Day 1 - Thursday, January 28, 2010

7:00

Registration & Breakfast

7:55

Welcome and Opening Remarks

Kun-Liang Guan, Ph.D., Professor, Pharmacology Cancer Biology Program, UCSD Moores Cancer Center

8:00

DISTINGUISHED KEYNOTE PRESENTATION

Ubiquitin-like Protein Activating Enzymes as Therapeutic Targets

Joseph Bolen, Ph.D.
Chief Scientific Officer
Millennium Pharmaceuticals: The Takeda Oncology Company

The ubiquitin–proteasome system (UPS) is responsible for the regulated degradation of intracellular proteins with important roles in a broad array of cellular functions. One drug which targets the UPS, the proteasome inhibitor bortezomib (VELCADE®), is approved for the treatment of patients with multiple myeloma or mantle cell lymphoma. The anti-cancer activity of bortezomib suggests that inhibitors of other enzymes that modulate UPS activity might lead to the development of new anti-cancer drugs with differentiated clinical use.

The NEDD8 activating enzyme (NAE) is the initial enzyme in a ubiquitin-like (UBL) protein pathway that regulates protein degradation mediated by cullin-dependent ubiquitin ligases. Activity of this pathway modulates the abundance of proteins known to be essential for cancer cell growth and survival. We have previously described discovery of MLN4924, a small molecule inhibitor of the NAE that is being evaluated in several clinical trials1. We have also demonstrated that MLN4924 is a mechanism-based inhibitor of NAE and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme. The stability of the NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity thereby accounting for the potent inhibition of the NEDD8 pathway by MLN49242.

These results suggest that other ubiquitin-like (UBL) protein pathways can be modulated by small molecule inhibitors directed against the cognate activating enzymes.

Session I - Targeting
Moderator: Kun-Liang Guan, Ph.D., Professor, Pharmacology Cancer Biology Program, UCSD Moores Cancer Center

8:45

Translational Science and Strategy in Oncology New Drug Development

Haifeng Bao, Ph.D., R&D Translational Sciences, MedImmune

9:10

Compensatory Signaling Between Receptor Tyrosine Kinases as an Adaptive Survival Mechanism for Tumor Cells: Rationale for Combinatorial RTK Targeting in Cancer

Elizabeth Buck, Ph.D., Research Investigator, Translational Research, OSI Pharmaceuticals

Deregulated signaling by receptor tyrosine kinases (RTKs) is a central mechanism leading to oncogenic transformation and tumorigenesis, and RTKs have been targets of intense interrogation for the design of anti-cancer agents. Although clinical studies have demonstrated success for both antibody and small molecule RTK inhibitors as single agents, acquired resistance is common, and recent efforts have focused on identifying the underlying molecular mechanisms leading to RTK resistance. Emerging data have revealed a general role for adaptive RTK signaling to provide a survival advantage for tumor cells when an individual RTK is targeted. Crosstalk between IGF-1R and EGFR can mediate resistance to inhibitors of either receptor, where blockade of IGF-1R or EGFR results in a rapid upregulation in the phosphorylation of the reciprocal receptor. Only when IGF-1R and EGFR are co-targeted is full and sustained inhibition of AKT observed, and this is associated with a synergistic induction of apoptosis and tumor growth regression in vivo. Compensatory signaling between IGF-1R and IR also occurs in a number of biological systems, including cancer cells. We have recently observed that specific inhibition of IGF-1R with a specific monoclonal antibody is accompanied by an increase in the phosphorylation of IR and is associated with decreased inhibition of the AKT pathway. In contrast, treatment with OSI-906, a small molecule dual inhibitor of IGF-1R and IR, resulted in enhanced blockade of AKT phosphorylation and increased activity/efficacy in vitro and in vivo. These data indicate that dual targeting of IGF-1R and IR may provide superior anti-tumor activity compared to selective inhibition of IGF-1R alone. This presentation will highlight recent data that provide a mechanistic foundation for improving anti-tumor activity through rational combinations of RTK inhibitors. Plasticity within the EGFR/IGF-1R/IR RTK circuitry will be discussed as a key mechanism underlying acquired resistance to inhibition of individual RTKs.

9:35

Networking and Refreshment Break

Session II - Monoclonal Antibodies
Moderator: Kun-Liang Guan, Ph.D., Professor, Pharmacology Cancer Biology Program, UCSD Moores Cancer Center

10:05

A Glycoengineered Anti-CD19 Antibody (MEDI-551) with Enhanced ADCC Effector Function is Effective as Monotherapy or in Combination Treatment in Mouse Models of B-cell Malignancies

Ronald Herbst, Ph.D., Director, Respiratory, Inflammation & Autoimmunity, MedImmune

