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Bevacizumab as a Palliative Treatment for Patients With Symptomatic Malignant Ascites Due to Advanced-stage Gastrointestinal Cancers

ABSTRACT: Malignant ascites represents a severe clinical problem for physicians and patients being confronted with this common symptom of advanced-stage gastrointestinal cancer. Unfortunately, there is no standardized and evidence-based treatment for malignant ascites and therapies which are commonly being used are only temporarily effective. Newer modes of therapy, such as the application of the tri-functional antibody catumaxomab, are associated with significant side effects and are limited to patients in stages of good overall performance. Therefore, there is still an urgent need for more effective, longer-lasting, and less toxic modes of treatment for peritoneal effusions caused by gastrointestinal cancers. Preclinical data strongly suggest that bevacizumab might be a very effective agent for the treatment of malignant ascites, which is in large part caused by the hyperpermeability-promoting factor VEGF. Emerging clinical results from cancer patients with malignant ascites treated with bevacizumab add further support to this idea. Bevacizumab has been tested in a variety of large clinical trials, has a good toxicity profile, and is effective in a number of human cancers underlying malignant ascites. In the present study, Bevacizumab will be administered as an intraperitoneal infusion at an absolute standardized dosage of 400 mg. This dosage was chosen because it is comparable to the approved standard dosage for intravenous administration which was also used in both studies reporting the successful and safe intraperitoneal administration of Bevacizumab to patients with malignant ascites. Finally, a standardized dosage seems more practical in the particular patient population treated in this study.

DISEASE(S): Gastrointestinal Neoplasms,Gastric Cancer,Colorectal Cancer,Esophageal Cancer,Gastrointestinal Cancers,Pancreatic Cancer,Ascites,Carcinoma Hepatocellular,Gastroesophageal Cancer,Malignant Ascites,Cholangiocarcinoma,Patients With Malignant Ascites Due To Advanced-stage Gastro-intestinal Cancers

PROVIDER: 2094961 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Purpose: Malignant ascites is an abnormal accumulation of fluid within the peritoneal cavity, caused by metastasis of several cancer types including colorectal cancer. Cancer cells in ascites reflect poor prognosis and can be a source of recurrence. They also represent a good source of specimens for the study of tumor heterogeneity. Single-cell RNA-sequencing (scRNA-seq) has recently emerged as a powerful tool for exploring and characterizing cellular heterogeneity in both normal tissues and cancers. However, molecular profiles of malignant ascites cells in response to treatment are still poorly understood. Materials and Methods: We have performed scRNA-seq of ascites-derived cells from a colorectal cancer patient to profile and characterize the cellular heterogeneity and different expression hallmarks within the cell populations before and after a chemotherapy treatment. The effect of different single cell preparation protocols, namely, manual and enzymatic methods, on cell viability and gene expression were also assessed. Results: Unbiased clustering of 19,653 cells in total reveals 12 sub-clusters with unique transcriptomic patterns from four major cell types: epithelial cells, myeloid cells, fibroblast, and lymphocytes. Interestingly, the percentages of cells recovered from different cell types appeared to be influenced by the preparation protocols; enzymatic and mechanical separations, with more than 90% reduction in myeloid cell number when enzymatic method was used. Subcluster analysis of epithelial cell populations before and after chemotherapy treatment identified distinct cell clusters with unique transcriptomic profiles. Moreover, there were only three out of 11 epithelial subclones with more than 50% reduction in tumor cell number after treatment. This finding indicated that most clones were resistant to the treatment, which reflected the poor treatment outcome observed in our patient. Conclusions: Overall, our study underscores cellular heterogeneity within malignant ascites and uncovers the gene expression profile of colorectal cancer ascites-derived cells in single-cell resolution. Our findings emphasize the potential benefit of using scRNA-Seq to monitor real-time treatment response in cancer patients.

