Celon Pharma Research - Our Research

Pipeline

Wnt/β-catenin pathway

IAP family

ErbB family

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The increasing interest of the scientific community, over the last decade, in the Wnt-dependent signaling pathways is supported by the documented importance of these pathways in a broad range of physiological conditions and disease states. For instance, it has been shown that inappropriate regulation and activation of these pathways is associated with several disorders including cancer, retinopathy, tetra-amelia and arthritis. In addition, several components of the Wnt-dependent signaling pathways appear to play important roles in diseases such as Alzheimer's disease, schizophrenia and bipolar disorder. Evidence that altered Wnt signaling is important for human tumor development came from three major findings:
1) the tumor suppressor Adenomatous Polyposis Coli (APC) binds to the Wnt pathway component β-catenin and is involved in its degradation,
2) mutations of APC in colon tumors lead to stabilization of the β-catenin protein and
3) tumor-associated mutations of β-catenin in colorectal cancer as well as in other tumor types lead to its stabilization, qualifying β-catenin as a proto-oncogene. WNT family of secreted-type glycoproteins play key roles in carcinogenesis and embryogenesis. Signals of glycoprotein WNTs are transduced through seven-transmembrane-type WNT receptors encoded by Frizzled (FZD) genes to the β-catenin - TCF pathway, the c-Jun-N-terminal kinase (JNK) pathway or the Ca2+-releasing pathway. In human breast cancer, evidence of β-catenin accumulation implies that the canonical Wnt signaling pathway is active in over 50% of carcinomas.

Luu HH, Zhang R, Haydon RC, Rayburn E, Kang Q, Si W, Park JK, Wang H, Peng Y, Jiang W, He TC. Wnt/beta-catenin signaling pathway as a novel cancer drug target. Curr Cancer Drug Targets. 2004 Dec;4(8):653-71

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Insensitivity to apoptotic stimuli is one of most problems in cancer treatment. Inhibition of activity of proteins that belongs to IAP (Inhibitor of Apoptosis Protein) family, named also BIRPs (BIR-domain-containing Proteins), is one of solutions of this problem. This family of proteins consist of seven members BIRC1-7. Survivin (BIRC5) is the most studied member of IAP family. Expression of this protein is cell-cycle-dependend, but there is no evidence that expression of survivin causes carcinogenesis. In our studies we aim to break blockade of apoptosis in cancer cell lines by decreasing protein level of the other IAP family members.

Verhagen AM, Coulson EJ, Vaux DL. Inhibitor of apoptosis proteins and their relatives: IAPs and other BIRPs. Genome Biol. 2001;2(7):REVIEWS3009.

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Epidermal growth factor receptor family members (ErbBs) are currently major targets of anticancer strategies and identifying the contribution of ErbBs to tumorigenesis is crucial for development of anti-ErbB therapies. The ErbB family of receptor tyrosine kinases includes four members: ErbB-1 (EGFR), ErbB-2 (HER2), ErbB-3 (HER3) and ErbB-4 (HER4). The association of ErbB receptor family with breast cancer development has been extensively described in literature. Overexpression of EGFR may serve as a prognostic marker with respect to survival in advance breast cancer and recurrence in operable breast tumors. ErbB2 overexpression occurs in roughly 25% - 30% of breast cancer and correlates with lower overall survival and shorter time to relapse. Many ErbB-2 overexpressing breast cancer cell lines, have elevated levels of phosphorylated ErbB-3 as well. The downregulation of ErbBs members in breast cell lines revealed in an inhibition of cell proliferation and spreading. RNA interference offers a new mode for high effective and selective inhibition of specific gene expression in cancer. This study was focused on using of siRNA against ErbBs member in breast cancer cell lines.

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