The vast majority of human lymphomas are of B cell origin, and B cell specific surface antigens are attractive targets for therapeutic intervention, as demonstrated by the success of the anti-CD20 antibody 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 antibody (Ab) target for B lymphoma therapy as it is expressed on the surface of early B cell progenitors through the latter stages of B cell differentiation. MEDI-551 is a new glycoengineered humanized anti-CD19 Ab. Removal of the fucose sugar modification from the Ab Fc portion resulted in enhancement of Fc-Fc? receptor binding and greatly improved antibody-dependent cellular cytotoxicity (ADCC) against multiple B leukemia and lymphoma cell lines. In in vitro ADCC assays with primary samples from patients with CLL and ALL, the activity of MEDI-551 exceeded the activity of rituximab. Further, MEDI-551 inhibited the growth of subcutaneous and disseminated human lymphomas in SCID. In addition, the combination of MEDI-551 with rituximab resulted in prolonged suppression of tumor growth as compared to either Ab alone. Together, the results demonstrate that MEDI-551 has potent activity against B cell derived malignancies in vitro and in vivo and warrant further evaluation of the Ab in the clinic.

Benefits:
Effect of mAb Fc modifications on activity in preclinical models
mAb optimization by glycoengineering
Comparison of anti-CD19 vs anti-CD20 targeted therapy in vitro and in vivo
Insights into complexity and predictive value of preclinical models
New approach for mAb combination therapy

10:30

Translational Considerations for Development of Potent Antibody-Based Therapeutics

Mohammad Tabrizi, Ph.D. , Vice President, Preclinical Development, AnaptysBio, Inc.

With the advancement in technologies employed for generation of antibodies, more potent antibody-based therapeutics (ABTs) are emerging. Currently, many bi- or tri-specific antibodies are in development and many of these ultra-potent constructs rely on recruiting endogenous immune effector cells to exert their pharmacological effects. As an example, the bi-specific T cell engagers carry dual specificity in their binding arms and rely on recruiting cytotoxic T lymphocytes of the host for killing cancerous cells. Although, current clinical results underline the potential significance for these bi-specific constructs as therapeutics, their development path to the clinic has been complex. In general, successful translational strategies for development of antibody-based therapeutics can greatly facilitate their path through various development stages and require integration of knowledge with respect to target antigen properties, antibody design criteria such as affinity, isotype selection, Fc domain engineering, pharmacokinetic (PK)-pharmacodynamic (PD) properties, and antibody cross-reactivity across species from the early stages of the development. For the ultra-potent antibody constructs where effector functions contribute significantly to the underlying mechanism of action, highly efficient pharmacological responses are anticipated where the binding curves denoting receptor occupancy lie to the right of the in vivo concentration-response curves (KD>EC50). In these instances, many factors for designing the most effective translational strategies will need to be evaluated. This presentation will focus on critical considerations relevant to development of ultra-potent anti-cancer antibody constructs.

Session III - Challenges of Modern Cancer Drugs
Moderator: Kun-Liang Guan, Ph.D., Professor, Pharmacology Cancer Biology Program, UCSD Moores Cancer Center

10:55

Challenges in Developing Preclinical Models of Hepatocellular Carcinoma

Cedo Bagi, Senior Research Fellow, Pfizer, Inc.

Liver is distinguished from other tissues by its detoxifying function, resistance to apoptosis and regenerative response to damage and plays a central role in pharmaceutical science due to drug metabolism and liver associated toxicities. In oncology, liver metastases are a frequent and deadly complication of many tumor types and hepatocellular carcinoma (HCC) which originates in the liver is the fifth most common cancer worldwide. HCC occurs when chronic insult, such as hepatitis or iron overload, continuously activates hepatocyte regeneration. Clinical management of HCC is challenging because it requires concurrent treatment of the malignant tumor, the underlying viral infection or cause of liver insult and also developing liver dysfunction. A lack of reliable pre-clinical HCC disease models that will allow for testing of complex therapeutic approaches is one of the main obstacles to development of novel therapies. In this talk we will discuss several topics relevant to preclinical HCC models, including: A) Liver vasculature and implications for tumor growth and metastases; B) Available human HCC cell lines and liver biopsies; C) Xenograft and orthotopic HCC models; D) Chimeric mice with humanized liver; E) Drug administration and tumor targeting; F) Availability of biomarkers and imaging technologies; G) Viral infection (HBV/HCV) and HCC models and H) Combination therapies. In summery, we endorse a multidisciplinary approach and use of multiple preclinical animal modes for assessment of efficacy and safety of combination therapies targeting not just HCC cells but also liver stroma and the immune system.

11:20

Lunch

12:50

Pharmacokinetics Of Hedgehog Pathway Inhibitor GDC-0449 In Patients With Refractory Or Untreatable Locally Advanced Or Metastatic Solid Tumors: The Role Of Alpha 1-Acid Glycoprotein Protein Binding

Richard A. Graham, Clinical Pharmacologist, Genentech, Inc.

