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Day 1: Monday, August
21
7:30 - 8:25 Registration and Morning Coffee
Biomarkers and Surrogates
8:25 - 8:35 Chairperson's Remarks
Dr. John Cuozzo, Director, Lead Discovery, Praecis Pharmaceuticals, Inc.
8:35 - 9:05 Targets Validation in Preclinical Cancer Prevention Studies
Konstantin Christov, M.D., Ph.D., Professor, Department of Surgical Oncology, University of Illinois at Chicago, USA
An overview will be made on the most frequently used molecular biomarkers for validation, and the efficacy of potention chemopreventive and antitumor agents. Experimental and clinical data will be provided for antiestrogens, antiandrogens, and retinoids respectively in breast and prostate cancer prevention trials. New potential strategies for modulating multiple targets will be discussed.
9:05 - 9:35 Yeast-Based Immunotherapy and the Treshold of EGFR Expression for Immune Recognition against Glioma Overexpressing Self-Antigen
David Apelian M.D., Ph.D., MBA, Chief Medical Officer, GlobeImmune Inc., USA
The administration of TarmogensTM ,which are whole, heat-inactivated Saccharomyces cerevisiae yeast containing defined quantities of target antigens, elicit T cell-mediated immune responses that recognize and ablate antigen-bearing tumors. Yeast delivering human or rat EGFR as the tumor antigen (GI-3000
Tarmogens) were tested as immunotherapeutics against intracranial rat glioma challenge. Intranasal administration in Fischer rats of GI-3000 expressing either rat or human EGFR proteins resulted in antigen-specific protection against intracranial challenge with 9L glioma transfected with non-mutated rat or human EGFR that was dependent on EGFR
overexpression, as demonstrated by flow cytometry of tumor cells isolated and analyzed from responding and non-responding animals.
9:35 - 10:05 Investigations of a Cdk4/6-Selective Kinase Inhibitor
Peter L. Toogood, Ph.D., Research Fellow, Medicinical Chemistry, Pfizer, Inc., USA
This presentation will describe the discovery and characterization of a small molecule kinase inhibitor that displays selectivity for Cdk4/6. The use of Cdk4/6 inhibitors for treating cancer will be discussed and the case for targeting Cdk4/6 examined. Results from in vitro and in vivo studies will be presented to illustrate the utility of inhibiting Cdk4/6 in cancer models. Preliminary data will be presented showing the effect of using a Cdk4/6 inhibitor in combination therapy.
10:05 - 10:45 Networking Coffee Break
(Sponsorship Available)
10:45 - 11:15 Mitogenic Signaling and akt Gene Silencing via PI3K Targeting by the bGBP Cytokine
Livio Mallucci, Professor, Pharmaceutical Sciences Research Division, King's College London, UK
Strong mitogenic signaling in cancer cells is a trait of aggressiveness. Enhanced ERK signaling enhances akt gene transcriptional activity for which PI3K activity is a requirement. The targeting and functional impairment of the p110 catalytic subunit of class 1A and class 1B PI3K by bGBP suppresses akt gene expression and interrupts cancer cell reliance on survival signaling by triggering an acute sequence of apoptotic events.
11:15 -
11:30 Rapid Discovery of Selective Small Molecule Inhibitors by Affinity Selection from Billion Component DNA-Tagged
Libraries
Dr. John Cuozzo , Director, Lead Discovery, Praecis Pharmaceuticals Inc.
The growing number of validated cancer targets has challenged the pharmaceutical industry to accelerate the discovery of novel inhibitors. To address this challenge, we have developed affinity-based selection methods to screen microgram amounts of target protein against small-molecule libraries synthesized using combinatorial methods, and deconvoluted using DNA tags specific to each molecule (DirectSelectTM). After identifying selected families, we synthesize these potentially active compounds free of the DNA tags to confirm binding and activity, and we have had a nearly complete success rate at this confirmation step. We have used this approach to identify novel sub-micromolar inhibitors of a variety of targets including kinases and proteases. We have also developed new methods which can selectively remove compounds that bind to undesirable targets or bind to additional desirable targets. DirectSelect technology has proven to be a fast and efficient engine for generating multiple families of novel and selective inhibitors for a variety of targets, and data substantiating these conclusions will be presented. |
11:30-11:45 Technology Trends
(Sponsorship Available)
Hear the latest technologies and development throughout the world of vaccines.
