Program leaders

• Prof. G.A.M.S. van Dongen, PhD (Otolaryngology/Head and Neck Surgery + Nuclear Medicine & PET research)
• Prof. O.S. Hoekstra, MD, PhD (Nuclear Medicine & PET research)
• C.R. Jimenez, PhD (OncoProteomics Laboratory, Medical Oncology)
• Prof. C.L. Verweij, PhD (Pathology)
• T. Würdinger, PhD (Neurosurgery)

Description

The VUMC CCA program 3 covers fundamental and translational research to identify new determinants for diagnosis, prognosis and tailored treatment for immunological and oncological diseases. Program 3 is subdivided in three disease oriented research lines:

1. Solid tumors
2. Hematological malignancies
3. Chronic inflammatory diseases

The emerging and rapidly growing fields of molecular imaging and genomics provide new opportunities to unravel the unique biology of a specific disease in a specific patient. Integrating imaging and global molecular information with clinical data will allow for a model that may yield tremendously valuable indicators for the individual patient to personalize diagnosis and predictions. This program is a key connection in the line: target discovery - ligand development - molecular imaging – molecular diagnostics- molecular targeted therapy

Solid tumors, hematological malignancies and chromic inflammatory diseases

• In all 3 research lines, modern state-of-art CT and MRI-machines enable imaging of anatomical details with high precision. In addition, imaging techniques like SPECT, PET, PET-CT and MRI provide, non-invasively, unique molecular and biological in vivo information at the tissue level (“molecular imaging”). For this purpose novel reporter probes will be developed and evaluated in (pre)clinical studies making use of the unique facilities (cyclotrons, GMP facilities, animal and clinical PET- and MRI-machines) and expertise available at the campus.
• Genomics and proteomics have emerged as global tools to measure genetic variation and gene expression at several levels ie., from a gene‘s primary structure to its protein products and their role in the biology of the organism. The VUmc Microarray-facility offers high resolution oligonucleotide arrays, CGH arrays and massive parallel sequencing for human and mouse studies. These genomic methods are increasingly being applied in studies to improve criteria for disease classification, such as for colorectal, lung and head and neck cancer, lymphoma and other malignancies, and in chronic inflammatory diseases such as rheumatoid arthritis.
• The OncoProteomics Laboratory employs high resolution mass spectrometry-based proteomics to enable biomarker discovery and validation in cancer cells, tissues and biofluids.
  Expertise includes:
  1. Protein expression profiling by robust and flexible label-free discovery workflow; 
  2. Candidate-based targeted mass spectrometry for multiplexed, antibody-free biomarker validation; 
  3. In-depth protein profiling of cells and tissues, organelles/subcellular compartments (eg., exosomes, cell surface, sub-nuclear compartments, secretome), biofluids (sputum, cerebrospinal fluid, stool), platelets;
  4. High-throughput biofluid peptide profiling for pattern diagnostics; 
  5. Kinome profiling and phosphoproteomics;
  6. Mining high-dimensional proteomics data. These approaches are being applied to develop novel biomarkers in the context of cancer screening (colon cancer, lung cancer) and to enable personalized treatment (various solid tumors, AML). 
• The glycoimmunology group at the Dept. of MCBI provides expertise in glycan profiling (glycomics) using mass spectrometry.
• It is the promise of high-throughput analyses that patterns of transcripts, proteins, post-translational modifications and/or metabolites can be used to define “molecular signatures” of different forms of the disease, as well as different stages in the clinical progression. The patterns that are generated with this integral approach, termed systems biology, provide insight into the processes that take place in a cell.

Research highlights within period 2006-2010

1. Identification of peripheral blood biomarkers to predict responsiveness to TNF-blockade in rheumatoid arthritis
2. Identification of peripheral blood biomarkers to predict responsiveness to IFN-beta therapy in multiple sclerosis
3. Gene signatures implicated with a 4-fold increased risk to develop arthritis in autoantibody positive arthralgia patients
4. Identification DNA copy number profiles associated with response to drug therapy in advanced colorectal cancer
5. Development of immuno-PET with long-lived positron emitters 124I and 89Zr for navigation of antibody development and clinical applications: European distribution of technology.
6. Development of TKI-PET (PET with Tyrosine Kinase Inhibitors radiolabed with 11C or 18F) for navigation of TKI development and clinical applications.
7. Development of PET and optical tracers for SN and tumor detection.
8. Development of nanobody technology for targeting critical growth factors and their receptors: perspectives for imaging and therapy
9. Identification of novel protein biomarkers for non-invasive early detection of colorectal cancer
10. Serum peptide mass spectral signature with prognostic value in NSCLC
11. Protein signature for identification of homology repair deficient breast tumors with diagnostic and prognostic value
12. Novel biomarkers for colon cancer screening
13. Implementation and standardization of PET: clinical practice and trials
14. Monitoring response using FDG, H2O PET scanning and DCE-MRI during treatment with EGFR and VEGF inhibitors in NSCLC

Perspectives

Within the next five years we foresee the discovery of targets for, and development and (pre)clinical evaluation of several new SPECT and PET tracers for diagnosis, staging, treatment planning and response evaluation as well as the exploitation of PET, PET-CT,MRI and PET-MRI imaging in the development of novel therapeutics. The innovative technologies described above should contribute to further individualization of treatment, e.g. by more accurate staging, prognostication and therapy response monitoring. In recent years, we and others have introduced and validated the sentinel node biopsy (a combined procedure of imaging, taking biopsies and morphological evaluation) which proved to be an important improvement within TNM staging. The multidisciplinary infrastructure developed for breast cancer and melanoma has now been extended to head and neck cancer, gastrointestinal and gynecological tumors, using the local expertise in ultrasound guided aspiration cytology and laparoscopic surgery.