GDC-0449 is the first orally bioavailable small-molecule inhibitor of the hedgehog signaling pathway and introduces a new anticancer drug class: the hedgehog pathway inhibitors. Following a single dose, the terminal half-life of GDC-0449 was 10-14 days in healthy volunteers, and plasma concentrations were sustained for 7 days in cancer patients. In the phase 1a trial in cancer patients, unique non-linear pharmacokinetics (PK) was observed. After single dose, Cmax increased in proportion to dose from 150 to 270 mg, but not from 270 to 540 mg. With multiple daily doses, the time to steady-state was 7-21 days, which is shorter than expected given a 10-14 day half-life. All doses showed similar steady-state concentrations, and a flat concentration-time profile was observed after dosing at steady state. Preclinically, GDC-0449 was highly bound to plasma proteins. In vitro experiments suggested saturable binding to alpha 1-acid glycoprotein (AAG) within the clinical GDC-0449 concentration range. Binding affinity for AAG was determined to be high (~1 µM) and reversible. A strong correlation was shown between AAG and GDC-0449 plasma concentrations, suggesting substantial contribution of AAG to the non-linear PK. Mechanistic PK modeling and simulation are ongoing to better understand the unusual behavior of GDC-0449. Multiple hypotheses for the PK nonlinearity were quantitatively evaluated using simulation. The PK model with both solubility limited absorption and tight binding to AAG best explained key human PK properties of both total and unbound drug, and will be further investigated to identify important PK covariates and support the dosing rationale for GDC-0449.

1:15

Amplification and/or High Expression of Myc Genes Sensitizes Preclinical Models to Aurora Kinase Inhibitors

Adam Pavlicek, Ph.D., Senior Principal Scientist, Pfizer, Inc.

Phase 1 proof-of mechanism studies with developmental anticancer agents would benefit from patient selection strategies that are based on molecular characteristics which confer sensitivity to the test agent. The Aurora-A kinase inhibitor development project with PF-03814735, currently in Phase 1 clinical trials, is such a project. We screened panels of carcinoma lines from various tissues for sensitivity to PF-03814735. Sensitivity to PF-03814735 in vitro was strongly correlated with amplifications in one of the Myc family genes (c-Myc, L-Myc, N-Myc) as well as mRNA expression levels of those genes. Collectively, findings from these studies are of potential value to identify patient populations with increased probability of benefit from Aurora-A kinase targeted agents.

1:40

De Novo Design of Potent BCL-xl Inhibitors by Scaffold Hopping and Data Mining

Hongmao Sun, Senior Principal Scientist, Hoffmann-La Roche, Inc.

Scaffold hopping is a widely applied de novo drug discovery technology to generate isofunctional compounds with novel backbones. Pharmacophore descriptors, reduced graphs, and shape-based similarity search are among the major approaches in scaffold hopping. In this study, we formulated a specific and accurate query by analyzing the intermolecular interactions between the protein BCL-xl and a potent Abbott inhibitor, followed by data mining of the Cambridge Structural Database (CSD). The selected scaffold was significantly different from the Abbott compound, yet the final optimized molecule inhibited BCL-xl with an IC50 of 200 nM.

Potential benefits of my talk:
1. Introduce to audience a new fast follow-up strategy that works;
2. Demonstrate how to make the best use of chemical information in public domain;
3. A successful drug discovery story carried out by one synthesis lab and a modeler;
4. What matters is the rationale instead of the number of compounds synthesized.

2:05

Leveraging The Interrelationship Of Biology, Chemistry And Pharmacology In The Strategic Development Of Antibody-Drug Conjugates As Effective Targeted Cancer Therapeutics

Dr. Saileta Prabhu, Scientist, Genentech

Antibody drug conjugates (ADCs), also commonly referred to as immunoconjugates, represent a novel approach to enhance the therapeutic index of potent cytotoxic agents by linking these drugs to a monoclonal antibody to confer tumor-selectivity by targeting tumor-associated antigens. ADCs were first evaluated as cancer therapeutics as early as mid-1970s, with proof of concept for ADCs demonstrated in hematological malignancies with the approval of gemtuzumab ozogomycin. Since then, dramatic progress has been achieved in the development of ADCs as witnessed by the advent of more than 20 ADCs in clinical development. This seminar will present our current understanding of factors impacting the disposition/pharmacokinetics, efficacy, and safety of ADCs. These can be broadly classified into physico-chemical factors such as properties of antibody, linker, and cytotoxin, and physiological-based factors such as antigen internalisation and distribution, and tumor biology. Case studies, in hematological and solid tumors based on our experience in developing anti-CD22/CD79b drug conjugates for non-Hodgkin’s lymphoma and Trastuzumab-DM1 for metastatic breast cancer, will be used to highlight some of the key physico-chemical and physiological factors important in the clinical development of ADCs, and to discuss some of the challenges that remain to be overcome to develop ADCs as targeted therapeutics for cancer.

2:30

Networking and Refreshment Break

3:00

The p21-Activated Kinase-4; An Emerging Therapeutic Target For Oncogenic Signaling And Tumor Growth

Brion Murray, Ph.D., Research Fellow, Pfizer Oncology, Pfizer La Jolla Laboratories

3:25

Challenges and Opportunities for Anti-Angiogenesis Drug Discovery and Development

Dana Hu-Lowe, Ph.D., Associate Research Fellow, Oncology Translational Research, Pfizer, Inc.

