is a pleiotropic, coordinated event whose underlying molecular determinants are still undefined. c-Fos emerges as a protein that increases membrane biogenesis to support exacerbated tumor growth. This c-Fos-regulatory activity involves its association to ER membranes and activation of the synthesis of phospholipids, key components of cell membranes, independently of its AP-1 transcription factor activity. Targeting therapies towards reducing c-Fos-controlled membrane biogenesis to control tumor growth will be discussed.
 
16:45-17:15 COFFEE BREAK
 
17:15-18:00 Tony Burgess, Ludwig Institute for Cancer Research
  "Targeting the EGFR Family - Opportunities in Glioma Therapy"
  Abstract: Glioblastoma is associated with the mutation of several genes capable signaling cell growth and survival from the cell surface, e.g. the EGF, PDGF, and FGF receptors. Although antibodies and kinase inhibitors which can interfere with EGFR signaling have been developed, these agents have been of limited value in the treatment of glioma. The opportunities, progress and pitfalls of EGFR targeted therapeutics will be presented.
   
18:00-18:45 Kristin Swanson, University of Washington
  "Dynamics of Glioma Growth and Invasion: How can Predicting Beyond the Tip of the Iceberg Advance Treatment of Brain Tumors?"
  Abstract: The pathway from molecular target to clinical compound is wrought with failures. Since most new therapies ultimately modulates either net dispersal or proliferation of glioma cells, we propose that some of these failures can be remedied with a quantitative understanding of in vivo effect at the level of dispersal and proliferation provided by our mathematical model.
 
19:00-20:30 POSTER SESSION + WINE & CHEESE
 
20:30- DINNER
   
   

Thursday, March 1, 2007

   
Session 3: Cellular and Genetic Complexities (Chair: Paul Kleihues)
   
08:30-09:15 Paul Mischel, University of California, Los Angeles
  "Using emerging information about patterns of sensitivity and resistance to design rational molecularly targeted combination therapies for glioblastoma"
  Abstract: The future of glioblastoma treatment lays in molecularly targeted treatments. This success of this strategy requires integration of emerging knowledge of mechanisms of sensitivity and resistance towards rational design of personalized combination therapies. I will address some of the challenges and opportunities we face as we begin to integrate this developing understanding into design of rational approaches for targeting the EGFR/PI3K axis in glioblastoma patients.
   
09:15-10:00 Ken Aldape, M.D. Anderson Cancer Center
  " A multigene predictor of outcome in glioblastoma"
  Abstract: We have conducted a meta-analysis of microarray data to identify a multigene (38-gene) predictor of outcome in glioblastoma. We have validated this predictor using RT-PCR assays from RNA derived from paraffin blocks. Interestingly, many genes in this predictor are associated with mesenchyme. The results point to a new avenues in which to understand treatment resistance in glioblastoma.
   
10:00-10:30 COFFEE BREAK
   
Session 4:
How can cellular and tumoral complexities be used for tumor targeting--1?
(Chair: Jeremy Rich)
   
10:30-11:15 Howard Colman, M.D. Anderson Cancer Center
  "Molecular Marker Driven Targeted Therapy in Newly Diagnosed Glioblastoma"
  Abstract: Increasing evidence indicates that multiple distinct molecular subtypes of GBM exist with differing clinical outcomes. We have developed a robust multi-marker predictor for prospective classification of newly diagnosed GBM into clinically distinct treatment groups. I will discuss a novel trial that incorporates prospective molecular classification and an adaptive randomization design for optimizing treatment and overcoming resistance to standard therapy.
   
11:15-12:00 Osvaldo Podhajcer, Leloir Institute Foundation
  "The role of the matricellular protein SPARC at the intersection of tumor cell: host interaction"
  Abstract: It is increasingly accepted that tumors grow as the result of a "cross-talk" between malignant cells and neighbouring stromal cells (fibroblasts, endothelial and inflammatory cells). SPARC is a secreted protein that was shown to be overexpressed in most human cancer including gliomas. We will discuss the role of SPARC as a key factor in tumor cell-host interaction and its potential utility as a target for cancer therapy.
   
12:00-1245 Mike Prados, University of California, San Francisco
  "Clinical Implications of Targeted and Novel Therapeutics"
  Abstract: As new ideas and targets are identified, it is important to rationally design clinical trials to deal with translational research.  Older trial designs do not allow for the enrichment of patients expected to benefit from targeted therapies, are expensive in terms of toxicity, time, and funding and do not exploit newer endpoints.  Translational research requires relevant clinical output, rapid clinical screening and believable endpoints.  A new paradigm for clinical trials will be discussed that will support novel agents and strategies.
   
