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GTCbio, Phoenix, AZ
Feb 21-22, 2008
Day 1, Thursday, February 21, 2008
7:00
Registration & Breakfast
8:00
Welcome and Opening Remarks
[KEYNOTE PRESENTATION]
Developing New Therapeutics for the Treatment of Cancer: Challenges and Opportunities
8:10
Jeffrey Hanke, Vice President, Cancer Research, AstraZeneca
Session I - The Successes and Setbacks of Modern Cancer Drugs
9:00
Successful Clinical Development of Sunitinib Malate (SUTENT®)
Darrel P. Cohen, M.D., Ph.D., Senior Director, Oncology Clinical Development, Pfizer Global Research and Development La Jolla
Sunitinib malate (SUTENT®) is an oral multikinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3 that targets both tumor cell proliferation and tumor angiogenesis. It was the first new compound ever approved at the same time for the treatment of two different cancers (advanced renal cell carcinoma and imatinib-resistant or intolerant gastrointestinal stromal tumor), predicated on a clinical development program that was scientifically based, strategically driven, rationally designed, and diligently executed. Factors contributing to its successful dual registration, including preclinical and early clinical proof of concept, viable dose schedule selection, and innovative registration trial designs, will be discussed.
9:30
Gleevec
Jay Mei, M.D., Ph.D., Director, Oncology Clinical Development, Novartis Pharmaceuticals
[PANEL]
10:00
What Leads to Success in the Discovery, Clinical Phases, and FDA Approval of Cancer Drugs
10:30
Networking & Refreshment Break
Session II - New Drug Compounds and Future Drugs for the Treatment and Prevention of Cancer
11:00
A Gycoengineered Anti-CD19 Antibody for the Treatment of B Cell Malignancies and Autoimmune Disease
Ronald Herbst, M.D., MedImmune, Inc.
B cell depletion has been established as an effective treatment for B cell malignancies as well as certain autoimmune diseases, as demonstrated by the success of the anti-CD20 targeting antibody (Ab) Rituximab. New approaches, however, are needed to address the clinical need, especially in cases of anti-CD20 resistance or relapse following anti-CD20 therapy. CD19 represents a particularly attractive Ab target as it is expressed on the surface of early B cell progenitors through the latter stages of B cell differentiation. Anti-CD19-aFuc is a new glycoengineered humanized anti-CD19 Ab. Removal of the fucose sugar modification from the Ab Fc portion, using BioWa’s Potelligent Technology, resulted in enhancement of Fc-Fc? receptor interaction. Further, enhanced binding to activating Fc receptors correlated with a dramatic enhancement of in vitro antibody-dependent cellular cytotoxicity (ADCC) effector function, and the glycoengineered anti-CD19 Ab effectively kills malignant as well as normal human B cells in vitro. Experiments with transgenic mice expressing human CD19 demonstrate depletion of blood as well as tissue B cells in vivo. Furthermore, anti-CD19-aFuc treatment resulted in significant inhibition of tumor growth in several SCID models of human lymphoma. Together, the data demonstrate that anti-CD19-aFuc has potent anti-lymphoma activity and maybe particularly useful in cases of anti-CD20 resistance or in relapsed patients. In addition, targeting CD19 holds promise for the treatment of certain autoimmune diseases.
11:30
Collagenases: Key Targets for Blocking Tumor Cell Invasiveness
Beverly Packard, Ph.D., President, OncoImmunin, Inc.
Even though almost all deaths from cancer, specifically solid tumors, are a direct result of metastatic disease, there are currently no therapeutic agents that target the molecular components responsible for a tumor cell’s migration out of its native environment and into a secondary site. This hole in the chemotherapeutic armamentarium exists despite considerable knowledge regarding the major molecules of and their organization in the extracellular environment as well as a long list of cellular processes believed to be associated with tumor cell metastasis. Part of the failure derives from contradictory data regarding the role(s) of proteases in the metastatic process. For example, there are data supporting metastasis as protease driven, dependent, associated and irrelevant. In order to address the issue of protease involvement in cancer metastasis, a new probe and assay to detect collagenase activity in live cell environments have been developed. Specifically, MMP activity on the surface of cells moving through or across extracellular matrices composed of the macromolecules that metastatic tumor cells would encounter during their transit is targeted. Results to be presented provide insight into reasons for inconsistencies from previous studies while supporting an important role for proteases in cell migration through macromolecular networks. Furthermore, drug development for targeting collagenase activity will be discussed.
