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THURSDAY, SEPTEMBER 16

7:00 am Registration Open

8:00-8:30 Morning Coffee

 

Protein Biomarkers for Cancer

8:25-8:30 Chairperson’s Opening Remarks
Paul Tempst, Ph.D., Director, Protein Center; Member and Professor, Molecular Biology Program, Memorial Sloan-Kettering Cancer Center

 

8:30-9:00 Aminopeptidase Activities as Biomarkers for Cancer

Paul Tempst, Ph.D., Director, Protein Center; Member and Professor, Molecular Biology Program, Memorial Sloan-Kettering Cancer Center

Human cells produce 550 proteases with widely different functions. Proteases have also been implicated in disease, notably in cancer where they promote both tumor progression and suppression. Examples of proteolytic activities have been observed in recent oncopeptidomic studies whereby subsets of the serum peptidome, uniquely shaped by exopeptidase activities, provided class discrimination between patients with different types of solid tumors. In addition, proteomic and bio-chemical analyses of cultured cells indicated distinct panels of secreted exopeptidases between invasive and non-invasive cancer. Owing to their low levels in plasma, these enzymes have rarely been found in classical proteomics-based screens and therefore never evaluated as potential biomarkers. We have developed activity tests, uniquely suited to probe the altered balance of exopeptidases in the blood and urine of cancer patients, that measure de novo peptide breakdown in large numbers of samples, followed by quantitation and statistical analysis. Studies on patient samples and mouse models of cancer led to identification of single enzymes (as opposed to complex panels) that can now be individually monitored. Using the new approaches and unique sets of reagents, clinical studies are underway at MSKCC to assess potential applications for early detection of cancer and monitoring recurrence of disease.

9:00-9:30 QSOX1 as a Potential Biomarker for Cancer

Douglas F. Lake, Ph.D., Associate Professor, School of Life Sciences, Arizona State University

A peptide was identified in plasma from patients with pancreatic cancer that was not found in plasma from normal donors. This peptide maps back to the Quiescin Sulfhudryl Oxidase 1 (QSOX1) protein. Stability studies indicate that the QSOX1 peptide is stable for at least 24 hours in whole blood at room temperature in EDTA anti-coagulant. Immunohistochemistry of Pancreatic tumor sections using anti-QSOX1 antibody demonstrates overexpression of QSOX1 in tumor cells, but not in adjacent stroma or inflammatory infiltrate. Subsequent studies suggest that QSOX1 may be a marker of invasive disease.

9:30-10:00 Nanoscale Real-Time Proteomics of Cancer

Dean W. Felsher, M.D., Ph.D., Associate Professor, Division of Oncology, Departments of Medicine and Pathology, Stanford University

We have applied a novel approach to measuring protein expression and activation in nanoscale patient tumor specimens: nanoscale immunoassay (NIA) (Through NIA we can detect as little as 2 picograms of protein in fewer than 25 cells and in lysate volumes of 4 nanoliters from peripheral blood, fine needle aspirates, fluid cytology samples, and frozen archived specimens. We can quantify changes in total protein, protein activation, and relative abundance of specific phospho-isoforms from leukemia and lymphoma patients receiving targeted therapy. Importantly, we can measure over 20 different oncoproteins and their phosphorylation state, distinguish benign from malignant hema-topoietic cells, and show a novel unique protein isoforms can predict when clinical outcome in CML. Even more remarkably in solid tumors, NIA can delineate differing biological signatures between non-tumor and tumor tissue in patients and distinguish oncoprotein signature changes in tumors in response to therapeutics. Using molecular NIA we are able to measure protein signatures with clinical material obtained from minimally invasive procedures such as FNAs or blood draws which should enable us to perform diagnostics and monitoring in patients with cancer.

