Ronit Satchi-fainaro
Tel Aviv University, Physiology and Pharmacology, Faculty Member
Page 1. 591 20 Ligand-Assisted Vascular Targeting of Polymer Therapeutics Anat Eldar-Boock, Dina Polyak, and Ronit Satchi-Fainaro 20.1 Overview of Tumor Angiogenesis Angiogenesis – the generation of new blood vessels ...
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... Standard Article. Polymer Therapeutics. Keren Miller,; Ronit Satchi-Fainaro. Published Online: 15 MAY 2008. DOI: 10.1002/9780470048672.wecb462. Copyright © 2007 John Wiley & Sons, Inc. All rights reserved. Book Title.... more
... Standard Article. Polymer Therapeutics. Keren Miller,; Ronit Satchi-Fainaro. Published Online: 15 MAY 2008. DOI: 10.1002/9780470048672.wecb462. Copyright © 2007 John Wiley & Sons, Inc. All rights reserved. Book Title. Wiley Encyclopedia of Chemical Biology. ...
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We report a chemiluminescent probe that permits the paired detection of tyrosinase (Tyr) and biological thiols. The Tyr-formed benzoquinone intermediate reacts with GSH and produces an enhanced chemiluminescence response.
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Research Interests: Biochemistry, Chemistry, Cancer, Medicine, Humans, and 15 moreEndothelial Cells, Escherichia coli, Mice, Animals, Peptide, Recombinant DNA, Amino Acid Profile, Protein Conformation, Amino Acid Sequence, Antitumor Activity, Histidine, Adenocarcinoma, Molecular Sequence Data, Pancreatic neoplasms, and Endostatin
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Surgical excision of a primary tumor was repeatedly shown to promote metastatic growth. However, several case studies have reported regression of metastases following tumor excision. Here we studied a luciferase-2-labelled human breast... more
Surgical excision of a primary tumor was repeatedly shown to promote metastatic growth. However, several case studies have reported regression of metastases following tumor excision. Here we studied a luciferase-2-labelled human breast cancer cell line (MDA-MB-231) orthotopically implanted in nude mice. Primary tumors and metastatic progression were continuously monitored by bioluminescence imaging, and the primary tumor was excised shortly following metastases identification. Intriguingly, a reliable and robust 10–100 fold decrease in metastatic signal occurred gradually within 24 h of tumor excision. Subcutaneous implantation of osmotic minipumps containing conditioned medium from tumor cells, simultaneously with tumor excision, significantly attenuated this metastatic regression, indicating a stimulating signal from the primary tumor to remote malignant foci. Independently of this cross-talk, NK cells also mediated this regression of metastases, as indicated by two approaches of NK-depletion. Importantly, following tumor excision, the metastatic foci regressed into dormant micrometastases; however, extensive surgery simultaneously with tumor excision attenuated this regression and elicited an outbreak of these dormant micrometastases. Based on our previous work, we hypothesized that surgical inflammatory stress responses underlie this metastatic progression. Indeed, a short perioperative β -adrenergic blockade and COX-2 inhibition (using propranolol and etodolac) prevented this metastatic outbreak. This is a first model for post-excision metastatic regression into dormancy, and for the perioperative efficacy of this combined drug regimen in the context of evident micrometastases of a human malignancy.
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An amendment to this paper has been published and can be accessed via the original article.
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Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor (PT) excision, but underlying mechanisms are elusive. Here we present a model of metastases regression and latency following PT... more
Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor (PT) excision, but underlying mechanisms are elusive. Here we present a model of metastases regression and latency following PT excision, and identify potential underlying mechanisms. Using MDA-MB-231HM human breast cancer cells that express highly sensitive luciferase, we were able to monitor early stages of spontaneous metastases development in BALB/c nu/nu mice. Removal of the PT caused marked regression of the smallest micro-metastases, but not of larger metastases, and in vivo supplementation of tumor secretome diminished this regression, suggesting that PT-secreted factors promote early metastatic growth. Correspondingly, cancer cell conditioned medium reduced apoptosis and enhanced MDA-MB-231HM adhesion in vitro. To identify specific mediating factors, cytokine array and proteomic analysis of MDA-MB-231HM secretome were conducted. Results identified significant enrichme...