12:00
Luncheon
1:00
Guanilib, a Guanylate Cyclase-C agonist, is a New Class of Oral Drug Candidate for GI Disorders and Colon Cancer
Kunwar Shailubhai, Ph.D., M.B.A, Senior Vice President, Discovery Research, Callisto Pharmaceuticals, Inc
Uroguanylin (UG), Guanylin (Gn), and bacterial heat stable enterotoxin (ST) are structurally related peptides that activate common guanylate cyclase-C (GC-C) signaling molecules and, via cyclic GMP (cGMP), regulate water and ion homeostasis in a variety of tissues and organs, including the gastrointestinal (GI) tract, kidneys, lung, prostate, etc. Previously, we reported that production of UG is dramatically suppressed in human colon tumor tissues and that this deficiency might be one of the primary reasons for colon carcinogenesis. We also showed that UG inhibited proliferation and induced apoptosis in colon carcinoma cells. In addition, oral treatment with UG not only inhibited formation of polyps but also retarded their progression to adenocarcinomas in Apc+/Min mice. The cGMP pathway also mediates anti-inflammatory effects of cellular molecules such as nitric oxide and hemeoxygenase-1, and therapies that induce cGMP (phosphodiesterase-4 inhibitors) demonstrate efficacy in murine models of IBD. Accordingly, we reasoned that agonists of GC-C, when administered orally might also produce anti-inflammatory effects in murine models of colitis. Indeed, treatment with SP304 (Guanilib) exhibited anti-inflammatory effects in TNBS- and DSS-induced colitis in mice. Importantly, the amelioration of colitis was also associated with downregulation of some of the important pro-inflammatory cytokines such as IL-4, IL-5, IL-23, and TNF. These results suggest that the GC-C receptor-mediated enhancement of intestinal mucosal cGMP production by Guanilib mediates anti-inflammatory effects in colitis models. Our recent data also suggest that Guanilib might also be useful for irritable bowel syndrome (IBS). Guanilib is expected to enter clinical trials in 2008. The seminar will cover: 1) functions of GC-C agonists in GI physiology; 2) cyclic GMP mediated signaling pathways, and their roles in anti-cancer and anti-inflammatory activities; 3) mechanism of action of Guanilib in GI disorders and colon cancer; and 4) Guanilib for treatment of IBS-C.
1:30
Abbott's Oral Bcl-2 Family Protein Inhibitor
Anne Hagey, Global Project Head, Oncology, Abbott Laboratories
2:00
DNA Damage Detection and Repair Pathways – Targets for Enhancing the Effectiveness of Cancer Therapeutics
Susan Ashwell, Director, Cancer Chemistry, AstraZeneca
DNA damage is a relatively common event in the life of a cell, and if unchecked, may result in mutation or cell death. Therefore, cells have evolved complex signaling networks to carefully monitor the integrity of the genome during DNA replication, and to initiate cell cycle arrest, DNA repair or apoptotic responses if errors are detected. It is these same pathways that limit the efficacy of DNA damaging cancer therapeutics by allowing DNA repair and hence cellular survival. Thus these pathways have become increasingly attractive targets for cancer drug discovery efforts, with several agents now in clinical trials. This presentation will discuss the rationale and promise of such agents to provide significant improvements in the treatment of cancer in the future.
2:30
Transcending Proteasome Inhibition for the Treatment of Cancer: Development of MLN4924 – an Inhibitor of NAE
Joseph Bolen, Ph.D., Chief Scientific Officer, Senior Vice President, Research & Drug Discovery, Millenium Pharmaceuticals
Inhibition of proteasome function in cancer cells has been shown to disrupt protein homeostasis resulting in cancer cell death. The clinical utility of this concept has been demonstrated by the proteasome inhibitor, bortezomib, which is approved for the treatment of multiple myeloma and mantle cell lymphoma. This precedent suggests that compounds targeting other components of the ubiquitin-proteasome system (UPS) could prove useful for the treatment of human malignancies. The Nedd8-activating enzyme (NAE) has been demonstrated to be an essential component of the Nedd8 conjugation pathway which controls the activity of a subset of UPS E3 ligases that are responsible for the timely ubiquitination and subsequent degradation of proteins with important roles in oncogenesis. Millennium has identified novel small molecule inhibitors of NAE, exemplified by MLN4924, that induce apoptosis in human tumor-derived cell lines in vitro and result in dramatic tumor growth inhibition in cancer animal models in vivo. These preclinical findings represent the foundation to support transition of MLN4924 into human clinical trials.