Anti-angiogenesis through targeting VEGF and its receptor tyrosine kinase (RTK) has been established as one of the important anti-cancer therapies in the clinic. However, the limitations of the class drugs have also been realized recently. One of the most critical issues is the intrinsic and acquired resistance to these drugs observed in many patients. Recently, resistance to anti-VEGF or VEGF RTK inhibitors has been studied in nonclinical systems and the understanding of the underlying mechanism of resistance is evolving (Bergers and Hanahan, Nature Rev Cancer, 2008). It is now recognized that in angiogenesis, tumor-associated endothelial cells (ECs) are not a homogeneous and stable population as once believed; rather, ECs in the tumor may confer cytogenetic instability because of the presence of excessive stimuli from tumor, stroma and infiltrating myeloid cells, as well as stress and hypoxia induced by therapies. Therefore, to effectively block angiogenesis, one must apply strategy to circumvent resistance and understand the dynamic regulation of molecular targets, pathways and state of activity of the vasculature and the microenvironment associated with cancer. Our approach toward providing insight into this issue has been 1) systematically dissect the molecular mechanism of resistance using paired resistant/sensitive ECs and nonclinical tumor models and 2) identification of targets involved in the angiogenesis processes and evaluation of their differential and complementary activity relative to VEGF/VEGF RTKs. One emerging target is ALK1 (Activin receptor Like Kinase 1), a type I TGF-beta receptor. Perturbation of ALK1 signaling, angiogenesis and tumor growth using an anti-ALK1 monoclonal antibody will be discussed.

Benefits:
1. Summarize current challenges in anti-angiogenic drug development
2. Share approaches that may address clinically relevant issues
3. The work touches upon the concept of how research may inform clinical decision-making, i.e. patient selection/personalized medicine, even for anti-angiogenic agents.
4. Reveal novel targets and their potential utility in cancer therapy.

Session IV - Novel Approaches and Emerging Targets
Moderator: Kun-Liang Guan, Ph.D., Professor, Pharmacology Cancer Biology Program, UCSD Moores Cancer Center

3:50

Discovery of Small Molecule Wnt Pathway Modulators

John Hood, Ph.D., CSO, Wintherix

The Wnt signal transduction pathway is a critical regulator of tissue homeostasis, stem cell function and, frequently, tumorigenesis. In total, ~600,000 new US cases of solid and hematological cancer have pathological activation of the pathway, exemplified by colon cancer in which activating mutations of the Wnt pathway are present in ~90% of patients. Despite the therapeutic attractiveness of this target, identifying druggable inhibitors of the pathway has proven elusive and there are currently no Wnt inhibitors in clinical testing. To that end, we have developed a platform of novel high throughput screening assays which were used to interrogate a large chemical library leading to the identification of multiple druggable Wnt inhibitor scaffolds. Exemplary compounds from these scaffolds display nanomolar cellular potency, tractable pharmacokinetic properties, high degree of specificity against the target and anti-tumor effects that are selective for Wnt-dependent tumor cells. This program is currently in the lead-seeking stage with an expected lead nomination in early 2010.

In addition, small molecule activators of the Wnt pathway hold clinical promise in regenerative therapies such as those requiring osteogenesis or neurogenesis. To that end the same screens used to identify small molecule Wnt pathway inhibitors were used to identify small molecule activators. These compounds amplify Wnt signaling leading to enhanced bone formation from osteoblast precursors and enhanced neurogenesis from neural precursors. This program is also in the lead-seeking stage with an expected lead nomination in early 2010.

4:15

How to Repurpose Cancer Promoting Inflammation into Tumor Elimination

Martin Oft, Fellow, Schering-Plough Biopharma (formerly DNAX)

Human tumor cells acquire and accumulate mutations and transcriptional changes that provide growth and survival signals and a tumor promoting microenvironment. During the last decades it has become clear that the mammalian immune system is able to recognize those genetic and epigenetic changes and that T cells specific to oncogenes and oncofetal antigens are present in human cancer patients and their tumors. Instead of eliminating those mutant cells, immune mediated inflammation increases however tumor incidence and progression. Epidemiologically, inflammatory disease inducing cytokines have also been linked to tumor progression. The nature of the pro inflammatory T cells which control the chronic inflammatory response and their regulation by cytokines like IL-23 became however known only recently. Therapeutic modification of the cytokines and the pro-inflammatory T cells in cancer can reverse the deregulation of tumor promoting inflammation and release the inhibition of tumor immune surveillance.