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Dendritic cells (DC) are antigen-presenting cells with an important role in the initiation and regulation of the innate and adaptive arms of the immune system. By efficient presentation of antigens, DC elicit an antigen-specific immune... more
Dendritic cells (DC) are antigen-presenting cells with an important role in the initiation and regulation of the innate and adaptive arms of the immune system. By efficient presentation of antigens, DC elicit an antigen-specific immune response. Therefore, we previously established in our laboratory a melanoma-DC-targeted NP that was evaluated and validated against aggressive melanoma. Although DC-therapy is mainly exploited in the treatment of cancer, DC are becoming a key therapeutic target in other pathologies such as infectious diseases. Viral pathogens, similarly, to cancer, modulate the host defense mechanisms to their benefit. COVID-19, an ongoing pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally and is already infecting tens of millions of people worldwide. Historically, vaccines are among therapies with the greatest impact in health and constitute an unmet medical need against coronavirus disease-19 (COVID-19) pandemic. To that end, we repurposed our recently published melanoma-targeted NP to co-deliver modulators of host immune response and SARS-CoV-2 specific antigen epitopes discovered by a computational approach integrating 3D information with large-scale statistical analysis. The immune response kinetics in patients infected with SARS-CoV-2 is poorly understood, but recent reports show that germinal B cells and active follicular T-helper cells, IgM/IgG SARS-CoV-2 antibodies, in addition to an enhanced cellular immunity, are found in patients with mild-to-moderate SARS-CoV-2 infection. Our preliminary data demonstrated that our nano-vaccine was able to activate specific immune cell response of effector T cells and B cells and decrease the regulatory activity of T cells, compared to controls. Moreover, we found that our DC-targeted SARS-CoV-2 NP successfully induced antigen-specific secretion of IgM and IgG antibodies with high binding affinity to the antigens. Importantly, our nano-vaccine elicited specific neutralization of Spike virus like particles (VLPs) by sera of immunized mice. We hypothesize that implementing our novel nano-vaccine platform for COVID-19 will lead to a safe and efficacious COVID-19 vaccine ready for first-in-human clinical trials. Citation Format: Daniella Vaskovich-Koubi, Ron Kleiner, Yulia Liubomirski, Eilam Yeini, Galia Tiram, Sabina Pozzi, Anat Eldar-Boock, Helena F. Florindo, Ronit Satchi-Fainaro. From cancer to COVID-19- development of a dendritic cell-targeted nano-vaccine for prevention and therapy of COVID-19 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 714.
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Research Interests: Cancer Research, Tumor microenvironment, Melanoma, Microglia, CD, and 3 moreChemokine, In Vivo, and CCR
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Research Interests: Biochemistry, Chemistry, Immunology, Molecular Biology, Biotechnology, and 15 moreCancer, Cell Biology, Cancer Research, Medicine, Gene expression, Gene Silencing, Humans, Mice, Animals, Cancer cell migration, Bioconjugate Chemistry, CD, Amino Acid Sequence, Biochemistry and cell biology, and Neoplasm metastasis
Glioblastoma (GB) is the most aggressive neoplasm of the brain. Poor prognosis is mainly attributed to tumor heterogeneity, invasiveness and drug resistance. Only a small fraction of GB patients survives longer than 24 months from the... more
Glioblastoma (GB) is the most aggressive neoplasm of the brain. Poor prognosis is mainly attributed to tumor heterogeneity, invasiveness and drug resistance. Only a small fraction of GB patients survives longer than 24 months from the time of diagnosis (ie, long‐term survivors [LTS]). In our study, we aimed to identify molecular markers associated with favorable GB prognosis as a basis to develop therapeutic applications to improve patients' outcome. We have recently assembled a proteogenomic dataset of 87 GB clinical samples of varying survival rates. Following RNA‐seq and mass spectrometry (MS)‐based proteomics analysis, we identified several differentially expressed genes and proteins, including some known cancer‐related pathways and some less established that showed higher expression in short‐term (<6 months) survivors (STS) compared to LTS. One such target found was deoxyhypusine hydroxylase (DOHH), which is known to be involved in the biosynthesis of hypusine, an unusual amino acid essential for the function of the eukaryotic translation initiation factor 5A (eIF5A), which promotes tumor growth. We consequently validated DOHH overexpression in STS samples by quantitative polymerase chain reaction (qPCR) and immunohistochemistry. We further showed robust inhibition of proliferation, migration and invasion of GB cells following silencing of DOHH with short hairpin RNA (shRNA) or inhibition of its activity with small molecules, ciclopirox and deferiprone. Moreover, DOHH silencing led to significant inhibition of tumor progression and prolonged survival in GB mouse models. Searching for a potential mechanism by which DOHH promotes tumor aggressiveness, we found that it supports the transition of GB cells to a more invasive phenotype via epithelial‐mesenchymal transition (EMT)‐related pathways.