3:00
Networking and Refreshment Break
3:30
Targeting Tie-1 Inhibits Tumor Growth and Sensitizes the Tumor Vasculature to Anti-Angiogenics
Lili Huang, Ph.D, M.D., Associate Director, Dyax Corp
DX-2240, a human antibody specifically targeting Tie-1 has been demonstrated to significantly reduce tumor growth as a monotherapy in mouse xenograft models. Immunohistochemical analyses of tumors from DX-2240-treated mice reveal altered tumor vascular morphology with abnormal vessel sprouting, decreased smooth muscle cell coverage and increased hypoxia and necrosis, indicating nonproductive vessel formation. These vascular changes induced by DX-2240 sensitize the tumor vasculature to other anti-angiogenic drugs, including VEGF pathway inhibitors. The findings of biochemical assays that correlate the activity of DX-2240 in vitro with its pharmacology in preclinical models will be presented.
4:00
Tyrosine Kinase Inhibitor Resistance and Rational Anti-Cancer Drug Combinations
John Haley, Senior Research Director, Translational Research, OSI Pharmaceuticals
Multiple resistance mechanisms have been described for EGF receptor tyrosine kinase inhibitors in the treatment of NSCLC. In NSCLC cells with an epithelial phenotype these include over activation of IGF-1 receptor and HGF receptor (Met) and mutation of EGFR (T790M). Recently we observed that NSCLC cells with a mesenchymal phenotype showed a marked reduction in sensitivity to EGFR TKIs, though the molecular rationale remained obscure. We recently found that the acquisition of a mesenchymal phenotype, deriving from an epithelial to mesenchymal-like transition, often correlated with tumor expression of functional PDGFR?, PDGFR? and/or FGFR1. Markers of both epithelial and mesenchymal lung phenotypes were identified and used to develop colorimetric and fluorescence IHC assays for measuring expression in human specimens. From these efforts, tissue markers can be identified for the matching of drug combinations, targeting the aberrant receptor signaling networks associated with cell survival and cancer progression, with appropriate patients. Approaches to the identification of patient stratification markers and patient selection markers are described that are applicable to many disease settings. These have involved combinations of proteomic, gene expression, and IHC measurements which overlap and complement to enable predictive markers to be identified.
4:30
Targeted Drug Delivery: How Far From the Bullseye?
Jeremy Barton, Senior Director, Medical Research, Hematology/Oncology, Biogen Idec
Utilizing an antibody to deliver a cytotoxic or radioisotope to a tumor is a logical extension of the concept of using a naked antibody as a cancer therapeutic especially as most antibodies approved by the FDA find their maximum benefits in combination with another therapy. The specificity of the antibody for its target should, in theory, allow selective delivery of the conjugate to the tumor cells with that target if there is little or no normal tissue expression. Despite intensive research over the last two decades, only one cytotoxic immunoconjugate and two radioimmunoconjugates are FDA approved. A review of the challenges of this approach to therapy will be made and a novel immunoconjugate targeting the Cripto antigen will be discussed to illustrate some of the technological advances that have been made in the field.
5:00
Poster Session & Networking Reception
Top of the page
Day 2, Friday, February 22, 2008
7:00
Continental Breakfast
8:00
Review of Day One
[KEYNOTE PRESENTATION]
Mechanism-Driven Approaches to Molecularly Targeted Cancer Drug Discovery
8:10
Robert Copeland, Vice President, Biology, Oncology Center of Excellence in Drug Discovery, GlaxoSmithKline
Oncology drug discovery at GSK is focused on molecularly targeted therapeutics for the treatment of cancer and for cancer supportive care indications. A guiding principle of our approach is that a detailed, mechanistic understanding of pathobiology and of drug action – at the molecular, cellular and organismal level – is essential for effective drug discovery. Towards this end we have built a discovery organization that encompasses robust biochemical, cellular biological and in vivo pharmacological interrogation of drug candidates. Examples of the application of these approaches to several cancer drug-seeking efforts will be presented.
Session III - Cancer Drug Development in Clinical Trials
9:00
Model-Simulated Design of Cancer Therapies
Ulrik Nielsen, Ph.D., Vice President, Research, Merrimack Pharmaceuticals
Computational biology is improving our understanding of complex biological systems. Using very large biological datasets of cell signaling we have constructed detailed, mechanistic models. These may be used to predict network responses to targeted therapeutics such as monoclonal antibodies and small molecule inhibitors. Using growth factor signaling as an example, we will present how computational modeling can be used to simulate the best therapy with single agents or combinations of targeted inhibitors.
9:30
Targeted Chemotherapy Using Immunoconjugates of Calicheamicin
Nitin K. Damle, Ph.D., Director, Oncology Discovery Research, Wyeth Pharmaceuticals
10:00
Networking and Refreshment Break
10:30
Post-Transcriptional Control as a Novel Approach to Anti-Angiogenesis: Small Molecules that Reduce VEGF Levels
Marla Weetall, Ph.D., PTC Therapeutics, Inc.
