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GTCbio, San Francisco, CA
Jan 14-15, 2008
Day 1, Monday, January 14, 2008
7:15
Registration & Breakfast
8:00
Opening Remarks
[FEATURED PRESENTATION]
8:10
Pfizer’s Emphasis on Imaging Biomarkers for Oncology Programs
Kenna Anderes, Ph.D., Director, Oncology Biomarkers, Pfizer Global Research & Development
Session I - Future Methods and Technologies for Oncology Biomarker Discovery and Validation
9:00
Biomarkers For Early Detection: Which Way To Go? Platforms, Biomarkers, and Their Potential Clinical Value With Emphasis on DNA Methylation-based Biomarkers
Victor Levenson, M.D., Ph.D., Research Associate Professor, Robert H. Lurie Comprehensive Cancer Center, Northwestern University
Different applications will most probably require different biomarkers. I will discuss only one subgroup – biomarkers for early detection of cancer – with a systemic overview on (a) requirements for a successful clinical biomarker; (b) general principles that my lab applies for biomarker development; (c) chemical nature of potential biomarkers; (d) benefits and limitations of different platforms used for biomarker development. I will illustrate these points using composite multiplexed DNA methylation-based biomarkers developed in my lab for breast and ovarian cancers as examples. These blood-based biomarkers already have the potential to identify corresponding diseases with 75-85% sensitivity and specificity; while still insufficiently accurate to be used as a stand-alone test, they will be used as the foundation for further improvement.
9:30
Accelerating Biomarker Assay Development to Validation
Paul Smith, Vice President, Research Markets, Axela Biosensors
Genomic and proteomic techniques have generated large numbers of candidate proteins for the early detection of cancer or as markers of disease progression. In order to understand the utility and performance of these markers, robust assays that are capable of monitoring expression in various sample matrices under a variety of conditions are required. This translation of discoveries into assays suitable for use in distributed validation studies can be time consuming and costly. In most cases different platforms are required for each step of reagent selection and qualification, assay optimization and single or multiplex implementation. Recently, real-time monitoring of protein interactions has been applied to significantly accelerate this process. Diffractive optics technology (dotTM) has been implemented in a bench top platform utilizing inexpensive, disposable sensors to enable kinetic measurements, antibody ranking and pairing, buffer optimization, cross reactivity studies and routine immunoassay directly in complex matrices. The open format design allows measurement across broad dynamic range; for example multiplex measurement of markers in serum differing by more than six orders of magnitude has been demonstrated. This is critical in development of oncology panels where multiple markers are required to provide adequate discrimination and these often combine both high and low abundance proteins. The user-configurable sensors allow co-determination of existing diagnostic targets and novel discoveries in the same small sample, significantly facilitating validation of clinical utility. Examples of each of these applications performed on the dotLab™ System will be discussed.
