Targeting Eph receptors with peptides and small molecules: Progress and challenges

Noberini, Roberta; Lamberto, Ilaria; Pasquale, Elena B.

doi:10.1016/j.semcdb.2011.10.023

Cited by 90 publications

(105 citation statements)

References 63 publications

(116 reference statements)

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“…In terms of therapeutic potential, ephrinB1 is expressed at the cell surface and could potentially be targeted. Although there are no inhibitors of ephrins in clinical use, a number of peptides and chemical compounds that target Eph receptors and inhibit ephrin binding or downstream kinase activation have been identified (56). These molecules show promise as probes to study Eph receptor/ephrin biology, as lead compounds for drug development and as targeting agents to deliver drugs or imaging agents to tumors.…”

Section: Discussionmentioning

confidence: 99%

Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis

Dun

Chalkley

Faulkner

et al. 2015

Molecular & Cellular Proteomics

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Brain metastases are a devastating consequence of cancer and currently there are no specific biomarkers or therapeutic targets for risk prediction, diagnosis, and treatment. Here the proteome of the brain metastatic breast cancer cell line 231-BR has been compared with that of the parental cell line MDA-MB-231, which is also metastatic but has no organ selectivity. Using SILAC and nanoLC-MS/MS, 1957 proteins were identified in reciprocal labeling experiments and 1584 were quantified in the two cell lines. A total of 152 proteins were confidently determined to be up-or down-regulated by more than twofold in 231-BR. Of note, 112/152 proteins were decreased as compared with only 40/152 that were increased, suggesting that down-regulation of specific proteins is an important part of the mechanism underlying the ability of breast cancer cells to metastasize to the brain. When matched against transcriptomic data, 43% of individual protein changes were associated with corresponding changes in mRNA, indicating that the transcript level is a limited predictor of protein level. In addition, differential miRNA analyses showed that most miRNA changes in 231-BR were up-(36/45) as compared with down-regulations (9/45). Pathway analysis revealed that proteome changes were mostly related to cell signaling and cell cycle, metabolism and extracellular matrix remodeling. The major protein changes in 231-BR were confirmed by parallel reaction monitoring mass spectrometry and consisted in increases (by more than fivefold) in the matrix metalloproteinase-1, ephrin-B1, stomatin, myc target-1, and decreases (by more than 10-fold) in transglutaminase-2, the S100 calcium-binding protein A4, and L-plastin. The clinicopathological significance of these major proteomic changes to predict the occurrence of brain metastases, and their potential value as therapeutic targets, warrants further investigation. Brain metastases affect 10 -20% of cancer patients with disseminated disease (1). Even small lesions can cause neurological disability, and the median survival time of patients with brain metastases is short, with about 80% mortality within one year of diagnosis. The molecular basis of cancer metastases to the brain remains unknown and with advances in the control of systemic disease, the incidence of brain metastases is increasing (1, 2). In the case of breast cancer, brain relapse typically occurs years after primary tumor excision, suggesting that disseminated breast cancer cells must first acquire specialized functions to invade and grow in this organ (3). Retrospective studies of breast cancer patients with brain metastases found that a young age at diagnosis, primary tumors that are estrogen receptor negative or overexpressing the human epidermal growth factor receptor 2 (HER2) 1 and/or epidermal growth factor receptor, and the From the ‡School

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Section: Discussionmentioning

confidence: 99%

Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis

Dun

Chalkley

Faulkner

et al. 2015

Molecular & Cellular Proteomics

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“…immunogenic or allergic responses). Thus, it is advantageous to use peptide that selectively bind to EphA2 and use its ability to mediate internalization (46). The normal tissues have low EphA2 expression compare to tumor tissues and based on our bio-distribution data, the use of the YSA peptide for drug delivery may reduce toxic side-effects by reducing exposure of cytotoxic drugs to normal cells.…”

Section: Discussionmentioning

confidence: 99%

EphA2 Targeting Pegylated Nanocarrier Drug Delivery System for Treatment of Lung Cancer

2014

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Purpose Evaluation of tumor targeting pegylated EphA2 peptide coated nanoparticles (ENDDs) of a novel anticancer agent DIM-C-pPhC6H5 (DIM-P) and Docetaxel (DOC) and investigate its antitumor activity and potential for treatment of lung cancer. Methods Nanoparticles were prepared with DIM-P and DOC (NDDs) using Nano-DeBEE. ENDDs were prepared by conjugating NDDs with 6His-PEG2K–EphA2 peptide and characterized for physicochemical properties, binding assay, cytotoxicity, cellular uptake studies, drug release and pharmacokinetic parameters. Anti-tumor activity of ENDDs was evaluated using a metastatic H1650 and orthotopic A549 tumor models in nude mice and tumor tissue were analyzed by RT-PCR and immunohistochemistry. Results Particle size and entrapment efficiency of ENDDs were 197±21 nm and 95±2%. ENDDs showed 32.5±3.5% more cellular uptake than NDDs in tumor cells. ENDDs showed 23 ± 3% and 26±4% more tumor reduction compared to NDDs in metastatic and orthotopic tumor models, respectively. In-vivo imaging studies using the Care stream MX FX Pro system showed (p<0.001) 40–60 fold higher flux for ENDDs compared to NDDs at tumor site. Conclusions The results emanating from these studies demonstrate anti-cancer potential of DIM-P and the role of ENDDs as effective tumor targeting drug delivery systems for lung cancer treatment.

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“…Dasatinib and nilotinib are two multikinase inhibitors that have been shown to inhibit EphB2, along with BCR-abl, c-Kit, PDGFR-β, other Eph receptors, and members of the src family [ 102 ]. The effect of nilotinib in osteosarcoma has not been investigated.…”

Section: Ephb2mentioning

confidence: 99%

Receptor Tyrosine Kinases in Osteosarcoma: Not Just the Usual Suspects

Rettew

Getty

Greenfield

2014

Advances in Experimental Medicine and Biology

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Despite aggressive surgical and chemotherapy protocols, survival rates for osteosarcoma patients have not improved over the last 30 years. Therefore, novel therapeutic agents are needed. Receptor tyrosine kinases have emerged as targets for the development of new cancer therapies since their activation leads to enhanced proliferation, survival, and metastasis. In fact, aberrant expression and activation of RTKs have been associated with the progression of many cancers. Studies from our lab using phosphoproteomic screening identified RTKs that are activated and thus may contribute to the signaling within metastatic human osteosarcoma cells. Functional genomic screening using siRNA was performed to distinguish which of the activated RTKs contribute to in vitro phenotypes associated with metastatic potential (motility, invasion, colony formation, and cell growth). The resulting RTK hits were then validated using independent validation experiments. From these results, we identified four RTKs (Axl, EphB2, FGFR2, and Ret) that have not been previously studied in osteosarcoma and provide targets for the development of novel therapeutics.

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Targeting Eph receptors with peptides and small molecules: Progress and challenges

Cited by 90 publications

References 63 publications

Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis

Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis

EphA2 Targeting Pegylated Nanocarrier Drug Delivery System for Treatment of Lung Cancer

Receptor Tyrosine Kinases in Osteosarcoma: Not Just the Usual Suspects

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