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The ability to detect pathways that malignant tissue depends on, combined with the specific gene-knockdown ability of siRNA/miRNA, may revolutionize cancer treatment. The capability of providing personalized care to cancer patients allows... more
The ability to detect pathways that malignant tissue depends on, combined with the specific gene-knockdown ability of siRNA/miRNA, may revolutionize cancer treatment. The capability of providing personalized care to cancer patients allows therapy to be specifically tailored for each case. Several studies of malignant and nonmalignant tissues have been performed in the context of global protein interaction networks in order to find the optimal targets, providing a list of potential gene and protein targets for each cancer type and for each patient. Nevertheless, due to poor stability of RNAi molecules in physiological conditions and its inability to cross cellular membranes, the in vivo delivery of siRNA and miRNA holds a great challenge and remains a crucial issue for its therapeutic success. Supramolecular carriers are often used in order to improve the physicochemical and biopharmaceutical properties of RNAi. Nanoscale drug delivery systems will enable the accumulation of the drugs in the tumors due to the enhanced permeability and retention (EPR) effect, and release the siRNA/miRNA only inside the target cell. In addition, a targeting moiety can increase the selectivity and specific uptake in the target tissue. Several vehicles (dendrimers, nanoparticles, polyplex, lipoplex, polymeric nanoconjugates) are being developed for siRNA/miRNA delivery. These vehicles provide an important tool for exploiting the full potential of nucleic acids as therapeutic agents. In this chapter, we will review the different approaches to deliver oligonucleotides in vivo.
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Overcoming drug resistance, emerging either on recurring cancer or metastasis, is a major target of cancer treatments. The combination of anti-angiogenic therapy with cytotoxic therapy offers a promising therapeutic approach. Paclitaxel... more
Overcoming drug resistance, emerging either on recurring cancer or metastasis, is a major target of cancer treatments. The combination of anti-angiogenic therapy with cytotoxic therapy offers a promising therapeutic approach. Paclitaxel (PTX) is a widely-used potent cytotoxic drug, which also exhibits anti-angiogenic activity at low doses. The use of the hydrophobic PTX to its full potential is limited by severe side effects, caused by the drug and its solubilizing agents. Integrins play a key role in cell matrix interactions. The highly restricted expression of integrin αvβ3, overexpressed on tumor endothelial and some epithelial cells, during tumor growth, invasion, and metastasis present an interesting molecular target for metastatic breast tumors. In addition, PTX acquired resistance correlated with integrin αvβ3 overexpression on breast cancer cells. We designed and synthesized a novel polyglutamic acid (PGA)-PTX-E-[c(RGDfK)2] nano-scaled conjugate. Polymer conjugation converted PTX to a water-soluble macromolecule, which passively targeted the tumor tissue exploiting the enhanced permeability and retention (EPR) effect, while extravasating via the leaky tumor neovasculature. The E-[c(RGDfK)2] enhanced the effects previously seen for PGA-PTX alone, utilizing the additional active targeting to the αvβ3 integrin. PGA is enzymatically-degradable by cathepsin B, leading to PTX release. PGA-PTX-E-[c(RGDfK)2] displayed a potent anti-angiogenic therapy, determined by several, well-established, in vitro assays. Mice bearing orthotopic mammary tumors demonstrated preferential tumor accumulation of the RGD-bearing conjugate, leading to enhanced antitumor efficacy and a marked decreased in toxicity compared with free PTX. The correlation between αvβ3 integrin expression on tumor cells and acquired PTX-resistance was determined by in vitro manipulation of αvβ3 overexpressing-cells and by examining subsets of primary versus metastatic or recurring tumors of PTX-treated patients as well as free and conjugated-PTX-treated tumor-bearing mice. Taken together, our conjugate alters the pharmacokinetics of free PTX. Inclusion of an active targeting moiety to integrin expressing-cells, have the potential to manipulate and overcome acquired drug resistance, which will hopefully warrant it as a novel targeted, anti-angiogenic and anticancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5225. doi:1538-7445.AM2012-5225
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Colorectal cancer (CRC) reflects the fourth most frequent etiology of brain metastasis (BM), with rising incidence. Yet, molecular mechanisms supporting the formation of these lesions from CRC are unknown. We aimed to explore drivers... more
Colorectal cancer (CRC) reflects the fourth most frequent etiology of brain metastasis (BM), with rising incidence. Yet, molecular mechanisms supporting the formation of these lesions from CRC are unknown. We aimed to explore drivers enabling tropism and adaptation of CRC cells to the brain environment and decipher mechanisms facilitating the process. We analyzed the FoundationOne database, which contains genomic alterations data of cancer-related genes in over 16,000 human CRC primary and metastasis samples. Increased prevalence of IRS2 gene amplification was observed in 13% of BM, compared to only 3% of primary tumors or other metastatic sites. IRS2 is a cytoplasmic adaptor mediating effects of insulin and IGF-1 receptors and is involved in more aggressive behavior of different cancer types. In agreement with the genomic data, immunohistochemistry of human clinical samples showed increased expression of IRS2 protein in BM. We constructed an in vitro system mimicking the brain micr...