10:00
Networking and Refreshment Break
10:30
The “Cell Search” Circulating Tumor Cell Assay: A Prognostic and Predictive Factor For Breast Cancer
Herbert Fritsche, Professor and Chief, Clinical Chemistry; Chairman, Scientific Advisory Board, MD Anderson Cancer Center; Health Discovery Corporation
The current and well-accepted hypothesis of cancer metastasis suggests that tumor cells are released into the blood and circulate until they are either eliminated by host response mechanisms or until they find a “friendly” environment in which to reside and proliferate. Thus, the detection of circulating tumor cells may represent an early indication of micro-metastasis or of aggressive tumors which are able to shed cells into the blood. Detection methods based on RT-PCR of specific tumor marker genes performed on whole blood specimens have been controversial for several reasons. The lack of tumor or tissue specificity of the selected genes coupled with the high sensitivity of PCR leads to false positive test results for the whole-blood, RT-PCR approach. These criticisms have led to interest in isolating epithelial cells in the blood using antibody labeled magnetic beads, either in positive or negative selection schema. After the circulating tumor cells are isolated, they may be characterized by immunohistochemistry and counted. Alternatively, these cells may be characterized by gene expression analysis using RT-PCR. Recently, the first of these approaches (Veridex Inc, Cell Search Assay) has been cleared by the United States Food and Drug Administration for use as a prognostic test in metastatic breast cancer patients. In these cases, the pre-treatment presence of tumor cells is prognostic of a poor outcome. And, the presence of tumor cells at the end of the first course of chemotherapy, is predictive of treatment failure. Thus, the test may permit the oncologist to make an early decision to discontinue first line therapy for metastatic breast cancer and pursue more aggressive alternative treatments. Current studies are underway to confirm the usefulness of CTC measurements in breast cancer patients who have late-stage disease, and to assess the clinical utility of circulating cell measurements of patients with early stage cancers of the breast and prostate. We have addressed the practical aspects of routine testing for CTC’s using the Veridex Cell Search method. We have established the long-term precision of the method CV=18% at a mean value = 44 cells and by recovery of added cells (recovery = 80-90% at 5-10 added cells). We have also confirmed the stability of CTC’s in the Cell Save tube for up to 3 days at room temperature. One data continue to demonstrate the prognostic value of CTC measurement for breast cancer patients. In a study of 124 metastatic breast cancer patients, those with negative CTC had a median overall survival of 28.3 months, while those with positive CTC had a median survival of only 12.8 months. The Veridex Cell Search system provides a reliable assessment of CTC and it’s use in the clinical management of breast cancer.
11:00
On-Chip Diagnostic Immunoassays of Tumor Specific Autoantibodies for the Early Detection of Cancer
Michael A. Tainsky, Ph.D., Professor of Cancer Genetics, Director, Program in Molecular Biology and Genetics, Karmanos Cancer Institute
The humoral immune response is an exquisite biosensor of novel proteins expressed by tumor cells. Panels of tumor antigens could provide a sensitive and specific multianalyte immunoassay for the presymptomatic of cancer. The development of early detection tests for cancers has previously depended on single biomarker molecules. Using a high-throughput cloning method, a panel of epitopes/antigens that react with autoantibodies to tumor proteins in the serum of patients with cancer have been isolated. The binding properties of these serum antitumor antibodies on microarrays and advanced bioinformatics tools led to a panel of diagnostic antigens. The sequences that were identified using high-throughput phage display cloning technology have led to the discovery of novel disease-related proteins. There are numerous advantages of employing serum antibodies as the analytes, not the least of which is the ability to readily adapt these assays to standard clinical platforms.
11:30
Multi-ethnic Comparisons of Genome-wide Alterations in Breast Cancer Using Paraffin Embedded Samples
Lisa Baumbach-Reardon, Ph.D., Associate Research Professor, Director, Molecular Genetics, The Dr. John T. MacDonald Foundation Center for Medical Genetics, University of Miami