4:40

Pharmacodynamic Biomarkers in Preclinical and Clinical Development of MLN4924, an Inhibitor of the NEDD8 Activating Enzyme

Allison Berger, Ph.D., Senior Scientist I, Discovery Oncology, Millennium Pharmaceuticals: The Takeda Oncology Company

Pharmacodynamic biomarker assessment is a key tool in the discovery and development of novel drugs in the ubiquitin proteasome pathway (UPP). Modulation of the UPP results in coordinated changes in levels of many proteins, presenting a large array of choices for monitoring PD effects. Inhibition of the NEDD8 activating enzyme (NAE) with the investigational drug MLN4924 can be monitored in xenograft tumors by evaluating several points in the UPP pathway including 1) neddylation levels of cullin proteins, 2) levels of multiple cullin ring ligase (CRL) substrates including Cdt-1, Nrf-2, and pIKB-alpha, and 3) downstream consequences of the stabilization of these proteins, including activation of DNA damage signaling, transcriptional regulation of Nrf-2 and NFKB target genes, and apoptosis. These PD assays have provided evidence of NAE inhibition and its downstream consequences in multiple xenograft models at efficacious doses. By taking into account the differences in PD response to NAE inhibition between cycling and non-cycling cells, as well as the assay formats best suited to evaluation of various human tissues (e.g. immunohistochemistry, ELISA, western blot, RT-PCR, etc), we developed a set of PD assays for use in Phase I trials of MLN4924. These assays have provided evidence of NAE inhibition in blood and skin biopsies at tolerated doses of MLN4924.

5:05

The Hippo Tumor Suppressor Pathway in Organ Size Control and Cancer

Kun-Liang Guan, Ph.D., Professor, Pharmacology Cancer Biology Program, UCSD Moores Cancer Center

The YAP is a transcription co-activator and a candidate human oncogene. YAP is amplified in some human cancers and plays a key role in organ size regulation. We showed that YAP is phosphorylated and inhibited by the Hippo tumor suppressor pathway. Phosphorylation of YAP S127 by the Lats tumor suppressor kinase results in 14-3-3 binding and cytoplasmic localization, therefore leading to YAP inhibition. Phosphorylation of YAP S381/S384 by Lats and CK1?/? recruits the SCF?-TRCP E3 ubiquitin ligase, which then promotes YAP ubiquitination and degradation. The S127 phosphorylation dependent translocation and the phosphodegron-mediated degradation coordinately suppress YAP oncogenic activity. Furthermore, we have established that the TEAD family transcription factors play a key role in mediating the biological functions of YAP. Together, our studies establish a mechanism of spatial and temporal regulation of YAP by the Hippo tumor suppressor pathway and their role in tumorigenesis.

5:30

Networking Reception and Poster Session
Drinks, Hors D'Oeuvres and Networking!

Day 2 - Friday, January 29, 2010

Top of the Page

7:30

Continental Breakfast

7:55

Review of Day One

Karen Lundgren, Ph.D., Principal Scientist, Pharmacology, Biogen Idec

8:00

DISTINGUISHED FEATURED PRESENTATION

Elizabeth Stafford, Ph.D, Scientific Reviewer, FDA/CDRH/OIVD

Session IV - Novel Approaches and Emerging Targets (continued)
Moderator: Karen Lundgren, Ph.D., Principal Scientist, Pharmacology, Biogen Idec

8:25

Anti-Cancer Drug Delivery Systems: The Next Frontier

Anand Sistla, Senior Principal Scientist, Pfizer

Novel drug delivery systems are finding greater use in cancer therapy for targeting potent small molecules. The aim of this targeting is not only to increase efficacy, but extends to decreasing undesired effects, thereby increasing the therapeutic index. Considering the narrow available chemical space and the high lipophilicity of the targets, these systems also present an avenue for enabling molecules that could not be delivered successfully due to poor pharmaceutical (or drug like) properties. The presentation aims to highlight the uses, successes, and challenges associated with the various delivery systems for small molecules along with a brief discussion on the transition from preclinical to clinical studies. Nanoparticles present the latest approach to delivery of anti-cancer agents and will be discussed.

8:50

Discovery and Development of Hsp90 Inhibitors

Karen Lundgren, Ph.D., Principal Scientist, Pharmacology, Biogen Idec

Hsp90 is a molecular chaperone that functions in the maturation and stabilization of cellular proteins. Hsp90, in complex with other co-chaperone proteins, catalyzes the conformational changes required for “client” protein function via its ATPase activity. Mutant and over-expressed oncoproteins that drive malignant progression are particularly dependent on Hsp90 chaperone activity. In tumor cells, inhibition of Hsp90 results in degradation of these proteins followed by cell death making Hsp90 a target of substantial interest for cancer therapy. Several Hsp90 inhibitors have entered into clinical trials. BIIB021 is a novel, synthetic, oral inhibitor of heat shock protein 90 (Hsp90) that binds competitively in the Hsp90 ATP binding pocket. Treatment with BIIB021 led to inhibition of tumor growth in human tumor xenograft models that express Hsp90 client proteins and oral administration of BIIB021 in combination with molecularly targeted therapies enhanced the activity of monotherapy alone. BIIB021 is a promising new Hsp90 inhibitor that is fully synthetic and designed to be given orally, thereby supporting flexible therapeutic dosing schedules. BIIB021 is currently undergoing Phase 1 and Phase 2 clinical trials in hematological and solid tumors.

