Uveal melanoma (UM) is a disease with many faces: ophthalmologists treat the primary tumor, but the patient faces the problem of developing metastases, which are often deadly after a short period.... Show moreUveal melanoma (UM) is a disease with many faces: ophthalmologists treat the primary tumor, but the patient faces the problem of developing metastases, which are often deadly after a short period. Recent insight, indicates the need for knowledge-based treatment of UM. The __pseudohypoxic__ and tumor promoting effects of bevacizumab as described in this thesis is especially relevant. Bevacizumab is frequently used off-label to treat macular edema in UM patients suffering of radiation retinopathy, without the knowledge of possible effect on still viable UM cells. We further observed that specific peptides, such as UMAP1, which can successfully be internalized by targeted UM cells, have demonstrated potential for UM-targeted treatment. These peptides have to be investigated in vivo, to ascertain whether they are a viable clinical tool. Labeling the peptides with radionuclides, and demonstrating specificity for UM cells are some of the challenges which have to be overcome. Another aspect in the patient-specific treatment of UM is the in vitro analysis of primary UM samples to predict treatment responses. In case of Dasatinib, we describe treatment responses associated with monosomy 3 and __kinase__ activity in different primary UM samples. Show less
The p53 tumor suppressor protein plays a key role in cancer and its direct or indirect inactivation is an almost universal feature of human tumors. P53 has a central position in the prevention of... Show moreThe p53 tumor suppressor protein plays a key role in cancer and its direct or indirect inactivation is an almost universal feature of human tumors. P53 has a central position in the prevention of genomic instability and protection of tumorigenesis. This thesis presents novel studies regarding the role of Hdmx in p53 inactivation during tumorigenesis, as well as the use of specific drugs for p53 reactivation as cancer treatment. Chapter 2 shows that constitutive Hdmx overexpression contributes to the neoplastic transformation of human fibroblasts and embryonic retinoblasts, thereby functionally resembling loss of p53. Chapter 3 establishes the importance of Hdmx as an oncogene in a subset of uveal melanomas. Importantly, the results described in this chapter extend the function of Hdmx beyond p53 inhibition. Chapter 4 evaluates the use of the specific p53 activating drugs Nutlin-3 and RITA in synergy studies as potential therapy for uveal melanoma. Chapter 5 is a more detailed analysis of the cellular responses to RITA. In particular, Chk2 is shown to be an essential mediator of the RITA-induced effects. Chapter 6 is a general discussion of the results presented in this thesis, and their implications for clinical exploitation and future research. Show less
This thesis describes the role of the immune system as an important phenomenon in the most frequently occurring form of eye cancer in adults, namely in uveal melanoma. We show that the immune... Show moreThis thesis describes the role of the immune system as an important phenomenon in the most frequently occurring form of eye cancer in adults, namely in uveal melanoma. We show that the immune system can be the cause of the tumor, and also plays a role in the development of a tumor, and may be an entry for therapy. In the first chapters of this thesis, we describe the phenomenon of "an inflammatory phenotype" in uveal melanoma. It appears that when this type of cancer shows more inflammation, the survival of patients decreases. A possible explanation for this observation is that one of the key players among the immune cells, the macrophage, plays an essential role in intra-ocular tumor growth. We demonstrate this in patient material, but also in experimental studies; we are able to inhibit tumor growth when we modulate the presence of macrophages. In this thesis, we also show that the immune system can be used effectively to eradicate eye melanomas in experimental models. T cell vaccination in combination with monoclonal antibodies gave promising results for treating eye cancer. Further research has to be performed to translate this into the clinic. Show less
Jager, M.J.; Ly, L.V.; Filali, M. el; Madigan, M.C. 2011
For a long time enucleation has been the treatment of choice for uveal melanoma. New treatment modalities have been developed e.g. transscleral thermotherapy (TTT), proton beam radiation,... Show moreFor a long time enucleation has been the treatment of choice for uveal melanoma. New treatment modalities have been developed e.g. transscleral thermotherapy (TTT), proton beam radiation, stereotactic radiotherapy and ruthenium application 1-3 . These treatment options offer a better chance to spare the eye. Despite new treatment options, the overall survival of patients treated for uveal melanoma did not improve. Ultimately, most patients die of metastatic disease. Therefore, there is need for an effective treatment for distant metastases. Identification of genes, proteins and pathways has started to provide some insight in the dissemination of uveal melanoma. For development of novel anti-cancer strategies, more sensitive and less invasive cancer models are required, to detect and monitor tumor growth and metastatic disease in vivo. Main objective of this thesis is the development of a new tumor model to study local tumor growth and metastatic disease and to explore tumor growth mechanisms of uveal melanoma. Show less
This thesis describes the results of genomic and proteomic analyses of uveal melanoma, aiming to define prognostic markers and/or profiles to categorize uveal melanoma and to indentify the... Show moreThis thesis describes the results of genomic and proteomic analyses of uveal melanoma, aiming to define prognostic markers and/or profiles to categorize uveal melanoma and to indentify the biological mechanism of metastatic disease of uveal melanomas. Show less