Approximately 178,000 US women will be identified with invasive breast cancer (BC) this year; about 41,000 will die from the disease. It is recognized that ethnic-specific disparities in stage of presentation/survival rates exist in BC patients. These disparities remain an enigma. To investigate a possible genetic basis, we are extending our study of genomic changes in BC samples from African-American (AA) women to a multi-ethnic cohort consisting of 20 each African-American, Hispanic and non-Hispanic white (Cauc) women matched for age of diagnosis, cancer stage, and hormone receptor status. Tissue samples are evaluated for gene expression differences, as well as DNA copy number (CNV)/chromosome alterations by CGH arrays. After successful completion of a pilot study to test feasibility of using paraffin embedded tissue (FFPE) samples from three AA and three Cauc BC pathology specimens, we have embarked on the larger three ethnic cohort study. We present here results of our initial study focusing on triple negative (ER-/PR-/Her2-) patients. Pathology specimens were freshly cut from FFPE blocks and marked by a pathologist as to normal versus tumor tissue. Almac Diagnostics isolated RNA, generated labeled cDNA, and hybridized tumor and normal cDNA to Almac Diagnostics proprietary Breast Cancer DSA Research Tool. To date, 18 triple negative cases have been studied - five AA, four Cauc and nine Hispanic patients. Each patient had self matched gene expression studies (tumor vs. normal). A main goal of this study was to identify the differentially expressed genes between the tumor and normal that are common or unique among the three ethnic groups. Using the FFPE samples, approximately 17516 transcripts (~30%) were expressed on the Breast Cancer DSA with intensity significantly higher than background. Thirty percent is a significantly higher than average proportion for FFPE tissues (average usually 20-25%). For the normal tissue samples, 9399 transcripts were detected in all three ethnic groups, while in tumor tissue samples, 10,296 transcripts were detected. There were also selected transcripts (hundreds to a thousand) that were detected in one or two ethnic groups only. Using two-way ANOVA (disease state and ethnicity) and a p-value cutoff of 0.01, a subset of 6479 highly consistent/significant genes were selected and further used in data quality control. Data QC indicated patient samples clustered well with respect to both ethnicity and normal versus tumor tissue. Additional methods of analysis included K-mean 2-Dimensional clustering and Principal Component Analysis. From these analyses of this limited sample set, we have already identified ethnic-specific expression patterns in tumor specimens. We are mapping clusters of differentially-expressed genes into pathway analysis. Our immediate plan is to extend this study to the full 60 sample cohort, as well as to assess CNV by CGH arrays. It is our hope that the completed study will result in an increased understanding of the biological basis of ethnic-specific BC disparities, leading ultimately to individualized, ethnic-specific diagnostic and therapeutic approaches.
12:00
An Array of Opportunities: Functional Protein Microarrays for Cancer Biomarker Discovery
Dawn Mattoon, ProtoArray R&D Manager, Invitrogen
Cancer presents a complex pathoetiology that is increasingly being addressed through proteomic systems biology approaches. Functional protein microarrays represent an important new discovery tool that enables cancer biomarker discovery at an unprecedented pace. The ProtoArray Human Protein Microarray v4.0 is comprised of approximately 8,000 human proteins arrayed in an addressable format suitable for use in a variety of biomarker discovery applications. Protein microarrays have been successfully applied to investigate the circulating antibody profile in several disease states including ovarian cancer and melanoma. To discover potential autoantibody biomarkers specific to ovarian cancer, sera from cancer patients and healthy individuals were profiled on protein microarrays, resulting in the identification of novel candidate biomarkers. Validation studies employing orthogonal technologies identified a biomarker panel that gave improved performance relative to the benchmark ovarian cancer antigen, CA-125. Protein microarray technology also has tremendous utility in profiling post-translational modifications for families of druggable enzymes. Despite their role in regulating the stability, localization and activity of protein substrates, the targets of specific E3 enzymes remain largely undefined. Protein microarrays have been utilized in proteomic in vitro ubiquitination screens employing recombinant enzymes and cellular fractions, which can be translated to the discovery of substrates for E3 ligases on a global scale.
Key Advantages of ProtoArray Technology:
• Rapid, sensitive, reproducible assay - experiment completed in hours, with ready access to clones, virus, or purified protein
• A broad range of sample types including sera, plasma, urine, and saliva can be directly profiled on the ProtoArray without the need to pre-fractionate or deplete abundant proteins using as little as 10ul of precious sample
• Full complement of high value service offerings for groups wishing to outsource ProtoArray projects
12:30
Luncheon
1:30
Differential Proteomics for Identifying Oncology Biomarkers
Aaron Kantor, Executive Director, Cell and Molecular Biology, Biomarker Discovery, PPD, Inc.