9:15

Networking an Refreshment Break

9:45

Parkash S. Gill, Professor of Medicine and Pathology, USC Keck School of Medicine, Norris Cancer Center

10:10

Non-Invasive Small Animal Imaging in Cancer Drug Research and Development

Cathy Zhang, Principle Scientist, Pfizer Global Research and Development, La Jolla Laboratory

Molecular imaging has emerged as a powerful tool in cancer drug discovery. These imaging modalities, including bioluminescence, fluorescence, ultrasonography, and [18F]FLT-PET/CT imaging, require diligent optimization and validation in order to be utilized in the preclinical and clinical studies. This presentation will illustrate how the imaging technology is employed in the research and development of several investigative agents such as P-cadherin mAb, CDK, Chk1, and γ–secretase inhibitors. With multidisciplinary efforts, these imaging readouts are validated using various conventional assay approaches such as RT-PCR, LC/MS, immunofluorescence and immunohistochemical analyses. Our work highlights the values of the non-invasive imaging technology for various applications such as disease model development, pharmacodynamic-endpoint assessment, drug distribution and translational biomarker development. The unique applications and limitations of each modality will be discussed.

Key learning
- Gain knowledge on the fundamental principle of the imaging technology.
- Imaging modality selection based on the biological properties of the target agent; and validation of the imaging readout using other tools.
- Develop orthotopic and metastasis models that reflect target biology using bioluminescence and fluorescence imaging
- In vivo pharmacodynamic assessment and translational biomarker development using multi-imaging modalities.
- Translational imaging study designed to establish the correlation of target modulation/imaging readout/efficacy to aid early clinical POM trial.

10:35

Preclinical Development of Tcd-717, A Second Generation of Choline Kinase Inhibitors, As A New Anticancer-Agent

Ana Ramírez de Molina, Director of Research and Innovation, TCD Pharma

Choline Kinase Alpha ChoKa, an enzyme implicated in phospholipid metabolism, has been recently involved in human carcinogenesis. It has been found overexpressed in several human tumours such as breast, lung, bladder, colorectal, ovary or prostate tumours. In addition, ChoKa overexpresion has been shown to be oncogenic and to synergize with other known oncogenes. Finally, it has been recently reported as a new marker to predict clinical outcome of patients with NSCLC. Following these results, our group has developed a program for the identification of ChoKa inhibitors that could be used as a novel strategy for cancer treatment. TCD-717 belongs to a second generation of a family of bis-quinolinium derivatives that exerts both potent in vitro antiproliferative activity against a large panel of human tumoral cells, and efficient antitumoral activity in vivo in nude mice with relative low toxicity. We have further investigated the properties of TCD-717 and report here the pattern of efficacy of this compound, as a candidate to be tested in clinical trials. Our results suggest that its clinical development can be efficiently applied to a wide spectrum of human tumours.

 10:50

Structure Analysis of ERG Oncoprotein: A Potential Target to Develop Prostate Cancer Drugs

Ajay K Saxena, Associate Professor, School of Life Sciences, Jawaharlal Nehru University

ERG oncoprotein belongs to ETS (E26 transformation specific domain transcription factor) family of eukaryotic proteins with highly conserved winged helix-turn-helix DNA binding domain. The ETS gene encoding domains are frequent target for chromosomal translocation that result in various types of leukemia’s, Ewing sarcoma and over-expression of some genes are implicated in other human diseases. TMPRSS2-ERG fusion also occurs in more than 50% of prostate cancer. Erg protein is required for definitive hematopoiesis, adult hematopoietic stem cell function and the maintenance of normal peripheral blood platelet numbers. However, the molecular details of how, ERG is involved in transcriptional regulation is not known. Our goal is to analyze the x-ray structure of ERG in native and complexed form and to develop potent inhibitors of ERG in order to cure prostate cancer disease. We have expressed and purified the full length ERG from E. coli. We are currently involved binding and x-ray crystallographic studies of ERG and their complexes with DNA. This structural information makes it possible to use computational tools to identify molecules which may bind to ERG. In addition, we have also cloned the ETS domain of ERG in E. coli expression vector. The protein was expressed as soluble fraction in E. coli and purified using standard chromatographic techniques. The crystallization of ETS-DNA complex are pursued for structure analysis by x-ray crystallographic technique. The details of the experiments will be discussed in meeting.

