Track 4: Bridging Silos in Biomarker Development

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Technology Showcase:
Protein Biomarkers

EMD logo11:30-11:45 am Drug-Induced Nephrotoxicity – Multiplex Detection of Key Kidney Damage Biomarkers in Rat Urine
April Livengood, Ph.D., Senior. Scientist, Immunoassays, EMD Chemicals
In 2008 the Predictive Safety Testing Consortium (PSTC), a public-private consortium led by the Critical Path Institute (C-Path) submitted a list of urinary biomarkers indicative of drug-induced kidney damage to the FDA and EMEA regulatory authorities. The FDA and EMEA have issued new guidelines on the submission of the biomarkers as indicators of kidney damage in pre-clinical studies. Rules Based Medicine worked with the members of the PSTC to develop the assays used in the kidney toxicity study, and made the assays available in the Rat Kidney MAP testing service. EMD and Rules Based Medicine have collaborated to develop these assays as commercially available kits, exclusively for the Luminex® xMAP® Technology platform, to support preclinical rat nephrotoxicity studies. This presentation will describe the assessment of temporal and dose-dependent changes in biomarker levels in response to known kidney damaging agents.

11:45-12:15 The Speed and Flexibility of Building Protein Biomarker Assays with the Peptide MRM Method Nextgen logo

Michael Pisano, Ph.D., Chief Executive Officer, NextGen Sciences, Inc.

Biomarkers are needed throughout the drug discovery and development pipeline, which means the biomarker assays need to work in different species and sample types. The translation from an animal model to the human situation needs to be available for the start of clinical studies. The Peptide MRM method is designed from the amino acid sequence of a protein. Thus, the translation of an assay from species to species is done computationally. The translation from sample type to sample type (e.g., tumor to plasma) of the same species is done experimentally. Examples of both types of translation will be included in the presentation.

Proteome Sciences12:15-12:30 Use of Isotopic Mass Tags for the Facilitated Development of SRM Mass Spectrometric Assays for Proteins and pPeptides
Malcolm Ward, Ph.D., Research Head, Proteome Science Lab, King's College
The true value of proteomics in healthcare is its quantitative nature. However, until recently the link between biomarker discovery and precise quantitation of targeted proteins has been slow, expensive and rife with failure. Learning from the small molecule world, isotope dilution assays linked to Selective Reaction Monitoring (SRM) is increasingly used for the quantitation of peptides and proteins. One drawback of this approach is the need to synthesise isotope-doped versions of the target peptide. For many biomarker candidates this may be difficult or impossible, due to post-translational modifications. To overcome this limitation Proteome Sciences has developed isotopic versions of its proprietary TMT® reagents to differently label sample and standard. The TMT-SRM method therefore allows use of either synthetic or natural reference standards and thus quickly and economically establish assays for any peptide or protein in a given sample material. Furthermore, because isotopic TMT’s are identical in structure to isobaric TMT’s there is minimal set up time or costs when moving from biomarker discovery to assay qualification and validation. Proteome Sciences is the only company to offer this novel method as part of their PS Biomarker Services. 

12:30-2:00 Lunch on your own

Plenary Keynotes

2:00-2:30 Use of Biomarkers and Translational Science to Accelerate and Improve Oncology Drug Development: Opportunities and Roadblocks

J. Carl Barrett, Ph.D., Vice President and Global Head, Oncology Biomarkers and Imaging, Oncology Translational Medicine, Novartis Institutes of BioMedical Sciences, Inc.

The steps in oncology drug development in patients include: optimizing dose-schedule, predicting patients that will respond, detecting tumor responses rapidly for proof-of-concept trials, using surrogate endpoints for disease monitoring, assuring safety of drug therapy, and developing rational-based combination therapies. Biomarkers are pivotal in meeting each of these challenges. A general strategy for using biomarkers in oncology drug development will be presented and includes: having a systematic biomarker plan for each new agent that is consistent, science-based and focused using common standards for assays and data; building a biomarker tool kit with analytically and clinically validated biomarker assays; building on clinical experience (positive and negative) and execution excellence involving a team effort (physicians, clinical staff, biomarker experts and data management) and building a strong partnership between Novartis and its clinical investigators.

2:30-3:00 Enabling Personalized Medicine through Application of Biomarkers in Clinical Development

Nicholas C. Dracopoli, Ph.D., Vice President, Biomarkers, Centocor Research & Development, Johnson & Johnson

The observer effect describes the changes that the act of observation will make on the phenomenon being observed and has many applications in the physical and experimental sciences. In drug development, if we consider biomarkers as the observer and the clinical trial as the phenomenon, we can ask how the process of analyzing biomarkers impacts the clinical trial process. It is clear that the simple act of collecting biopsies, let alone completing complex bioanalytical studies of these samples, impacts the ability to run clinical trials quickly and economically. Consequently, it is necessary to demonstrate that the value derived from the observation exceeds the cost to the phenomenon. This presentation will discuss how different types of biomarkers can be used during the drug development process to increase probability of success in the successive stages of drug discovery and development, and support decisions for further investment in subsequent development phases. Several examples of biomarker applications to confi rm mechanism of action, explore PK/PD interactions and to derive predictive markers in ongoing drug development programs will be described.


