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Title: Epithelial Ovarian Cancer: molecular and clinical predictors for platinum resistance
Other Titles: Epitheliaal ovarium carcinoma: moleculaire en klinische predictoren voor platinum resistentie
Authors: Cadron, Isabelle; S0038793
Issue Date: 9-Mar-2012
Abstract: Most patients with ovarian cancer are still diagnosed in advanced stage disease needing intensive therapy with debulking surgery and chemotherapy. However, 25 % of patients will progress during or will relapse within 6 months of the primary therapy. These patients are called the platinum resistant patients. Unfortunately there are not many therapeutic options for this group of patients available. This doctoral thesis was performed in an effort to identify platinum resistant patients at diagnosis by searching for molecular and clinical predictors for platinum resistance. In this way the burden of a cytotoxic therapy compromising bone marrow reserve and quality of life could be avoided and targets for more individualised therapy could be found. Proteins represent the actual functional molecules in a cell and when a mutation occurs at the DNA level, it is the protein that ultimately will be affected. Therefore the study of the proteome, meaning the entire protein content produced by a cell during its life cycle, can help us to detect changes occurring during a particular disease process. Challenges in proteomic studies in blood are the presence of high abundant proteins masking the detection of the low concentrated ones, inter- and intra-individual differences and the need for prospectively and well controlled collected samples. Therefore we took part in a European consortium, the OVCAD study, where biological samples of ovarian cancer patients were prospectively collected according to a strict protocol. In this way we were able to collect a substantial number of samples in a relative short study period. In an attempt to minimise variation in protein content and to improve the probability of finding an ovarian cancer specific marker we decided to perform proteomic analysis on tumor tissue biopsies. Moreover, as ovarian tumor tissue biopsies consist of a heterogeneous amount of cells, we preferred to work with laser microdissected ovarian cancer cells. In the molecular part of this thesis, we firstly identified current problems and obstacles in proteomic studies and subsequently defined a protocol to combine laser microdissection and SELDI-TOF MS analysis in ovarian cancer tissue to achieve robust protein profiles. We demonstrated that changes in sample handling have influences on the protein profile and that strict protocols are necessary to obtain reliable results.Using this protocol we performed a first analysis on LMD ovarian tumor tissue of platinum sensitive vs. resistant patients. Based on the obtained profiles we determined that CM10 and IMAC30 were the ProteinChip surfaces of interest to be used further SELDI-TOF MS analysis.This model was then applied on the prospectively collected OVCAD samples and a prediction model was build to classify patients according to platinum sensitivity. Furthermore, we were able to confirm differentially expressed peaks in the lower molecular mass range between platinum resistant and sensitive patients. One of the upregulated peaks in patients with platinum sensitive disease with an m/z value of 2885 Da, could be identified as Histone H2B type 1-D (H2B1D_Human). Histone modification is currently used in other cancers as target for therapy and this finding could therefore have a clinical impact and warrants further investigation. Subsequently a validation study was performed but was not able to confirm the results of the training set. We believe other techniques such as immunohistochemistry should be considered to establish the role of Histone H2B type 1-D in the predictions of platinum resistance in ovarian cancer. In the clinical part of this dissertation, we assessed the clinical data of patients included in the OVCAD study in relation to their platinum free interval to determine clinical predictors for response. After multivariate analysis we identified the presence of peritoneal carcinomatosis, high levels of CA125 at the end of therapy and the achievement of complete remission at the end of primary therapy as the most significant factors for platinum resistance. These data could guide us in the follow-up of EOC patients who are at risk for early relapse.In a next chapter we evaluated the effect of a dose dense or weekly paclitaxel carboplatinum regimen for recurrent ovarian cancer in an attempt to overcome platinum resistance. Both regimens achieved good RR of 37% in the platinum resistant group. Toxicity varied between both schemes but was acceptable. In conclusion the molecular studies in this thesis need further investigation and might have a clinical impact in the search for targeted therapy in resistant epithelial ovarian cancer. Secondly, in the clinical part we identified patients at risk for early recurrence and we suggest that even in platinum resistant patients a rechallenge with a modified paclitaxel and platinum containing regimen is a valuable treatment option.
Table of Contents: Chapter 1: General Introduction
1.1. Clinical aspects of Epithelial Ovarian Cancer
1.1.1. Epidemiology
1.1.2. Symptoms – Diagnosis
1.1.3. Treatment
1.1.3.1. Surgery
1.1.3.2. Chemotherapy
1.1.3.3. Recurrent disease
1.1.4. Prognosis
1.2. Platinum resistance
1.3. Proteomics
1.3.1. General introduction
1.3.2. Proteomics in ovarian cancer
1.3.3. Methods for proteomic analysis
1.3.3.1. MALDI-TOF MS
1.3.3.2. SELDI-TOF MS
1.4. Laser microdissection
1.5. OVCAD: OVarian CAncer: Diagnosing a silent killer

Chapter 2: Objectives

Chapter 3: Proteomic studies
3.1. Application of proteomics in ovarian cancer: which sample should be used?
3.2. The utility of proteomics in gynecological cancer
3.3. Methods in molecular biology: protocol for proteomic analysis of laser microdissected ovarian cancer tissue with SELDI-TOF MS
3.4. The use of laser microdissection and SELDI-TOF MS in ovarian cancer tissue to identify protein profiles
3.5. Prediction of platinum resistance by protein profiling of laser microdissected ovarian cancer cells: an OVCAD study
3.6. Protein profiles for prediction of platinum resistance in ovarian cancer fails validation, a prospective OVCAD study

Chapter 4: Clinical studies
4.1. Analysis of clinical predictive factors for platinum resistance in epithelial ovarian cancer within the prospective collected dataset of the OVCAD study
4.2. The “Leuven” dose dense paclitaxel / carboplatin regimen in patients with recurrent ovarian cancer
4.3. The “Leuven” paclitaxel / carboplatin weekly regimen in patients with recurrent ovarian cancer

Chapter 5: General discussion

Chapter 6: Summary
6.1. Summary
6.2. Samenvatting

Curriculum Vitae

List of publications
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Laboratory of Protein Phosphorylation and Proteomics
Section Woman - Miscellaneous (-)
Gynaecological Oncology
Biochemistry Section (Medicine) (-)
Laboratory of Phosphoproteomics (-)

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