 11:05

Profiles of Contributing Genes to Sensitive/Resistant Phenotype of 11 Different Oncology Therapeutic Agents Across 240 Cell Line

Christine L. O'Day, Senior Manager, Cell Biology, MDS Pharma Services

AAs more kinase inhibitors and other less cytotoxic drugs have entered the oncology market, it is imperative for clinical success to identify subsets of the population that have increased sensitivity or resistance to given agents. To this end, we have cultured 240 cell lines with defined genetic analysis to correlate sensitive and resistant cell lines. To test this hypothesis, we have screened 11 clinical and pre-clinical oncology agents to identify sensitive and resistant genes in each drug class. The list of oncology agents tested included inhibitors of mTorr, ABL, MEK, PDGF, VEGF, FLT3, Aurora kinases, HSP90, EGFR, Topo II and microtubulin disassembly. Four of the drugs are multikinase inhibitors. Compounds were run in a multiplexed assay using a 10 pt dose response spanning five logs of sample concentration and evaluated for antiproliferative effects, ability to induce apoptosis and the ability to enhance or decrease cells in G2M. Once analyzed, cell lines were separated into sensitive, resistant and intermediate in their activity towards the agent. Sensitive and resistant cells were further profiled against, mutation, expression and SNP data to identify genes involved in the sensitive/resistant phenotype. As expected, the most sensitive cell lines against a clinical ABL inhibitor were the CML derived cell lines. The multikinase inhibitors, primarily directed at VEGF/PDGF angiogenic pathways not detectable in this monolayer cell proliferation assay, were found to be sensitive against a common subset of cell lines. Genetic tendencies common between these cell lines are being investigated. In addition, a MEK inhibitor was selective against BRAF mutations presenting in many melanomas. All of the 30 most sensitive cell lines against the MEK inhibitor had either a BRAF or a RAS mutation but exclusive of retinoblastoma RB mutations. In the 30 most sensitive cell lines, 50% had BRAF mutations and 0% had RB mutations. In contrast, in the 30 most resistant cell lines, 0% had a BRAF mutation and 25% had RB mutations. In fact, 10 of the 11 known RB mutations were present in the 50 most resistant cell lines. Moreover, it is known that cyclin D overexpression confers resistance and since RB is a substrate of cyclin D, it follows that RB mutations may also confer resistance to MEK inhibitors. Further analysis may provide a complete picture of sensitivity and resistance to MEK inhibition and give insight for design of promising combination therapies.

11:20

A Novel Modular Targeting System for Redirecting Immune Effector Cells Including T-, NK, and DCs to Tumor Cells

Michael Bachmann, Professor, Technical University Dresden

Already in 1987 we described a nucleocytoplasmic shuttling of the nuclear autoantigen La/SS-B in dependence on oxidative stress conditions including a release and binding to living cells. Based on a series of monoclonal anti-La antibodies developed and characterized by us over the past decades we established a novel modular immunotargeting system allowing us to redirect immune effector cells T-, NK and DCs to tumor cells. The flexible system consists of bispecific recombinant antibodies directed to a peptide epitope of La and activating receptors on the respective immune effector cell CD3, NKG2D, Slan. The novel system can be used for a targeting of tumor cells either in an antigen-specific manner e.g. by scFvs specific for distinct tumor-associated antigens, TAAs when tagged with the selected La peptide epitope or based on a stress-induced presentation of La e.g. by radiation or cytostatic drugs or both in parallel and, thus allows the redirecting of effector cells even to escape variants or cells neighboring and nursing tumor cells. The modular system has the same killing efficiency as the respective single chain bispecific diabodies developed in parallel by us for targeting of three different TAAs on either prostate, acute myeloid leukemia or colon cancer cells.

11:35

Luncheon

Session V - Cancer Drugs in Clinical Trials
Moderator: Karen Lundgren, Ph.D., Principal Scientist, Pharmacology, Biogen Idec

12:35

Live Attenuated Listeria Cancer Vaccines: A Safe and Effective New Class of Therapy

Dr. John Rothman, Executive VP: Science & Operations, Advaxis

The objective of cancer immunotherapy is to stimulate the immune system to respond to cancer as if it were a bacterial infection. Bacterial vaccine vectors use the intrinsic properties of pathogenic microbes to redirect the strong immune responses used to clear bacteria toward selected tumor targets. The immune response to the bacteria Listeria monocytogenes is complex, multi-focal and powerful; and involves both innate and adaptive responses, changes in marrow and hematologic function, responses by the vessel walls, and alterations of the tumor microenvironment that in an integrated fashion resulting in therapeutic efficacy. Over the past 20+ years Lm vaccines have demonstrated anti-tumor efficacy in a variety of tumor models with a number of different tumor antigens. They have recently advanced to clinical testing where they have been shown to be safely administered to late stage cancer patients and resulted in a strong efficacy signal. Pre-clinical and clinical findings will be discussed that support the idea that live attenuated Listeria vaccines that infect target cells within the body and secrete antigen-adjuvant fusion proteins in situ represent an attractive new way to treat cancer safely and with a higher degree of efficacy than seen with other forms of antigen delivery.