10:00-10:30 Networking Coffee Break

 

Biomarkers for Cancer Patient Selection

10:30-11:00 CAIX: A Biomarker for Hypoxia and a New Tool for Selecting and Monitoring Patients Receiving CAIX Targeted Therapies

Walter P. Carney, Ph.D., Head, Oncogene Science, Siemens Healthcare Diagnostics, Inc.

Carbonic anhydrase (CAIX) is a transmembrane oncoprotein with an extracellular domain that is highly expressed in a variety of cancers and induced by hypoxia. Studies have shown that the state of hypoxia correlates very well with resistance to radiation and chemotherapies and thus a biomarker for hypoxia, such as CAIX, could be important for guiding therapies. The surface location of CAIX allows quantitation by IHC, ELISA or imaging. We have developed both a CAIX IHC test as well as a CAIX ELISA test that could be used as companion diagnostic in clinical trials of CAIX targeted drugs. Quantitation of CAIX by IHC in tumor tissue and quantitation of the circulating levels of CAIX by ELISA may be used to identify patients with CAIX positive tumors for radiation/chemotherapy decisions. The CAIX hypoxia biomarker tests may also be used to select patients for CAIX targeted therapies, to monitor the efficacy of CAIX targeted therapies or to predict clinical outcomes from CAIX targeted therapies. The combination of an IHC test and ELISA test will allow continuous monitoring of patients from initial diagnosis to early detection of recurrence of CAIX positive tumors.

11:00-11:30 Drug Signaling Network-Based Biomarkers for Colorectal Cancer Patient’s Response to Cetuximab

Jae K. Lee, Ph.D., Director and Associate Professor, Biostatistics and Epidemiology, Department of Public Health Sciences, University of Virginia School of Medicine

In this study we demonstrate that drug signaling network-based biomarker prediction models can not only predict patients’ therapeutic responses but also provide more direct insight on drug signaling gene-network activities of individual patients. First, in vitro drug activity and gene expression data of 60 NCI and 106 GSK cancer cell lines were used to identify drug sensitivity biomarkers for EGFR inhibitor. Known functional biomarkers related to this drug’s molecular mechanisms of action were obtained from literature and then examined and filtered for their expression correlations with each drug activity using the above cell line data. The gene network-based model of EGFR inhibitor was then made with its 16 drug-signaling networks based on these two biomarker sets. Independent prediction scores of this model on 43 colorectal cancer patients who were treated with cetuximab and K-RAS wild were significantly associated with their clinical responses and outcomes.

11:30-12:00 pm Combination of the Biomarker TOP2A and TIMP-1 Identify the Majority of Breast Cancer Patients Responding to Treatment with Anthracyclines

Kirsten Vang Nielsen, Ph.D., Senior Principal Scientist, Research & Development, Dako A/S

HER2 (Human epidermal growth factor receptor 2), TOP2A (topoisomerase II alpha) and TIMP-1 (tissue inhibitor of matrix metalloproteinase 1) have all been identified as biomarkers that can predict the treatment outcome associated with anthracycline-containing chemotherapy. By screening for TOP2A and TIMP-1 in combination, nearly twice as many patients classified as anthracycline responsive were identified compared with using the biomarkers individually. TOP2A is measured by the FISH pharmDx™ Kit developed by Dako and TIMP-1 by IHC.

12:00-12:30 SPDEF and SPDEF Induced Biomarkers for Bridging Cancer Diagnosis, Prognosis and Drug Development

Ashwani Sood, Ph.D., Member and Assistant Professor, Oncology, Department of Microbiology and Immunology, SUNY at Buffalo, Roswell Park Cancer Institute

SPDEF is frequently over expressed during breast and prostate cancer progression. SPDEF expression is induced following activation of androgen receptor; and transfection of SPDEF enhances tumorigenicity in immunodeficient mice High SPDEF expression predicts poor overall survival in breast cancer patients and early cancer recurrence in prostate cancer patients. SPDEF expression is detected in circulating breast tumor cells. SPDEF is immunogenic and anti-SPDEF immunity delays mammary tumor development in mice.

12:30 Close of Conference