12:45-14:30 LUNCH
   
Session 5: How can cellular and tumoral complexities be used for tumor targeting--2? (Chair: Howard Colman)
   
14:30-15:15 Jeremy N. Rich, Duke University Medical Center
  "Cancer Stem Cells in Therapeutic Resistance and as Molecular Targets"
  Abstract: I will discuss potential roles for cancer stem cells in radioresistance, chemoresistance, angiogenesis, and tumor invasion.   We and others are seeking molecular mechanisms underlying these behaviors that may provide novel targets for therapeutic intervention.  I will also describe efforts to develop specific anti-cancer stem cell therapies.
   
15:15-16:00 Theresa Whiteside, University of Pittsburgh School of Medicine
  "Vaccination for Glioblastoma: Antigen Discovery and Beyond"
  Abstract: Novel therapies for glioblastoma are clearly needed. We have been developing therapeutic anti-glioma vaccines for patients with this tumor. Our efforts began with a pilot clinical trial testing vaccination with autologous “bulk” glioma cells admixed with IL-4 gene-transduced fibroblasts. An antigen discovery program supported by the JSM Foundation has led to the identification of immunogenic peptides derived from Glioma Associated Antigens (GAA). These peptides are currently in use in the dendritic cell (DC)-based novel clinical trials for patients with recurrent glioblastoma.
   
16:00-16:45 Gabriel Rabinovich, University of Buenos Aires School of Medicine
  "The Sweet Escape: Impact of Protein-Glycan Interactions in Tumor Cell Evasion of Immune Responses"
  Abstract: Tumor cells have devised multiple strategies to thwart immune attack. We will discuss the pivotal role of galectin-1, a highly conserved sugar-binding protein expressed by tumor and stromal cells, in promoting escape from T cell-dependent immunity. Understanding the paradigms by which protein-glycan interactions regulate tumor immunity and inflammation might contribute to the design of rational antitumor strategies.
   
16.45-17:15 COFFEE BREAK
   
Session 6: Modeling complexity (Chair: Mark Noble)
   
17:15-18:00 Luis Parada, University of Texas Southwestern Medical Center at Dallas
  "CNS Stem Cells & Cancer Stem Cells"
  Abstract: It is only in the last decade that the existence of self-renewing cells in the brain has become fully appreciated. As a consequence classic models of gliomagenesis entertained dedifferentiation as a requisite for tumor initiation. New concepts have arisen with the continuing study of “adult” neural stem cells in vivo and in vitro. Preparation of neurosphere cultures from primary glioma tissue from human tumors and from mouse...
   
18:00-18:45 Abhijit Guha, University of Toronto
  "Transgenic Glioma Models as Gene Discovery Tool"
  Abstract: Current transgenic models of human cancers are based on tissue specific altered expression of known genetic aberrations found in the corresponding human cancer. Random mutagenesis strategy on our glioma model led to discovery of novel human tumor suppressor genes involved in astrocytoma progression, demonstrating the added potential of transgenic models as a “gene discovery” reagent.
   
18:45-19:30 David H. Gutmann, Washington University School of Medicine
  "Mouse Models of Low-Grade Glioma"
  Abstract: Mouse models of brain tumors afford unique opportunities to understand the molecular and cellular biology of low-grade glioma formation and progression. This presentation will focus on the use of mouse models of neurofibromatosis-1 (NF1)-associated glioma to define the contribution of the tumor microenvironment, intracellular growth control pathways, and timing of Nf1 inactivation to tumorigenesis.
   
19:30- WINE TASTING AND DINNER
   
   

Friday, March 2, 2007

   
Panel Discussion   Are the complexities a block to progress or an exploitable advantage? Where do we go from here? (Chair: Susan Fitzpatrick)
   
09:00-10:30 J. Rich , H. Colman, M. Prados, M. Noble, W. Cavenee, B. Caputto

   
10:30-11:00

Meeting Summary, Wrap-up and Future Directions
--Paul Kleihues

(Chair: Abhijit Guha)
   
12:30-14:00 FAREWELL LUNCH
   
14:00 Bus back to Cordoba
 
 
   
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