• The objective of cancer immuno-therapy is to make the immune system see cancer as if it is a bacterial infection. Live attenuated bacterial vectors facilitate this process.
• Listeria monocytogenes (Lm) is uniquely suited for this purpose. Work in this area with other bacterial vectors has found them to be too toxic at effective doses.
• Lm strongly stimulates innate immunity, infects myeloid cells activating them cross presenting to the adaptive immune system, infects marrow to upregulate myeloid precursors, infects vascular endothelium to facilitate chemotaxis and extravasation of activated immune cells, and alters the tumor microenvironment by reducing Tregs and MDSC.
• Over 20 years of research has found numerous Lm vaccines able to eliminate tumors in normal and transgenic animals and prevent recurrence upon reinoculation with tumor cells.
• Preliminary human research has found that a live Lm vaccine can be safely administered to late stage cancer treatment failures, and has demonstrated a strong efficacy signal supporting further development.
• Mechanistically, having a non-pathogenic bacterial strain infect targeted cells of interest and synthesize an API in situ is appears to be a safe and effective new way to treat cancer.

1:00

The Discovery and Early Development of AZD7762, an Inhibitor of Checkpoint Kinases

Sonya Zabludoff, Ph.D., Associate Director, Cancer Bioscience, AstraZeneca R&D Boston

Conventional DNA-targeting therapies such as chemotherapy and radiation are among the most common cancer treatments and have produced significant increases in patient survival. Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a maintained therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and survival. The remaining checkpoints are in part controlled by checkpoint kinase 1 (Chk1) that is activated in response to DNA damage. This inhibition of Chk1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and survival. Inhibitors of Chk1 therefore offer the potential to enhance the efficacy of both conventional chemo- and radiotherapies and increase patient response rates in a variety of clinical settings.

Key pre-clinical findings that led to the discovery of AZD7762 as a highly potent, intravenous potentiating agent for DNA damaging chemo and radiotherapies will be described. In addition, novel combinations and biomarker strategies will be discussed. AZD7762 is currently in Phase I clinical trials.

1:25

TRAIL-Receptor Agonists as a Targeted Therapy for Cancer

Cancer occurs when cells accumulate mutations that enable them to escape the mechanisms that normally restrict their ability to survive and proliferate. One mechanism by which inappropriate cells are deleted is via apoptosis, or programmed cell death, and members of the tumor necrosis factor (TNF) superfamily of cytokines represent key extracellular regulators of this process. Apo2 ligand/ TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) is a member of the TNF superfamily that binds the death receptors DR4 and DR5, thereby activating caspases and initiating an apoptotic cascade. Early studies indicated that Apo2L/TRAIL had a potent ability to trigger apoptosis in tumor cell lines selectively over normal cells, highlighting its potential as a candidate therapeutic in cancer. These observations led to the development of recombinant human Apo2L/TRAIL (dulanermin) and several agonistic anti-TRAIL-receptor (TRAIL-R) antibodies that target either one or both death receptors as potential therapeutics which are currently in early clinical development. Despite the varying properties among these agents, including receptor selectivity and half-life, all have demonstrated in vitro activation of intracellular caspases, as well as in vivo monotherapy and combination activity in a wide variety of tumor xenograft models. Preliminary clinical results suggest that TRAIL-R agonists are generally well-tolerated and have shown evidence of anti-tumor activity. However, the development and implementation of serum-based pharmacodynamic assays to monitor TRAIL-R agonist activity in patients and, more importantly, the identification of molecular signatures that define a patient population likely to respond, will be key to the future success of these promising agents in the treatment of cancer.

1:50

Therapeutic Cancer Vaccines: Changing Paradigms in Prostate Cancer

Ravi A. Madan, Assistant Clinical Investigator Laboratory of Tumor Immunology and Biology/Medical Oncology Branch, National Cancer Institute

Therapeutic cancer vaccines represent an emerging treatment for prostate cancer. The goal of cancer vaccines is to induce an immune-mediated anti-tumor response by targeting weakly immunogenic or non-immunogenic antigens that are over-expressed by cancer cells. The two types of cancer vaccines furthest along in clinical development are vector-based vaccines and antigen presenting cell-based vaccines. Currently, docetaxel with prednisone is the only FDA approved chemotherapy regimen shown to improve survival for metastatic castration-resistant prostate cancer and additional treatments are needed. Recent large randomized controlled phase II and III trials have demonstrated statistically significant improvements in overall survival in patients with metastatic castration-resistant prostate cancer. Another smaller phase II study at the National Cancer Institute potentially identified a population of prostate cancer patients that are most likely to respond to cancer vaccines. In addition that study also demonstrated increased clinical benefit for patients who had a substantial immune response to vaccine therapy. Cancer vaccines have different effects on the tumor than standard cytoreductive chemotherapy. Although the biologic effects of vaccines on the immune system initiate a dynamic response that is unlikely to lead to immediate reduction in tumor size, it may induce long lasting effects after the treatment is discontinued. With a broader understanding of the novel impact of therapeutic cancer vaccines, prostate cancer patients in the near future are likely to benefit from cancer vaccines alone and in combination with standard therapeutics.

2:15

Conference Concludes

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