Differential proteomic profiling can be used to distinguish cancer and normal samples. Our strategy enables the detection, identification and quantification of a larger number of putative biomarkers in oncology, leading to a molecular signature of proteomic patterns, free of pre-facto bias. We apply liquid chromatography-mass spectrometry (LC-MS) with electrospray ionization for the measurement of tryptic fragments. The approach relies on linearity of signal versus molecular concentration, reproducibility of sample processing and overall spectral intensity normalization to enable quantitative comparison of multiple samples. Thousands of molecular species can be monitored with median coefficients of variation on replicates of about 15%. We will present successful case studies of the strategy, including, 1) analysis of serum and tissue from murine models of prostate cancer and 2) biomarker identification using the cerebrospinal fluid from human subjects with central nervous system (CNS) lymphoma. Approximately 80 CSF proteins were identified and found to be different in CNS lymphoma subjects and controls. Results from independent training and test studies were in strong agreement. One marker was confirmed by immunoassay and shown to potentially improve diagnosis and predict outcome.
2:00
Translating Proteomic Oncology Discoveries to the Clinic: Development of Analytical Reference Materials, Reagents, Data, and Technology Assessment/Validation
Henry Rodriguez, Ph.D., MBA, Director, Clinical Proteomic Technologies for Cancer, NCI, NIH
Proteomics technologies have revolutionized cell biology and biochemistry by providing powerful new tools to characterize complex proteomes, multiprotein complexes and posttranslational modifications. Although proteomics technologies could address important problems in clinical and translational cancer research, attempts to use proteomics approaches to discover cancer biomarkers in biofluids and tissues have been largely unsuccessful and have engendered considerable skepticism. The National Cancer Institute has taken a leading role in facilitating the translation of proteomics from research to clinical application, through its Clinical Proteomic Technologies Initiative for Cancer (http://proteomics.cancer.gov). This program is designed to accelerate the transition of proteomics technologies from basic research tools to reliable and robust clinical research platforms. This presentation outlines a strategy for the advancement of clinical proteomic technologies that perform consistently across platforms, instruments and laboratories to facilitate biomarker discovery.
• Challenges of Discovering and Validating Clinical Protein Biomarkers
o Bottlenecks to the clinical measurement of proteins
o Why so few validated protein biomarkers
o Strategies to overcoming the bottlenecks:
- Build a multidisciplinary team framework
- Refine and standardize technologies, and statistical/analytical methods
- Develop and evaluate new technical approaches
- Build a foundation of technologies; data; reagents and standards; analysis systems
2:30
How to Fast Track Biomarkers from Discovery to Validation - Leading to Clinical Implementation
Samir M. Hanash, Program Head, Molecular Diagnostics, Fred Hutchinson Cancer Research Center
3:00
Networking and Refreshment Break
Session II - Challenges to Clinical Translation of Biomarkers
3:30
Regulatory Perspectives on Cancer Biomarkers
Francis Kalush, Ph.D., Office of In Vitro Diagnostics, CDRH, FDA
4:00
Biomarkers in Different Phases of Drug Development
Scott Patterson, Executive Director, Medical Sciences, Amgen, Inc.
Biomarkers can be employed in various stages of drug development from first-in-human (FIH) studies through to post-marketed therapeutics. The reasons for their application vary as does the required assay robustness and known (or not) clinical utility. The consideration of these factors is commensurate with the stage of clinical development and what decisions the results of those assays could drive. For example, in FIH studies biochemical or imaging assays that demonstrate the molecule under investigation is modulating the target pathway (what we refer to as biochemical coverage) are important to determine that the therapeutic is acting in the manner anticipated. The development of exposure:response relationships from the results of these pharmacodynamic assays may be used to guide dose ranging studies. Both important considerations when program progression decisions are being made. Patient stratification for targeted therapeutics is also critically important, whether it be an expression profile that describes the responsive tumor type, presence of the target at appropriate levels, or mutational status of the target or key pathway elements. A range of different tools to measure the analytes are required to execute on this strategy from multiplexed protein arrays, flow cytometric analyses, to sensitive mutational analysis methods. This presentation will provide examples of the application of this strategy and the approaches employed.