The novel molecular imaging techniques have promise to step beyond the classical TNM-paradigm. To this end, we aim to optimize the use of genomics and proteomics technology to reach a molecular signature of disease subtypes e.g. in colon, head and neck and lung cancer, lymphoma, and other malignancies, and in chronic inflammatory disease such as rheumatoid arthritis. In addition, we aim to translate protein candidate biomarkers into non-invasive routine antibody-based assays. The available expertise will allow for integrated application and assessment of imaging, sampling and profiling. Promising applications will be evaluated with respect to their clinical relevance and (cost) effectiveness. Efforts will be put on forming a link between molecular profiling and molecular imaging. Molecular profiling by genomics and proteomics will contribute to identification of relevant disease markers and targets. These markers will yield new molecular tests and the targets can be exploited in the development of disease specific contrast agents (e.g. using monoclonal antibodies, peptides or small molecules) for imaging as well as for therapy. Combined molecular profiling – molecular imaging approaches will be applied in several tumor types, e.g. colorectal, head and neck, lung, lymphoma and other malignancies, and in chronic inflammatory disease.

Imaging will contribute to increased insight in tumor biology and pathophysiology, e.g. by pharmacokinetic and dynamic PET analysis. Also molecular interactions can be confirmed and elucidated, which might be of particular value in the development of new cutting-edge therapeutic agents like monoclonal antibodies, peptides and small molecules that target the root courses of the disease. Emerging imaging innovations that are candidates for large-scale clinical application will be further evaluated with respect to their (cost) effectiveness in clinical practice, as is presently done with several PET applications.

Summary of the research aims for the coming 5 years

Information on disease biology must be enhanced to facilitate the development of disease specific diagnostic and therapeutic approaches. Opportunities can be found (but are not restricted) in the following areas:

1. Application of methods to measure DNA (e.g. maCGH,and deep sequencing) and expression profiles (e.g. expression arrays and proteomics) in pathological and healthy tissue, or surrogate tissues like blood, urine and faeces. This approach aims to identify disease signatures, markers and targets. These markers and targets will be exploited for the development of molecular tests and tracers for imaging. Alternatively the cell type can be identified.
2. For the aforementioned aim, SOPs have to be developed for banking of tissues, blood, saliva, and feces.
3. Characterization of molecular signatures of tumors (precurser lesions, established tumors, metastases) or immunological diseases, which are of value for selection of the proper therapeutic intervention.
4. Definition and integration of molecular profiles at various stages of development and progression, to provide a comprehensive view of the pathways involved in pathogenesis.
5. Definition of tumor/pathogen and host interaction.
6. Validation of the predictive value of various biomarkers using either tissues (see above), body fluids or images of well defined patient groups who had well-defined therapy with accurate follow-up.
7. Development of novel in vivo imaging tools enabling non-invasive biological and molecular disease characterization for individual patients. For example for early response monitoring or for prediction of poor response upon therapy (e.g. hypoxia and angiogenesis in case of cancer therapy) or for evaluation of the specificity of targeted drugs. Disease-specific contrast agents and software tools for quantification will be developed.
8. Initiation of clinical studies with molecular targeting agents to validate molecular targets, by taking tissue samples and or imaging, and to predict the efficacy of a given therapy.
9. Initiation of clinical studies with targeted mass spectrometry and antibody-based methods to assess the biomarker potential in body fluids of disease-related proteins and to establish values for sensitivity and specificity.

Collaboration

In and outside VUmc:

Projectleaders with projects in program 3 are based at several departments in the VUMC: Pathology, Otolaryngology/Head & Neck Surgery, Nuclear Medicine & PET Research, Molecular Cell Biology, Rheumatology, Hematology, Medical Oncology, Pulmonology, Gastroenterology, Radiology, Gynecology. Bilateral collaborations with leading national and international research groups have been established in the fields of genomics, proteomics, and molecular imaging. In these fields VUmc also participates in many strategic consortia (STW, TIPharma, CTMM, EU and NCI programs). In addition, many collaborations and preferred partnerships exist with leading innovative industries in the fields of molecular diagnosis, molecular imaging, and molecular targeted therapy.

Means

Research within VUMC CCA program 3 requires availability of various technology platforms, i.e. presence of state-of-the-art facilities and know-how. The following technology platforms are available, or planned to be available and in active operation within the coming year:

1. Microarray-facility that includes massive parallel sequencing
2. OncoProteomics Laboratory
3. Functional genomics unit
4. (molecular)Imaging facilities
5. Tissue microarray facility
6. Human monoclonal antibody phage display facility
7. Bio-informatics support

The technology platforms are organized as user-groups. For each facility a business plan has been made. For optimal use of capacity, an inventory is made of projects planned for each facility. Program 3 of VUMC CCA takes care for optimal use of these facilities, and if required the particular user-group will be contacted. In addition, projects making use of the facilities will be reviewed at a regular basis.