promet project as a whole [click to download as pdf]

The aim of PROMET is to elucidate the mechanisms and the signature of minimal residual disease in prostate cancer and to develop novel therapeutic approaches to prevent the development of minimal residual disease to overt metastasis. In close collaboration of basic scientists with clinical researchers the pathways of minimal residual disease are explored using functional genomics and expression profiling as technology platforms, advanced experimental models of minimal residual disease using bioluminescence, multiphoton microscopy, nanotechnology and optoacoustic technology for detection and treatment. Innovative imaging and therapeutic strategies developed by the industry and selected for their potential to enhance detection and eradicate minimal residual disease are tested in preclinical models for subsequent clinical evaluation.

The goal is to identify at least 2 signal transduction targets and to develop a diagnostic test for the detection of the presence of minimal residual disease and to define a novel therapeutic strategy for the treatment of this disease in prostate cancer. Thus, earlier detection and disease-specific treatment may decrease morbidity and mortality and ultimately have an impact on socio-economical costs.

In this targeted approach to combat minimal residual disease in prostate cancer we will pursue various levels at which we attack the malignant process and validate these at a phenotypic and functional level. We will be developing novel means of detecting and treating minimal residual disease. By integrating a variety of state of the art approaches, we aim at

• Identifying and validating at least 2 target genes for detection of minimal residual disease in prostate cancer
• Developing an integral in vivo model of minimal residual disease allowing the study of the mechanisms and signatures
• Evaluate the in vivo detection of minimal residual disease by means of nanoparticles and optoacoustics
• Developing a therapeutic strategy for the treatment of minimal residual disease in prostate cancer

 

The work of the consortium improved our understanding of the mechanisms of minimal residual disease and has led to the identification of a set of marker genes for the detection of minimal residual disease. These are currently being evaluated in retrospective clinical sample sets and prospectively in lymph nodes of patients undergoing radical prostatectomy. These results will be compared to high end imaging modalities such as diffusion weighted imaging analysis.

By means of iTRAQ proteomics 2 potential proteins of interest as potential markers have been isolated and are currently being evaluated and validated in different clinical sample sets. Taken together these data the consortium has been able to demonstrate that differential gene and protein expression of minimal residual disease exists. There is good preliminary evidence that minimal residual disease can be recognized and possibly targeted with such marker genes.

The development of different animal models addressing different issues of the problem of minimal residual disease using bioluminescence and thus significantly and drastically decreasing the number of experimental animals required for experiments has allowed to gain insight into the mechanisms and the gene expression involved. Experimental models cover hormone-sensitive prostate cancer and dormancy, which did not exist for prostate cancer until now and are important additions to the prostate cancer researchers’ armamentarium. In addition we have established a dorsal chamber metatarsal model for multiphoton fluorescent microscopy detection and quantification of micrometastases in vivo allowing to study the cellular mechanisms of homing, extravasation and implantation.

The consortium has validated the most promising markers in the literature. Results indicate a dire need of novel markers as the proposed markers did not increase prognostic and predictive information.

In close collaboration with the industry (Fukuda Denshi) we developed a novel optoacoustic instrument that allows to alternately record optoacoustic and ultrasound imaging and improved the hardware by decreasing reconstruction artifacts by different algorithms and displacement compensated averaging (DCA). These proposed methods are computationally inexpensive and make real-time imaging possible. Furthermore, we have been able to demonstrate that functionalized gold nanoparticles work as contrast agent for optoacoustics. Also in collaboration with the industry (Berthold) we have improved the sensitivity of CCD cameras for the detection of minimal residual disease, allowing to decrease the detection threshold to approximately 100 cells in vivo.

Treatment of minimal residual disease is challenging as chemotherapy aside few strategies exist. Chemotherapy can only interfere with dividing cells. As soon as cells are dormant or not proliferating, few options are available. Early treatment with bisphosphonates allows decreasing the number of metastases and the future tumor load. Further treatment approaches are being developed.

 

More information under promet publications.