4:30
Clinical Designs for Reimbursement
Neil Palmer, Vice President, Pricing & Reimbursement, RTI Health Solutions
[PANEL]
5:00
Reimbursement and Regulatory Approaches to Biomarker Discovery and Validation
Moderator: Eugene Chiu, Co-founder, Vice President, Business Development, Predictive Biosciences
5:30
Poster Session & Networking Reception
Top of the page
Day 2, Tuesday, January 15, 2008
7:30
Continental Breakfast
7:55
Review of Day One
Session III - Clinical Application and Development of Oncology Biomarkers
[FEATURED PRESENTATION]
8:00
Biomarker Application in Oncology Clinical Development
Michael M. Shi, Director and Biomarker Project Leader, Exploratory Oncology Development, Novartis Pharmaceutical Corporation
This talk will discuss the application of biomarkers to address the following key challenges and opportunities in developing novel targeted cancer therapeutics:
- To verify the impact of novel drugs on targets/pathways by monitoring pharmacodynamic biomarkers
- To evaluate molecular response as an early clinical efficacy read-out
- To increase drug development predictability
- To give the right drug to the right patients at the optimal dose
8:45
Utilizing Urinary Protein Biomarkers for Managing Cancer Survivors
Anthony P. Shuber, Chief Technical Officer, Predictive Biosciences
With increasing cancer therapeutic efficacies and the development of better methodologies for early detection, the cancer survivor population has been growing steadily over the years. Currently 3.5% of the US population is made up of cancer survivors. In addition to the risk of having a recurrence of their primary cancer, these patients also have an increased risk of developing a secondary cancer. To date, due to the increased risk of this patient population, and the need for monitoring methodologies with high performance characteristics, more costly and complex diagnostic procedures generally reserved for diagnosing symptomatic patients have been used for recurrence monitor. However, as this patient population grows, there is a clear need for the development of more cost effective clinical algorithms and assays that would result in more efficient management of cancer survivors. Matrix metalloproteinases are a family of zinc-dependent endopeptidases that have been shown to be key regulators of tumor growth and metastasis formation. Detection of matrix metalloproteinases (MMPs) in the urine of cancer patients has been shown to correlate with disease status in a variety of cancers. Numerous studies have now shown that, in particular, biologically active MMP-2 and MMP-9 are found at higher frequency in the urine of cancer patients than in the urine of normal, age-match, sex-matched controls. Currently, we are developing a non-invasive diagnostic assay utilizing urinary MMPs, as monitors of disease-free status and cancer recurrence in bladder cancer. Initial studies using urinary levels of MMP-2 and MMP-9 to discriminate disease-free patients from those with bladder cancer resulted in approximately 86% (24/28) sensitivity and 84% (169/202) specificity at a fixed protein level. In addition, we have incorporated a novel analytical algorithm called Clinical Intervention Determining Diagnostic (CIDD), which results in extremely high (~100%) Negative or Positive Predictive Value. Further validation of these results and full development of a clinical test to monitor for bladder cancer recurrence are currently underway.
9:15
Development and Clinical Validation of a Prognosis Biomarker of Breast Cancer
Ginette Serrero, Ph.D, CEO, A & G Pharmaceuticals
The development of targets that have therapeutic and diagnostic applications called theranostic is of increasing importance in Oncology. A&G Pharmaceutical has developed a biological approach to identify and develop novel target for breast cancer. The selection of biomarker suitable for driving novel diagnostic development necessitates examining biological parameters of the target during the discovery and validation phases of development. A case study will be presented to illustrate the importance of this process for clinical applications of the biomarker.
9:45
Development of a Novel Ovarian Tumor Triage Test
Eric Fung, Vice President and CSO, Vermillion, Inc
Proteomics offers the potential for discovering biomarkers that may be useful in a variety of clinical applications, including cancer detection, recurrence monitoring, and prediction of treatment response. Despite the tremendous amount of resources devoted to discovering biomarkers using proteomics, none of these candidate biomarkers have yet to be used clinically in ovarian cancer. This is in large part due to the combination of pre-analytical factors, such as demographic biases and the heterogeneity of the disease, and analytical factors, such as the complexity of the proteome. We have used proteomics approaches to derive a marker panel of 7 biomarkers that improve the positive predictive value of discriminating benign from malignant ovarian tumors. This panel has been validated in patients from multiple institutions and in both retrospective and prospective series. These results suggest that the markers may be robust enough for clinical utility. A subset of these markers has been demonstrated to consistently help in detecting early stage ovarian cancer.