Contact Suzanne Carroll at 781-972-5452 or scarroll@healthtech.com
for sponsorship opportunities
Tumor Targeting & Validation
11:45 - 12:15 Nanodelivery: Materializing the Potential of Cancer Molecular Medicine
Esther Chang, Ph.D., Professor, Departments of Oncology and Otolaryngology at the Lombardi Cancer Center, Georgetown University Medical Center, USA
Our laboratory has developed a platform nanotechnology comprising a cationic liposomal nanocomplex bearing molecules that home to the surface of tumor cells. When systemically administered, this tumor targeting nanocomplex can efficiently and selectively deliver not only nucleic acid-based therapeutics, but also diagnostic contrast agents and small molecules to primary tumors and metastases in animal models of a variety of human cancers. The nanodelivery of imaging agents results in a significant improvement in the sensitivity and resolution in detecting metastatic lesions. Moreover, the various nucleic acid-based therapeutics have been shown to dramatically synergize with conventional radio- and chemotherapies. This approach is now entering clinical
trials
12:15 - 1:40 Luncheon Technology Workshop or Lunch on Your Own
(Sponsorship Available)
1:40 - 1:45 Chairperson's Remarks
1:45 - 2:15 De-Ubiquitinases as Novel Anticancer Targets
Michael R. Mattern, Ph.D., Vice President Research, R&D, Progenra, Inc., USA
Several de-ubiquitinating enzymes (DUBs, isopeptidases) are targets for anticancer drug discovery. Many DUBs prevent oncoprotein degradation by removing ubiquitin tags, and inhibitors of these DUBs may thus exert antitumor activity. Progenra has developed a novel technology platform for isopeptidases that remove ubiquitin (DUBs) and ubiquitin-like proteins (e.g., SUMO protease), the principle being isopeptidase-catalysed liberation of a reporter enzyme. The assay is facile, reproducible, robust, and cost-efficient, and for high throughput screening, superior to fluorogenic ubiquitin (Ub-AMC) or FRET-based assays. Progenra is also developing a functional DUBs protein chip for rapid genome-wide target validation and specificity screens for all human DUBs. Screening of cancer-related DUBs with compound and natural product extract libraries has revealed novel chemical entities.
Fully Human Monoclonal Antibodies
2:15 - 2:45 Development of Mapatumumab (HGS-ETR1), A Fully Human Monoclonal Antibody with Agonist Function to the Tumor Necrosis
Factor Apoptosis Inducing Ligand (TRAIL) Receptor TRAIL-R1
Gilles Gallant, Ph.D., Vice President, Clinical Oncology and HGS-Europe, Human Genome Sciences, USA
TRAIL is a member of the TNF ligand superfamily that activates apoptosis in an array of human cancer cell lines by binding to one of two receptors (TRAIL-R1 and TRAIL-R2). Mapatumumab (HGS-ETR1), an agonistic human monoclonal antibody (mAb), was developed to target specifically the TRAIL-R1 receptor. In vitro experiments demonstrated that mapatumumab bound specifically to the TRAIL-R1 receptor and efficiently induced apoptosis in vitro in TRAIL receptor expressing human tumor cell lines. The in vitro apoptosis inducing activity of mapatumumab was enhanced by pretreatment with chemotherapeutic agents. In vivo, mapatumumab can significantly inhibit tumor growth in xenograft models of human tumors. Mapatumumab is currently in Phase I/II clinical development.
2:45 - 3:15 Fully Human Monoclonal Antibodies to Hepatocyte Growth Factor with Therapeutic Potential against HGF/c-Met-Dependent Human Tumors
Teresa L. Burgess, Ph.D., Associate Director of Research, Cancer Biology, Amgen Inc.
Compelling evidence from studies in human tumors and both cellular and animal tumor models indicates that signaling through the HGF/c-Met pathway mediates a plethora of normal cellular activities, including proliferation, survival, migration, and invasion, that are at the root of cancer cell dysregulation, tumorigenesis, and tumor metastasis. We generated and characterized fully human monoclonal antibodies that bind to and neutralize human HGF. Antibodies with subnanomolar affinities for a unique epitope in the beta-chain of HGF were neutralizing in paracrine and autocrine cell models and importantly, these antibodies inhibited HGF-dependent autocrine-driven tumor growth and caused significant regression of established U-87 MG tumor xenografts. Our results suggest that an antibody to an epitope in the beta-chain of HGF has potential as a novel therapeutic agent for treating patients with HGF-dependent tumors.
3:15 - 3:30 Discovery and Validation of a Promising New Target for Therapeutic Monoclonal Antibodies: The Immunomodulatory Protein B7-H4 is Overexpressed in Human Breast and Ovarian
Cancers
Dr. Jackie Papkoff, CSO, CFD Therapeutics, Inc.
We discovered that B7-H4 (DD-O110) protein is overexpressed on the surface of a majority of human breast and ovarian adenocarcinomas with low/no expression in normal tissues. Whereas overexpression of B7-H4 in tumor epithelial cells can promote tumor formation, B7-H4 also negatively regulates T cell activation and therefore may inhibit an anti-tumor immune response. We generated monoclonal antibodies which recognize native B7-H4 protein, bind B7-H4 on live human tumor cell lines and internalize. Efficacy studies with a set of monoclonal antibodies are in progress.
3:30 - 4:00 Networking Refreshment Break
(Sponsorship Available)
New Targets
4:00 - 4:30 Attracting Support for Innovative Therapies: Opening Wallets as well as Minds
Michael Salgaller, Ph.D., Senior Associate, Tucan Capital Corporation, USA
The more disruptive and cutting-edge a technology, the more difficult it can be to attract investment. This presentation will highlight the challenges currently facing the field, as well as potential strategies for successfully attracting support.
4:30 - 5:00 CXCR4: Pre-Clinical Data of a Compelling Cancer Therapeutic Target
Alton Boynton, Ph.D., President, Northwest Biotherapeutics, Inc., USA
CXCR4 is over expressed in greater than 75% of cancers. CXCR4 is a cell surface receptor responsible for three critical functions of cancer cells as demonstrated by specific antibody inhibition of receptor function: 1) cell proliferation; 2) cell motility and movement of cancer cells away from the primary tumor; and 3) invasion into tissues at distant sites, setting up micrometastatic lesions. We have completed pre-clinical animal studies demonstrating that antibodies to CXCR4 very significantly prolongs survival, reduces by 70% metastasis to the lung and very significantly reduces the growth of the primary tumor.
5:00 End of Day One
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