VEGF expression is modulated at transcriptional and post-transcriptional levels. Chronic up-regulation of VEGF is highly dependent on post-transcriptional control. PTC Therapeutics has identified PTC299, an orally bioavailable small-molecule that potently inhibits VEGF production (EC50 = 2 nM) in vitro and in vivo, and inhibits tumor growth in vivo (ED90 = 1 mg/kg BID). PTC299 was active in vivo in multiple xenograft models and was additive or synergistic with standard chemotherapeutic agents. Preclinical IND-enabling toxicology studies have demonstrated that PTC299 is well-tolerated in rats and dogs and suitable for development.
11:00
The Discovery and Early Development of ARQ 197, a Selective c-Met Inhibitor
Mark Ashwell, Ph.D., Vice President, Chemistry, ArQule
ARQ 197 is a novel orally bioavailable small molecule c-Met receptor tyrosine kinase inhibitor advancing into Phase 2 clinical trials. This presentation will describe the identification of ARQ 197 and its pre-clinical characterization in a variety of in vitro and in-vivo assays. ARQ 197 was well-tolerated in Phase 1 trials and has exhibited signs of tumor response in late stage cancer patients with metastatic disease and these results will also be presented.
11:30
Delta-like Ligand 4 as a Novel Anti-angiogenesis Target in Tumors
Irene Noguera-Troise, Ph.D., Staff Scientist, Oncology & Angiogenesis, Regeneron Pharmaceuticals, Inc.
Tumor growth is dependent upon a functional vasculature, as evidenced by the decreased tumor growth following blockade of Vascular Endothelial Growth Factor (VEGF), a critical mediator of both normal and pathological angiogenesis. Using microarray analysis, we previously identified Delta-like ligand 4 (Dll4) as a VEGF-regulated gene in mouse xenograft tumor models. Dll4 is expressed by tumor endothelial cells and acts as a ligand for Notch receptors. Importantly, like VEGF, genetic ablation of even a single Dll4 allele results in early embryonic lethality associated with severe vascular defects. Dll4 also has a critical role in tumor angiogenesis; inhibition of Dll4 results in excessive, non-productive tumor angiogenesis, with poorly perfused vessels and elevated levels of tumor hypoxia. This presentation will discuss:
• Blocking Dll4-Notch pathway induces aberrant angiogenesis and reduces tumor growth in numerous preclinical tumor models
• Tumor growth is reduced upon Dll4 blockade even in tumors resistant to VEGF-therapies
• In many tumor models, combination treatment with VEGF and Dll4 blocking agents is more efficacious than single agent treatments.
• Blockade of Dll4-Notch is associated with a rapid induction of tumor hypoxia
12:00
EphB4 and Dll4
Parkash S. Gill, M.D., Professor of Medicine and Pathology, USC Keck School of Medicine, Norris Cancer Center
12:30
Luncheon
Session VI - New Drug Delivery Methods
1:30
Oral Presentations from Submitted Abstracts
Submit your abstract by January 22, 2008
2:00
Tf as a Carrier for Anti-cancer Drugs
Daniel Kamei, Ph.D., Assistant Professor, Bioengineering and Biomedical Engineering, UCLA
An effective cytotoxic agent for cancer therapy should demonstrate reduced toxicity by having an increased specificity towards cancer cells. To address this challenge, several research groups have investigated conjugating various cytotoxins to the iron transport protein transferrin (Tf), since its receptor is overexpressed on the surfaces of cancer cells. However, the short timeframe in which Tf can deliver its drug can limit its efficacy. We therefore engineered the cellular trafficking pathway of Tf to increase this timeframe, and diphtheria toxin (DT) conjugates of the Tf variant were experimentally found to be significantly more cytotoxic than DT conjugates of wild-type Tf in an in vitro cell-killing assay. This presentation will highlight our novel approach for engineering trafficking pathways to design protein-based drug delivery vehicles. The following four main elements of our methodology will be described in the context of this Tf project:
• Trafficking analysis
• Trafficking modeling
• Molecular engineering
• Experimental validation
2:30
Drug Delivery Using Monoclonal Antibodies
Ginette Serrero, CEO, A&G Pharmaceuticals
3:00
Nanotechnology-based Drug Delivery
Daryl Drummond, Director of Liposome Research, Hermes Biosciences, Inc.
3:30
Conference Concludes
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Organized by:
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Tiffany Chin |
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Invited Speakers:
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Visit our web to see invited speakers!
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Deadline for Abstracts:
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January 21, 2008
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Registration:
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Register 2, the 3rd goes FREE - Register Now!
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E-mail:
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tiffany.chin@gtcbio.com
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