Angiogenesis pathway.doc

Angiogenesis is thephysiological process of the growth of new blood vessels from pre-existing vessels. Angiogenesis can be induced by solid tumor growth. In the meantime, angiogenesis provides solid tumor with oxygen and nutrients to make it reach a certain size.There are many important targets related to angiogensis including EGFR,HER2, VEGFR, PDGFR, FGFR, FLT3, HIF, ALK, VDA, S1P receptor. Most of those targets are receptor tyrosine kinases (RTK)s.Vascular Endothelial Growth Factor Receptor (VEGFR) is the receptor of VEGF. VEGFR is involved in cell proliferation, migration, survival and permeability. The VEGFs include five known structurally-related mammalian ligands (VEGFA, VEGFB, VEGFC, VEGFD, and placenta growth factor, PLGF) and there are also three structurally related VEGFRs subtypes (VEGFR1, VEGFR2, and VEGFR3).EGFR is a trans-membrane receptor belonging to the erbB/HER-family of RTK. EGFR exists on the cell surface and can be activated by EGF and TGF-alpha. Many important signaling cascades, like MAPK, Akt, and JNK pathways, could be the downstream of EGFR.Erbb2 (HER2) belongs to Erbb family lacks the capacity to interact with a ligand because its extracellular region exists in a fixed, unfolded conformation. Erbb2 (HER2) acts as an amplifier of the Erbb signaling network. The adaptors and effector of Erbb2 includes Shc, Syk, RasGAP, Grb2/7, Abl, Mapk8, PLC and STAT1/3. Erbb3 lacks kinase activity and can form heterodimeric complexes with Erbb2. The ERBB2ERBB3 dimer can be an important cancer therapeutic target.Janus kinases (JAKs) are non-receptor tyrosine kinases which play the key role in JAK-STAT signaling pathway. A large number of cytokines depend on JAK including interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Jak kinases are involved in malignant cell growth and survival. Jak kinases have been shown to modulate activation of Ras-Raf-MAP kinase pathways which are implicated in malignant transformation. The function of Jak kinases is also related to Abl. Jak kinases have been also implicated in the regulation of p53-dependent cell-cycle arrest and apoptosis, for example, Jak kinases can regulate the levels of Bcl-XL, Bcl-2 and Bax expression by their effects on Stats and other receptor linked pathways such as the PI-3 kinase and the Ras-MAPK pathwaysTGF-beta/SmadTransforming Growth Factor (TGF) can induce anchorage-independent growth, as a founding member of the largest family of secreted morphogens in mammals. There are four subclasses of the TGF family with different biological functions including activins, inhibins, bone morphogenetic proteins (BMPs), and Mullerian-inhibiting substance (MIS). After transmembrane serine/threonine kinases binding form a heteromeric complex of type II and type I receptors, TGF signaling pathway isactivated. Smad signaling pathway is activated after the phosphorylation of the type I receptor by the type II kinase.In the eponymous TGF pathway this occurs via ligand-induced cooperative assembly of the receptor complex, thus allowing the kinase domain of the type II receptor tophosphorylate the type I receptor, as well as other receptor-bound components. In the canonical pathway, signaling to the transcriptional achinery is transduced by aunique family of intracellular signaling mediators called Smads. There are so many important targets related to Smad including HDAC1, Notch, STAT3, ERK and p38.MAPKMAPK (mitogen-activated protein kinase) is a family of serine-threonine kinases that regulate multiple cellular functions such as mitogens, proinflammatory cytokines, gene expression and cell survival/apoptosis. ERK1/2, p38, ERK3/4, ERK5, ERK7/8, JNKs, and SAPKs have been identified in MAPK family.The mitogen-activated protein kinase (MAPK) is the backbone of four major signal transduction cascades leading to the phosphorylation and activation of extracellular signal-regulated kinases 1 and 2 (ERK1-2), JNK, p38 and ERK5. MAPK 1 and 2 are typically referred to as MEK1 and 2 and share 80% structural homology. These dual-specificity tyrosine/threonine protein kinases are active in 30% of all human cancers where MAPK signalling pathway is implicated.1 MEK exists just downstream of RAF in the classical MAPK pathway known as RAS-RAF-MEK-ERK pathway. Phosphorylation of MEK by RAF results in the phosphorylation of ERK1 and ERK2 these appear to be the only targets of MEK. The phosphorylation of ERK modifies the activity of a number of transcription factors resulting in altered gene expression that results in cell proliferation, typically blocking apoptosis, and is involved in a number of other processes which drive cancer progression, such as cell motility, metastasis, and angiogenesis.2The activation of the MAPK signalling pathway begins when growth factors, hormones