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ABSTRACTColorectal cancer (CRC) is currently the fourth leading etiology of brain metastasis (BM). Yet, mechanisms supporting the formation of CRC BM are mostly unknown. In order to identify drivers that lead to tropism and adaptation of... more
ABSTRACTColorectal cancer (CRC) is currently the fourth leading etiology of brain metastasis (BM). Yet, mechanisms supporting the formation of CRC BM are mostly unknown. In order to identify drivers that lead to tropism and adaptation of CRC cells to the brain environment, we analyzed an extensive genomic database, consisting of over 36,000 human CRC primary and metastasis samples. Several genomic alterations specific for BM were noted, among them increased prevalence of insulin receptor substrate 2 (IRS2) amplification, observed in 7.6% of BM, compared to only 2.9% of primary tumors or other metastatic sites (p<7E-05). This observation was validated by Immunohistochemistry studies of human clinical samples, showing increased expression of IRS2 protein in BM. IRS2 is a cytoplasmic adaptor mediating effects of insulin and IGF-1 receptors and is involved in more aggressive behavior of different cancer types. In order to study the ability of IRS2 to promote growth of CRC cells under...
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Development of chemo-resistance is a major challenge in glioblastoma (GB) treatment. This phenomenon is often driven by increased activation of genes associated with DNA repair, such as the alkyl-removing enzyme O6-methylguanine-DNA... more
Development of chemo-resistance is a major challenge in glioblastoma (GB) treatment. This phenomenon is often driven by increased activation of genes associated with DNA repair, such as the alkyl-removing enzyme O6-methylguanine-DNA methyltransferase (MGMT) in combination with overexpression of canonical genes related to cell proliferation and tumor progression, such as Polo-like kinase 1 (Plk1). Hereby, we attempt to sensitize resistant GB cells using our established amphiphilic poly(α)glutamate (APA): small interfering RNA (siRNA) polyplexes, targeting Plk1. Furthermore, we improved brain-targeting by decorating our nanocarrier with sulfonate groups. Our sulfonated nanocarrier showed superior selectivity towards P-selectin (SELP), a transmembrane glycoprotein overexpressed in GB and angiogenic brain endothelial cells. Self-assembled polyplexes of sulfonated APA and siPlk1 internalized into GB cells and into our unique 3-dimensional (3D) GB spheroids inducing specific gene silencin...
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Colorectal cancer (CRC) reflects the fourth most frequent etiology of brain metastasis (BM), with rising incidence. Yet, molecular mechanisms supporting the formation of these lesions from CRC are unknown. We aimed to explore drivers... more
Colorectal cancer (CRC) reflects the fourth most frequent etiology of brain metastasis (BM), with rising incidence. Yet, molecular mechanisms supporting the formation of these lesions from CRC are unknown. We aimed to explore drivers enabling tropism and adaptation of CRC cells to the brain environment and decipher mechanisms facilitating the process. We analyzed the FoundationOne database, which contains genomic alterations data of cancer-related genes in over 16,000 human CRC primary and metastasis samples. Increased prevalence of insulin receptor substrate 2 (IRS2) gene amplification was noted in BMs relative to primary tumors and other metastatic sites. IRS2 is a cytoplasmic adaptor mediating effects of insulin and IGF-1 receptors and is known to be involved in more aggressive behavior of different cancer types. In agreement with the genomic data, immunohistochemistry of human clinical samples showed increased expression of IRS2 protein in BMs. We subsequently constructed an in ...
