Abstract 4855: AMC303 inhibits tumor growth and metastasis in animal models by targeting CD44v6, a co-receptor of multiple oncogenic receptor tyrosine kinases

2019 ◽  
Author(s):  
Tina Heumann ◽  
Vanessa Al-Rawi ◽  
Thorsten Läufer ◽  
Martin Augsten ◽  
Alexandra Matzke-Ogi ◽  
...  
Keyword(s):  
Animal Models ◽  
Tumor Growth ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Tumor Growth And Metastasis

scholarly journals The syndecan-1 heparan sulfate proteoglycan is a viable target for myeloma therapy

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 2041-2048 ◽  
Author(s):  
Yang Yang ◽  
Veronica MacLeod ◽  
Yuemeng Dai ◽  
Yekaterina Khotskaya-Sample ◽  
Zachary Shriver ◽  
...  
Keyword(s):  
Animal Models ◽  
Tumor Growth ◽  
Heparan Sulfate ◽  
Tumor Development ◽  
Normal Function ◽  
Heparan Sulfate Proteoglycan ◽  
Sulfate Proteoglycan ◽  
Primary Tumors ◽  
Tumor Growth And Metastasis

Abstract The heparan sulfate proteoglycan syndecan-1 is expressed by myeloma cells and shed into the myeloma microenvironment. High levels of shed syndecan-1 in myeloma patient sera correlate with poor prognosis and studies in animal models indicate that shed syndecan-1 is a potent stimulator of myeloma tumor growth and metastasis. Overexpression of extracellular endosulfatases, enzymes which remove 6-O sulfate groups from heparan sulfate chains, diminishes myeloma tumor growth in vivo. Together, these findings identify syndecan-1 as a potential target for myeloma therapy. Here, 3 different strategies were tested in animal models of myeloma with the following results: (1) treatment with bacterial heparinase III, an enzyme that degrades heparan sulfate chains, dramatically inhibited the growth of primary tumors in the human severe combined immunodeficient (SCID-hu) model of myeloma; (2) treatment with an inhibitor of human heparanase, an enzyme that synergizes with syndecan-1 in promoting myeloma progression, blocked the growth of myeloma in vivo; and (3) knockdown of syndecan-1 expression by RNAi diminished and delayed myeloma tumor development in vivo. These results confirm the importance of syndecan-1 in myeloma pathobiology and provide strong evidence that disruption of the normal function or amount of syndecan-1 or its heparan sulfate chains is a valid therapeutic approach for this cancer.

scholarly journals HER Tyrosine Kinase Family and Rhabdomyosarcoma: Role in Onset and Targeted Therapy

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1808
Author(s):  
Carla De Giovanni ◽  
Lorena Landuzzi ◽  
Arianna Palladini ◽  
Giordano Nicoletti ◽  
Patrizia Nanni ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Myogenic Differentiation ◽  
Growth Factor Receptor ◽  
Her Family ◽  
Her2 Mutation ◽  
Epidermal Growth ◽  
Egfr Family

Rhabdomyosarcomas (RMS) are tumors of the skeletal muscle lineage. Two main features allow for distinction between subtypes: morphology and presence/absence of a translocation between the PAX3 (or PAX7) and FOXO1 genes. The two main subtypes are fusion-positive alveolar RMS (ARMS) and fusion-negative embryonal RMS (ERMS). This review will focus on the role of receptor tyrosine kinases of the human epidermal growth factor receptor (EGFR) family that is comprised EGFR itself, HER2, HER3 and HER4 in RMS onset and the potential therapeutic targeting of receptor tyrosine kinases. EGFR is highly expressed by ERMS tumors and cell lines, in some cases contributing to tumor growth. If not mutated, HER2 is not directly involved in control of RMS cell growth but can be expressed at significant levels. A minority of ERMS carries a HER2 mutation with driving activity on tumor growth. HER3 is frequently overexpressed by RMS and can play a role in the residual myogenic differentiation ability and in resistance to signaling-directed therapy. HER family members could be exploited for therapeutic approaches in two ways: blocking the HER member (playing a driving role for tumor growth with antibodies or inhibitors) and targeting expressed HER members to vehiculate toxins or immune effectors.

scholarly journals The role of tyrosine kinases in the pathogenesis of idiopathic pulmonary fibrosis

2015 ◽  
Vol 45 (5) ◽  
pp. 1426-1433 ◽  
Author(s):  
Friedrich Grimminger ◽  
Andreas Günther ◽  
Carlo Vancheri
Keyword(s):  
Growth Factor ◽  
Animal Models ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Phase Iii

