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Histological and clinical effects of Imipramine in the treatment of patients with cancer over-expressing Fascin1.

ABSTRACT: Primary objectives: Evaluate the effect of the imipramine treatment on the development of histological manifestations associated with the mesenchymal epithelial transition during the period of time from the analysis of the diagnostic biopsy to the surgical resection intervention. Primary endpoints: Comparison of the histological traits of invasive tumour front of the surgical tumour resection specimen between the intervention group and the placebo group:1. Fascin1 expression in tumour tissue: It will be analysed by immunohistochemistry and the application of Immunoscore.2. Histological manifestations of the epithelial-mesenchymal transition (EMT): Tumour budding, cytoplasmic pseudo-fragments, infiltrating growth pattern and poorly differentiated nests. It will be evaluated by histological analysis.3. Invasive histological manifestations: discontinuous extramural extension, lymphatic, venous and perineural infiltration. It will be evaluated by histological analysis.4. Histological manifestation of the immune response: Peritumoral and intratumour lymphocyte infiltration. It will be evaluated by histological analysis.5. EMT molecular manifestations: FSCN1, SNAIL and SLUG gene expression. It will be evaluated by NGS analysis of the primary tumour.

DISEASE(S): Colorectal Cancer And Triple Negative Breast Cancer Patients (tnbc) Who Shown Overexpression Of Fascin1 In The Diagnostic Biopsy Tissue.,Pacientes Con Cáncer Colorrectal Y Con Cáncer De Mama Triple Negativo (tnbc) Que Muestran Sobreexpresión De Fascina1 En El Tejido De Biopsia Diagnóstica.

PROVIDER: 2541275 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Every year more than 42,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT). Paraffin sections from patients with (n=9) or without (n=10) progressive endometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory) T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunosurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4 and WIF1, quantitive RT-PCR was performed to verify down regulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa (IK) endometrial cancer cell lines stably transfected with PRA (IKPRA), PRB (IKPRB) and PRA+PRB (IKPRAB) were cultured in the presence/absence of progesterone (MPA) and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT makers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA-regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signalling. Intact progesterone signaling in non-progressive endometrial cancer seems to be an important factor stimulating immunosurveillance and inhibiting transition from an epithelial to a more mesenchymal, more invasive phenotype. From 4 non-progressive and 4 progressive patients, snap-frozen endometrial cancer tumor specimens were used for microarray analysis. Gene expression data of progressive disease was compared with non-progressive disease.

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Histological and clinical effects of Imipramine in the treatment of patients with cancer over-expressing Fascin1.

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