and chemokines interact with respective tyrosine kinase receptors. Frequently, it is observed that the MAPK pathway is activated in tumors where receptor tyrosine kinases, such as EGFR, are overexpressed due to somatic mutation, gene amplification and/or increased autocrine or paracrine signalling. Upon ligand binding to the extracellular domain of the receptor, the receptor tyrosine kinases dimerize and induce activation of kinase activity in the cytoplasmic domain, leading to phosphorylation of C-terminal tyrosine residues. This provides docking sites for proteins containing Src homology 2 (SH2) or phosphotyrosine binding domains, such as adaptor protein growth factor receptor-bound protein 2 (GRB2). Following these events, the adaptor proteins recruit further effectors, including the guanine-nucleotide exchange factor, SOS (also known as son of sevenless). In the plasma membrane, SOS is recruited and nucleotide exchange of GDP for GTP occurs with RAS proteins (KRAS, NRAS, and HRAS). As a consequence, GTP-bound RAS activates the closely related RAF protein kinases (CRAF, BRAF, and ARAF). Recruitment of RAF to the plasma membrane facilitates the completion of the RAF catalytic kinase activity including the phosphorylation of the MAPK kinases (MAPKK), MEK1 and MEK2, dual-specificity kinases that recognize and phosphorylate tyrosine and threonine residues in the Thr-X-Tyr activation loop of the MAPKs. Activated ERK1 and ERK2 phosphorylate cytosolic signalling proteins such as p90 ribosomal S6 kinase (RSK) and MAPK-interacting serine/threonine kinase (MNK), and transcription factors (Elk-1, CREB, c-Fos and c-Jun).3Aside from constitutive receptor tyrosine kinase overexpression, constitutive activation of the RAS-RAF-MEK-ERK pathway can result from mutations in RAS, BRAF, and/or MEK genes. Mutations in RAS family genes (HRAS, KRAS, and NRAS) are observed to be a result of single-amino-acid substitutions in codons 12, 13, and 61. BRAF mutations are common in the P-loop (exon 11) and in the activation segment (exon 15) of the kinase domain. The substitution of a valine residue at position 600 for glutamic acid (V600E) is found in an overwhelming majority of BRAF mutations involved in human cancers. The majority of BRAF mutations destabilize the inactive conformation of the protein, disrupting the interaction between the P-loop and the activation segment.2Constitutive activation of the kinase signalling pathway, RAS-RAF-MEK-ERK, has been associated with cancers of the lung, colon, melanoma, lung, thyroid, leukemia, and pancreatic cancer. As a consequence there is great utility in targeting the RAS-RAF-MEK-ERK axis in oncology drug development. In addition, there appears to be crosstalk between RAS-RAF-MEK-ERK with other signalling pathways. For example, RAS can activate the PI3K-AKT pathway, aside from having shared inputs, and there appears to be some compensation for signalling activity when one or the other is inhibited. Research has shown that when mTOR is inhibited, MAPK activity can still occur as a result of PI3K activation through RAS. Dual activation of these two pathways is observed in a number of cancer types including melanoma, prostate and colorectal cancer, and provides the rationale for combining therapeutic agents.2MAPK inhibitors include compounds targeting MEK the first MEK inhibitor, CI-1040 (PD-184352), was tested in humans in 2000 through a joint partnership between Pfizer and Warner-Lambert. However, the compound was not shown to be effective following a Phase II clinical study that tested the compound in a range of cancers (breast cancer, small cell lung cancer (SCLC), pancreatic cancer, and colon cancer). Based on the concept of CI-1040, Pfizer explored the development of a similar compound called PD-0325901 that was touted to have improved biological and pharmaceutical properties than its precursor. However, the compound failed in a Phase II clinical trials for evaluation against non-small cell lung cancer (NSCLC), breast cancer, colon cancer, and melanoma, due to safety concerns. Aside from Pfizer, other pharmaceutical companies have developed compounds targeting the MAPK signalling pathway including AstraZeneca and Array BioPharma. Together, these two companies led the development of ARRY-142886/AZD6244 as a monotherapy for melanoma, colon cancer, NSCLC, and pancreatic cancer. Bayer has also explored targeting MEK as an anti-cancer strategy with the development of BAY869766/RDEA119 in combination with Sorafenib for the treatment of liver cancer. In addition, the pairing of BAY869766 with Gemcitabine for the treatment of pancreatic cancer has also been investigated by Bayer. Collaboration between Genentech and Exelixis is ongoing for the evaluation of GDC0973/XL518 in combination with GDC0941 for ad