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a median survival time from diagnosis of 2–3 years. Although the pathogenic pathways have not been fully elucidated, IPF is believed to be caused by persistent epithelial injury in genetically susceptible individuals. Tyrosine kinases are involved in a range of signalling pathways that are essential for cellular homeostasis. However, there is substantial evidence from in vitro studies and animal models that receptor tyrosine kinases, such as the platelet-derived growth factor receptor, vascular endothelial growth factor receptor and fibroblast growth factor receptor, and non-receptor tyrosine kinases, such as the Src family, play critical roles in the pathogenesis of pulmonary fibrosis. For example, the expression and release of tyrosine kinases are altered in patients with IPF, while specific tyrosine kinases stimulate the proliferation of lung fibroblasts in vitro. Agents that inhibit tyrosine kinases have shown anti-fibrotic and anti-inflammatory effects in animal models of pulmonary fibrosis. Recently, the tyrosine kinase inhibitor nintedanib has shown positive results in two phase III trials in patients with IPF. Here, we summarise the evidence for involvement of specific tyrosine kinases in the pathogenesis of IPF and the development of tyrosine kinase inhibitors as treatments for IPF.

scholarly journals Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
T. Y. S. Le Large ◽  
M. F. Bijlsma ◽  
B. El Hassouni ◽  
G. Mantini ◽  
T. Lagerweij ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Lines ◽  
Pathway Analysis ◽  
Focal Adhesion ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Receptor Tyrosine Kinases ◽  
Ductal Adenocarcinoma ◽  
Pdac Cell

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease, with minimal therapeutic options. Aberrant tyrosine kinase activity influences tumor growth and is regulated by phosphorylation. We investigated phosphorylated kinases as target in PDAC. Methods Mass spectrometry-based phosphotyrosine proteomic analysis on PDAC cell lines was used to evaluate active kinases. Pathway analysis and inferred kinase activity analysis was performed to identify novel targets. Subsequently, we investigated targeting of focal adhesion kinase (FAK) in vitro with drug perturbations in combination with chemotherapeutics used against PDAC. Tyrosine phosphoproteomics upon treatment was performed to evaluate signaling. An orthotopic model of PDAC was used to evaluate the combination of defactinib with nab-paclitaxel. Results PDAC cell lines portrayed high activity of multiple receptor tyrosine kinases to various degree. The non-receptor kinase, FAK, was identified in all cell lines by our phosphotyrosine proteomic screen and pathway analysis. Targeting of this kinase with defactinib validated reduced phosphorylation profiles. Additionally, FAK inhibition had anti-proliferative and anti-migratory effects. Combination with (nab-)paclitaxel had a synergistic effect on cell proliferation in vitro and reduced tumor growth in vivo. Conclusions Our study shows high phosphorylation of several oncogenic receptor tyrosine kinases in PDAC cells and validated FAK inhibition as potential synergistic target with Nab-paclitaxel against this devastating disease.

scholarly journals The Oncogenic Signaling Disruptor, NDRG1: Molecular and Cellular Mechanisms of Activity

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2382 ◽  
Author(s):  
Jason Chekmarev ◽  
Mahan Gholam Azad ◽  
Des R. Richardson
Keyword(s):  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Tumor Development ◽  
Pancreatic Tumors ◽  
Cellular Mechanisms ◽  
Oncogenic Signaling ◽  
Tumor Growth And Metastasis ◽  
B Lineage ◽  
Cbl Protein ◽  
Docking Protein

NDRG1 is an oncogenic signaling disruptor that plays a key role in multiple cancers, including aggressive pancreatic tumors. Recent studies have indicated a role for NDRG1 in the inhibition of multiple tyrosine kinases, including EGFR, c-Met, HER2 and HER3, etc. The mechanism of activity of NDRG1 remains unclear, but to impart some of its functions, NDRG1 binds directly to key effector molecules that play roles in tumor suppression, e.g., MIG6. More recent studies indicate that NDRG1s-inducing drugs, such as novel di-2-pyridylketone thiosemicarbazones, not only inhibit tumor growth and metastasis but also fibrous desmoplasia, which leads to chemotherapeutic resistance. The Casitas B-lineage lymphoma (c-Cbl) protein may be regulated by NDRG1, and is a crucial E3 ligase that regulates various protein tyrosine and receptor tyrosine kinases, primarily via ubiquitination. The c-Cbl protein can act as a tumor suppressor by promoting the degradation of receptor tyrosine kinases. In contrast, c-Cbl can also promote tumor development by acting as a docking protein to mediate the oncogenic c-Met/Crk/JNK and PI3K/AKT pathways. This review hypothesizes that NDRG1 could inhibit the oncogenic function of c-Cbl, which may be another mechanism of its tumor-suppressive effects.

Sign in / Sign up

Export Citation Format

Share Document