3:00-4:00 Networking Refreshment Break with Poster and Exhibit Viewing


Protein Biomarkers for Cancer Targeted Therapy

Chairperson's Opening Remarks

Lance A. Liotta, M.D., Ph.D., Professor, Life Sciences, Department of Molecular and Microbiology; Co-Director, Applied Proteomics & Molecular Medicine, George Mason University, College of Arts and Sciences

4:00-4:30 Towards a More Efficient Protein Biomarker Development Process

Henry Rodriguez, Ph.D., M.B.A., Director, Clinical Proteomic Technologies for Cancer, Center for Strategic Scientific Initiatives, Office of the Director, National Cancer Institute

CPTC’s initiatives are paradigm shifting in that they aim to develop a more refined, efficient, and reliable biomarker discovery process. These pipelines are anticipated to produce better credentialed candidate leads, ultimately accelerating the discovery of new cancer biomarkers for diagnostics and prognostic purposes.

4:30-5:00 Use of Activated Protein Pathway Biomarkers at the Bedside: Realizing the Promise of Personalized Therapy

Lance A. Liotta, M.D., Ph.D., Professor, Life Sciences, Department of Molecular and Microbiology; Co-Director, Applied Proteomics & Molecular Medicine, George Mason University, College of Arts and Sciences

Recently, whole genome mutational scanning analysis of a number of solid tumors has revealed that cancer is a protein pathway disease at the functional level. However, since genomic and transcript profiling likely cannot alone sufficiently predict protein pathway activation in each patient’s tumor, and it is these signaling pathways that represent the targets for new molecular guided therapeutics, it is critical that we begin to define human cancer at a functional pathway activation level. Post-translational modification such as phosphorylation drive and underpin nearly all cell signaling processes that are aberrantly activated in cancer and are epigenetic events, and not necessarily directly predictable using genomic approaches. Thus, the promise of proteomics resides in the study of molecules that are not just predictive or prognostic factors, but extend beyond correlation to causality. We have invented a new type of technology, called reverse phase protein microarrays, to generate a functional map of known cell signaling networks or pathways for an individual patient obtained directly from a biopsy specimen. This patient-specific circuit diagram provides key information that identifies critical nodes or pathways that may serve as drug targets for individualized or combinatorial therapy through the quantification of phosphorylation states of proteins. The identification of activated networks on a patient-by-patient basis can be used as both a diagnostic and a therapeutic guide to patient selection and stratification.

5:00-5:30 Towards Renal Cell Carcinoma Biomarker Discovery using Personalized Oncoproteomics

Josip Blonder, M.D., Senior Research Scientist, Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick/NCI Frederick

It became obvious that personalized medicine may improve the outcome of a patient diagnosed with cancer. So far, the translation of proteomic assays to applicable diagnostic and/or prognostic tests in clinical oncology has been disappointing. Therefore, personalized oncoproteomic approaches facilitating identification of tumor proteins in peripheral blood of an individual diagnosed with cancer are critically needed. Here, we describe a proteomic approach for cancer biomarker discovery that relies on concurrent profiling of peripheral pre-operative plasma specimens along with tumorous and normal adjacent kidney tissue obtained during a surgery from a single patient diagnosed with non-metastatic renal cell carcinoma. Multidimensional subtractive personalized oncoproteomics coupled with rigorous bioinformatic data processing resulted in a panel of eight biomarker proteins implicated in RCC biology of the patient under the study.

5:30-6:00 MRM and iMALDI for Protein Biomarker Discovery and Validation

Christoph H. Borchers, Ph.D., Director, Biochemistry & Microbiology, University of Victoria Genome BC Proteomics Center

For protein biomarker discovery and validation two mass spectrometry centric approaches – Multi-Reaction Monitoring (MRM) and immuno-MALDI (iMALDI) – have great potential since these approaches are rapid, highly specific and enable absolute and multiplex protein quantitation. The University of Victoria – Genome BC Proteomics Centre has developed a 45 protein MRM-assay for validation of numerous cardio-vascular disease (CVD) biomarkers in human blood plasma and developed iMALDI approaches for the clinic. We applied the MRM-assay in a medium scale project analyzing 60 blood samples in triplicate verifying four proteins that are distinguishable between different CVDs. The combined approach of the immuno-enrichment of peptides followed by MALDI-MS (iMALDI) has been developed into a clinical assay for hypertension. This iMALDI technique will replace the currently used radio-immunoassay in a Vancouver hospital due to its higher specificity, speed, accuracy and sensitivity at lower cost.


6:00 Close of Day