10:15
Networking and Refreshment Break
[FEATURED PRESENTATION]
10:45
Biomarkers for Clinical Decisions in Phase I/II Trials at AstraZeneca
Joseph Paul Eder, M.D., Senior Director, Clinical Research Discovery Medicine, Oncology, AstraZeneca
11:30
Integration of a Companion Diagnostic Strategy into Oncology Drug Development: Phase II Ovarian Cancer Trials of Pertuzumab, a HER2 Dimerization Inhibitor, as a Case Example
Lucas Amler, Ph.D., Director, Molecular Diagnostics, Genentech, Inc.
12:00
Luncheon
1:00
Visualizing the Chemical Content of Individual Cells
James Felton, Ph.D., Senior Bioscientist; Associate Director, Lawrence Livermore National Laboratory; UC Davis Cancer Center
Time of Flight Secondary Mass Spectroscopy uses an ion beam to raster across individual cells and tissue. The million data points acquired from 50,000 mass spectra for each cell allows for chemical identification and statistical differentiation of cell types and cancer stage. Paraffin embedded tissue works well with this method. This method has the potential to add a whole set of chemical biomarkers to be used in early diagnosis and prognosis.
1:30
Oncotype DXTM Breast Cancer Assay: Lessons Learned from 3 Years on the Market
Gary Palmer, Senior Director, Medical Affairs, Genomic Health
The Oncotype DXTM Breast Cancer Assay has been commercially available for almost 3 years and has now been ordered by over 7,000 physicians who in aggregate have ordered over 30,000 tests. To achieve such adoption over a relatively short time frame has necessitated meeting challenges in several arenas, including explaining a technology (RT-PCR) that was not well known among the target group of physicians, insuring reimbursement, and changing a treatment “paradigm” that physicians had followed for years. We will discuss some of these challenges, including what challenges were faced in the launching of a new genomic test, what questions need to be answered BEFORE a product is developed to minimize any difficulties at the time of launch, and how the field of genomic classifiers is developing and changing.
2:00
[ORAL PRESENTATIONS]
Oral Presentations from Selected Abstracts
Click here to submit an abstract (Deadline: December 14, 2007)
Session IV - Enabling Biomarkers in Cancer Drug Development
2:30
From Blockbuster to Personalized Medicine
Karol Sikora, M.D., Ph.D., FRCP, Medical Director, Medical Solutions PLC and Professor of Cancer Medicine, Hammersmith Hospital
The plethora of new drugs for cancer with well defined molecular mechanisms has led to an upsurge in molecular diagnostics. Predisposition screening, early detection, pharmacodynamic biomarkers, surrogates of clinical efficacy, response signatures and toxicity prediction are the six categories of diagnostic that will revolutionize cancer medicine. Their integration into clinical practice will be driven by the spiraling costs of cancer care and the increasing prevalence of cancer caused by its conversion into a chronic controllable illness. The era of the cancer blockbuster will be over by 2012 when all current cytotoxics become generic. New commercial provider laboratories are emerging to deliver the effective provision of diagnostic pathology.