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1108 In recent years it has become clear that angiogenesis, new capillary blood vessel growth from pre-existing vasculature, is crucial for tumor progression and metastases. Consequently, the microvascular endothelial cell, recruited by a... more
1108 In recent years it has become clear that angiogenesis, new capillary blood vessel growth from pre-existing vasculature, is crucial for tumor progression and metastases. Consequently, the microvascular endothelial cell, recruited by a tumor, has become an important target in cancer therapy. Akt, a serine/threonine protein kinase, has been implicated in the vascular endothelial growth factor (VEGF) signaling pathway of many tumor types promoting VEGF secretion. Akt is chronically activated not only in tumor cells, but also in VEGF-stimulated tumor endothelial cells, and induces angiogenesis via its downstream effectors. For that reason, Akt has become an attractive drug target for cancer therapy. Several Akt inhibitors are today in clinical trials but they all suffer from lack of selectivity and specificity.
In order to overcome those limitations, we propose to inhibit the overexpressed Akt1 in tumors and their surrounding endothelial cells by using RNA interference. Still, this...
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Colorectal cancer (CRC) reflects the fourth most frequent etiology of brain metastasis (BM). Yet, molecular mechanisms supporting it are unknown. We aimed to explore drivers enabling adaptation of CRC cells to the brain and decipher... more
Colorectal cancer (CRC) reflects the fourth most frequent etiology of brain metastasis (BM). Yet, molecular mechanisms supporting it are unknown. We aimed to explore drivers enabling adaptation of CRC cells to the brain and decipher mechanisms facilitating the process. We analyzed the FoundationOne database, which contains genomic alterations data of cancer-related genes in over 16,000 human CRC primary and metastasis samples. Increased prevalence of IRS2 gene amplification was observed in 13% of BM, compared to only 3% of primary tumors or other metastatic sites. IRS2 is a cytoplasmic adaptor mediating effects of insulin and IGF-1 receptors and is involved in more aggressive behavior of different cancer types. In agreement with the genomic data, immunohistochemistry of human clinical samples showed increased expression of IRS2 protein in BM. We constructed an in-vitro system mimicking the brain microenvironment using cultured human astrocytes or their conditioned media. Under these...
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Brain metastases (BMs) from colorectal cancer (CRC) are currently the fourths leading cause of BMs, and their incidence is on the rise. Yet, mechanisms mediating the formation of BMs from CRC are unknown. We aimed to explore genomic... more
Brain metastases (BMs) from colorectal cancer (CRC) are currently the fourths leading cause of BMs, and their incidence is on the rise. Yet, mechanisms mediating the formation of BMs from CRC are unknown. We aimed to explore genomic drivers enabling tropism and adaptation of CRC cells to the brain environment and decipher mechanisms facilitating the process. We analyzed FoundationOne database, which contains genomic alterations data of cancer-related genes in over 16,000 human CRC primary and metastasis samples. Increased prevalence was noted in the insulin receptor substrate 2 (IRS2) gene, which was significantly amplified in BMs relative to primary tumors and other metastatic sites. IRS2 is a cytoplasmic adaptor mediating effects of insulin and IGF-1 receptors and is known to be involved in more aggressive behavior of different cancer types. In agreement with the genomic data, immunohistochemistry of human clinical samples showed increased expression of IRS2 protein in BMs. Next, ...
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Small sized, microscopic, non-invasive, avascular and therefore asymptomatic tumors can remain in their dormant stage for considerable period of time depending on numerous processes. One crucial mechanism underlying the transformation... more
Small sized, microscopic, non-invasive, avascular and therefore asymptomatic tumors can remain in their dormant stage for considerable period of time depending on numerous processes. One crucial mechanism underlying the transformation from a dormant phenotype to a fast-growing phenotype is the ability of the tumor cells to induce angiogenesis, a phenomenon termed as the “angiogenic switch”. Suspected dormant tumor-generating clone, derived from aggressive tumor-forming U-87 MG human glioblastoma cell line, was isolated using single-cell clone and identified by gene expression signature of dormant tumors (Almog et al., Cancer Research 2009). In order to evaluate the phenotypic differences between cell lines that generate dormant avascular tumors or fast-growing angiogenic tumors, we established a pair of mCherry-labeled human glioblastoma cell lines, U-87-D (Dormant) derived from the parental U-87-F (Fast-growing). While the two cell lines share similar growth rate in vitro, we found...