Project description:Background: Malignant ascites is often present at diagnostic in women with advanced ovarian cancer (OC) and its presence is associated with a worse outcome. Human peritoneal mesothelial cells (HPMCs) are key components of malignant ascites. Although the interplay between HPMCs and OC cells is believed to be critical for tumor progression, it has not been well characterized. The purpose of this study was to assess the effect of ascites on HPMCs and clarify the role of HPMCs in OC progression. Methods: Human OC ascites and benign peritoneal fluids were assessed for their ability to stimulate HPMC proliferation. Conditioned medium from ascites- and benign fluid-stimulated HPMCs were compared for their ability to attenuate apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL). We conducted a comparative analysis of global expression changes in ascites-stimulated HPMCs using Agilent oligonucleotide microarrays. Results: As compared to benign peritoneal fluids, malignant ascites stimulated the proliferation of HPMCs. TRAIL-induced apoptosis was attenuated in OC cells exposed to conditioned medium from ascites-stimulated HPMCs as compared to OC cells exposed to conditioned medium from benign fluid-stimulated HPMCs. A total of 649 genes were differentially expressed in ascites-stimulated HPMCs. Based on a ratio of more than 1.5-fold and a P < 0.05, 484 genes were up-regulated and 165 genes were down-regulated in ascites-exposed HPMCs. Stimulation of HPMCs with OC ascites resulted in differential expression of genes mainly associated with the regulation of cell growth and proliferation, cell death, cell cycle and cell assembly and organization, compared to benign peritoneal fluids. Top networks up-regulated by OC ascites included Akt and NF-M-NM-:B survival pathways whereas vascular endothelial growth factor (VEGF) pathway was down-regulated. Conclusions: The results of this study not only provide evidence supporting the importance of the interplay between cancer cells and HPMCs but also define the role that the tumor environment plays in these interactions. The expression profiles from human peritoneal mesothelial cells (HPMC) cultures exposed to peritoneal fluids and ovarian cancer ascites were compared using the Agilent Whole Human Genome Oligonucleotide microarrays, containing 44,000 genes. Microarrays were performed on HPMCs exposed to 3 malignant ascites from women with advanced (stage III/IV) serous OC and two benign peritoneal fluids. First, we generated lists of significantly up-regulated and down-regulated genes that were differentially expressed between OC ascites (OVC346, OVC508 and OVC509) and control OV370 peritoneal fluid. Then, the set of genes that were commonly expressed between control peritoneal fluids (OV370 and OV401) were subtracted from the first list of genes to generate a dataset of differentially expressed genes between malignant ascites and benign peritoneal fluids.

Project description:Background: Malignant ascites is often present at diagnostic in women with advanced ovarian cancer (OC) and its presence is associated with a worse outcome. Human peritoneal mesothelial cells (HPMCs) are key components of malignant ascites. Although the interplay between HPMCs and OC cells is believed to be critical for tumor progression, it has not been well characterized. The purpose of this study was to assess the effect of ascites on HPMCs and clarify the role of HPMCs in OC progression. Methods: Human OC ascites and benign peritoneal fluids were assessed for their ability to stimulate HPMC proliferation. Conditioned medium from ascites- and benign fluid-stimulated HPMCs were compared for their ability to attenuate apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL). We conducted a comparative analysis of global expression changes in ascites-stimulated HPMCs using Agilent oligonucleotide microarrays. Results: As compared to benign peritoneal fluids, malignant ascites stimulated the proliferation of HPMCs. TRAIL-induced apoptosis was attenuated in OC cells exposed to conditioned medium from ascites-stimulated HPMCs as compared to OC cells exposed to conditioned medium from benign fluid-stimulated HPMCs. A total of 649 genes were differentially expressed in ascites-stimulated HPMCs. Based on a ratio of more than 1.5-fold and a P < 0.05, 484 genes were up-regulated and 165 genes were down-regulated in ascites-exposed HPMCs. Stimulation of HPMCs with OC ascites resulted in differential expression of genes mainly associated with the regulation of cell growth and proliferation, cell death, cell cycle and cell assembly and organization, compared to benign peritoneal fluids. Top networks up-regulated by OC ascites included Akt and NF-κB survival pathways whereas vascular endothelial growth factor (VEGF) pathway was down-regulated. Conclusions: The results of this study not only provide evidence supporting the importance of the interplay between cancer cells and HPMCs but also define the role that the tumor environment plays in these interactions.

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Bevacizumab as a Palliative Treatment for Patients With Symptomatic Malignant Ascites Due to Advanced-stage Gastrointestinal Cancers

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