3:00
Development of PD and Response Biomarkers for Deacetylase Inhibitor Vorinostat (suberoylanilide hydroxamic acid, SAHA, Zolinza™)
Andrey Loboda, Ph.D., Molecular Oncology Profiling, Merck Research Laboratories
Vorinostat is a histone deacetylase inhibitor approved for treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies and is under evaluation for the treatment of several other hematologic and solid malignancies. We assessed vorinostat-induced gene expression changes in PBMC specimens collected in a Phase I pharmacokinetic/ pharmacodynamic trial in patients with advanced, refractory cancer. PBMCs were collected pre-dose and 2, 4, 8, 14, and 24 hr after a single 400-mg oral dose of vorinostat. Changes in gene expression and histone acetylation were evaluated. Acetylated histone H3 accumulated in PBMCs 4 to 14 hours post-dose with maximum accumulation occurring between 4 and 8 hours post-dose. Significant differential gene expression relative to pre-dose was observed at each time point with a peak number of differentially expressed genes at 8 hrs post-dose. Classification of treated versus untreated PBMC samples using biomarkers derived from vorinostat response data in a panel of human lymphoma cell lines (pre-dose vs. 2-8 hr post-dose) was 100% accurate for samples collected at 2-8 hr post-dose. The major pattern of changes in gene expression exhibited the following time course: A rise in amplitude from 2 to 8 hr, peaking at 4 to 8 hr, and then reversing at 14 to 24 hr with a trend back towards baseline at 24 hr. A large set of genes follow this pattern with prominent downregulation of MYC and upregulation of GADD45B, PUMA, and ABCB1. At 2 to 8 hr post-dose this pattern correlated with increased histone acetylation, which also peaked at 8 hr post-dose. In addition to the major pattern of gene expression changes, which were similar across clinical and preclinical samples, significant regulation of cytokine protein expression was observed in the clinical data set. Upregulation of the Th1 cytokine, interferon gamma, and downregulation of the Th2, cytokine IL4, appeared early post-dose, peaked at 4 to 8 hr and was maintained 14 to 24 hr post-dose. Several gene expression signatures were developed from preclinical models as biomarkers for clinical response to vorinostat. The signatures were evaluated in peripheral blood mononuclear cell (PBMC) specimens from a Phase I study of oral vorinostat in patients with advanced leukemias or myelodysplastic syndromes (MDS). The following three gene expression signatures in PBMCs were shown to be predictive of clinical improvement or response for the AML patients. First, a positive prediction trend was observed when a preclinical 40-gene resistance prediction signature was evaluated in baseline (pre-dose and first day of dosing) AML PBMC specimens. If this trend is maintained in pretreatment samples of a larger patient population, it may allow for exclusion of up to 50% of non-responders from future clinical trials. Second, a similar prediction of resistance was obtained based on expression levels of known reactive oxygen species scavengers that were overexpressed in patients showing clinical improvement relative to patients without clinical improvement, indicating that cellular ability to withstand oxidative stress may be protective with respect to vorinostat exposure. Further evaluation of changes in gene expression profiles following treatment with vorinostat in advanced solid and hematologic malignancies and validation of these findings are warranted.
3:30
EGFR 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 PDGFRa, PDGFRb 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.
4:00
Human Monoclonal Antibodies Against Components of the IGF Systems and Other Cancer-related Proteins
Dimiter Dimitrov, Ph.D., Sc.D., Senior Investigator, Protein Interactions, CCRNP, CCR, NCI-Frederick, NIH
Monoclonal antibodies (mAbs) are currently perhaps the most promising biotherapeutics against cancer. Most of the antibodies approved for clinical use are chimeric murine/human or humanized monoclonal antibodies. Fully human monoclonal antibodies (hmAbs) contain only human sequences and presumably would exhibit less toxic and immunogenicity effects (if any) compared to chimeric and humanized mAbs. We have constructed two large (10 billion antibodies) libraries displayed on phage from cells obtained from total of 60 humans. These libraries have been successfully used for identification of a number of hmAbs against cancer-related proteins including IGF-I and IGF-II (Feng, Y., Zhu, Z., Xiao, X., Choudhry, V., Barrett, J. C., and Dimitrov, D. S.: Novel human monoclonal antibodies to insulin-like growth factor (IGF)-II that potently inhibit the IGF receptor type I signal transduction function. Mol. Cancer Ther. 5(1): 114-120, 2006). We are also currently developing fully hmAbs against other cancer-related proteins including but not limited to Her2, mesothelin, CD22, ephrinB2, DR4 and DR5. Our long-term goal is to develop clinically useful hmAbs against cancer.
4:30
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 for invited speakers!
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Deadline for Abstracts:
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Dec 14, 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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