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Ultra-high-resolution and ultra-sensitive fluorescence methods for objective sub-cellular diagnosis of early disease and disease progression in breast and prostate cancer



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This is the home page of a collaborative European research project that started in June 2008. Here you can read about the objectives, the scope, who are the members and what are the results of the project.




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Scope

The overall objective of this proposal is to develop and validate a quantitative, minimally invasive diagnostic tool for early and conclusive detection, diagnosis and monitoring of disease and disease progression of breast and prostate cancer, with negligible sampling-related side-effects. A methodology will be developed making use of a combination of the probably most exciting recent advances in the field of light microscopy, for fluorescence-based optical imaging of individual sample cells. It includes advances which will take the spatial resolution far beyond the fundamental limits of optical resolution, the sensitivity down to an ultimate single-molecule level, and multi-parameter detection schemes significantly increasing the fluorescence information by which these cellular images can be analysed.

Apart from detecting and identifying tumour markers in the samples, tumour-specific spatio-temporal molecular distributions within the intact sample cells will be exploited. This is to date an almost unexploited dimension of diagnostic information. By combining and supporting these novel optical methods with state-of-the-art affinity molecule biotechnology, tumour biomarkers, fluorophore chemistry, and bioinformatic validation tools, all possible means will be exploited to extract a maximum amount of information out of very small amounts of sample material. Given the high incidence of breast and prostate cancer, and the utmost importance of an early and conclusive diagnosis of these diseases, this project has a very high relevance.

Objectives

The objectives of the proposal are:

  1. To improve spatial resolution of state-of-the-art light microscopy in pathology by an order of magnitude.
  2. To improve the sensitivity of fluorescence-based imaging of FNA acquired cells to the ultimate single-molecule level.
  3. To take multi-parameter fluorescence imaging of individual FNA acquired cells to its extreme in terms of information content, largely based on photon statistical approaches and parameters extracted from non-linear effects.
  4. To develop standardised FNA-based sampling of suspected breast and prostate cancer lesions with negligible side-effects, and with optimised needle visibility for ultra-sound guided needle positioning.
  5. To select already known molecular and cyto-morphological markers that will be compatible with the developed fluorescence imaging techniques and can be highly anticipated, when investigated by these techniques, to strongly correlate with malignant transformation and clinical tumour aggressiveness.
  6. To identify existing and develop new affinity molecules to these markers, which are highly specific and fluorophore-labelled for optimised fluorescence readout properties.
  7. To refine bioinformatic evaluation and data processing to find the combination of fluorescence read-out parameters that most strongly correlate with the relevant clinical parameters and yield the strongest diagnostic reliability.
  8. To optimise the combination of techniques and procedures, in accordance with the conclusions of goal VII, to maximise sensitivity and specificity for FNA-based diagnostics of breast and prostate cancer, enabling a decisive improvement of the outcome for the patients suffering from these diseases.

Organisation

The project is organised into seven work packages Apart from the management work package, the work packages are:

  • WP1: Development of nanoscopy and transient state microscopy.
  • WP2: Development of ultra-sensitive and multi-parameter detection schemes.
  • WP3: Development of FNA, sample collection and handling, supply of cultured cells and selection of tumour markers.
  • WP4: Affinity molecule development and labelling.
  • WP5: Integration of techniques and prototype construction.
  • WP6: Clinical validation and bioinformatic evaluation.

The overall flow of activities is illustrated in the flowchart below:

Partners of the consortium

The expertise needed for this project is multidisciplinary and comprises clinical cytology, cancer proteomics, molecular biotechnology, fluorophore chemistry, fluorescence microscopy, nanotechnology, optics, solid state detector technology, data processing, and bioinformatics. The level and width of competence required cannot be found on a national level but requires a European initiative.

The consortium involves 12 partners, nine academic institutions and three SMEs:

1 (coordinator) Royal Institute of Technology, Stockholm KTH:a
KTH:b 		Sweden
2 VibraTech AB, Stockholm VITECH Sweden
3 Karolinska Institutet, Stockholm KI Sweden
4 Max-Planck- Gesellschaft zur Förderung der Wissenschaften e.V., Institute for Biophysical Chemistry, Göttingen MPIBPC Germany
5 Heinrich-Heine University, Düsseldorf HHU Germany
6 SensL Inc, Cork SENSL Ireland
7 Becker&Hickl GmbH, Berlin B&H Germany
8 Lübeck University Hospital, Lübeck LUEBECK Germany
9 University of Siegen, Siegen UNISI Germany
10 University of Turku UTURKU Finland
11 University of Helsinki UH Finland
12 Academisch Ziekenhuis Leiden (Leiden University Medical Center) LUMC Netherlands

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UP   per(at)biomolphysics.kth.se - July 5 2012