Bio

Professional Education


  • Master of Science, Hebrew University Of Jerusalem (2005)
  • Bachelor of Science, Unlisted University (2003)
  • Doctor of Philosophy, Tel-Aviv University (2012)
  • Engineer, Technion, Israel Instit Of Technology (1996)

Stanford Advisors


Research & Scholarship

Current Research and Scholarly Interests


(I) Screening for biomarkers of tumor-associated immune cells
(II) Development of smart probes for early detection of pancreatic cancer.

Publications

Journal Articles


  • Prospective Identification of Glioblastoma Cells Generating Dormant Tumors PLOS ONE Satchi-Fainaro, R., Ferber, S., Segal, E., Ma, L., Dixit, N., Ijaz, A., Hlatky, L., Abdollahi, A., Almog, N. 2012; 7 (9)

    Abstract

    Although dormant tumors are highly prevalent within the human population, the underlying mechanisms are still mostly unknown. We have previously identified the consensus gene expression pattern of dormant tumors. Here, we show that this gene expression signature could be used for the isolation and identification of clones which generate dormant tumors. We established single cell-derived clones from the aggressive tumor-generating U-87 MG human glioblastoma cell line. Based only on the expression pattern of genes which were previously shown to be associated with tumor dormancy, we identified clones which generate dormant tumors. We show that very high expression levels of thrombospondin and high expression levels of angiomotin and insulin-like growth factor binding protein 5 (IGFBP5), together with low levels of endothelial specific marker (ESM) 1 and epithelial growth factor receptor (EGFR) characterize the clone which generates dormant U-87 MG derived glioblastomas. These tumors remained indolent both in subcutaneous and orthotopic intracranial sites, in spite of a high prevalence of proliferating cells. We further show that tumor cells which form U-87 MG derived dormant tumors have an impaired angiogenesis potential both in vitro and in vivo and have a slower invasion capacity. This work demonstrates that fast-growing tumors contain tumor cells that when isolated will form dormant tumors and serves as a proof-of-concept for the use of transcriptome profiles in the identification of such cells. Isolating the tumor cells that form dormant tumors will facilitate understanding of the underlying mechanisms of dormant micro-metastases, late recurrence, and changes in rate of tumor progression.

    View details for DOI 10.1371/journal.pone.0044395

    View details for Web of Science ID 000308458400064

    View details for PubMedID 22970208

  • Tumor-Initiating Cells of Various Tumor Types Exhibit Differential Angiogenic Properties and React Differently to Antiangiogenic Drugs STEM CELLS Benayoun, L., Gingis-Velitski, S., Voloshin, T., Segal, E., Segev, R., Munster, M., Bril, R., Satchi-Fainaro, R., Scherer, S. J., Shaked, Y. 2012; 30 (9): 1831-1841

    Abstract

    Tumor-initiating cells (TICs) are a subtype of tumor cells believed to be critical for initiating tumorigenesis. We sought to determine the angiogenic properties of TICs in different tumor types including U-87MG (glioblastoma), HT29 (colon), MCF7 (breast), A549 (non-small-cell lung), and PANC1 (pancreatic) cancers. Long-term cultures grown either as monolayers ("TIC-low") or as nonadherent tumor spheres ("TIC-high") were generated. The TIC-high fractions exhibited increased expression of stem cell surface markers, high aldehyde dehydrogenase activity, high expression of p21, and resistance to standard chemotherapy in comparison to TIC-low fractions. Furthermore, TICs from U-87MG and HT29 but not from MCF7, A549, and PANC1 tumor types possess increased angiogenic activity. Consequently, the efficacy of vascular endothelial growth factor-A (VEGF-A) neutralizing antibody is limited only to those tumors that are dependent on VEGF-A activity. In addition, such therapy had little or reversed antiangiogenic effects on tumors that do not necessarily rely on VEGF-dependent angiogenesis. Differential angiogenic activity and antiangiogenic therapy sensitivity were also observed in TICs of the same tumor type, suggesting redundant angiogenic pathways. Collectively, our results suggest that the efficacy of antiangiogenic drugs is dependent on the angiogenic properties of TICs and, therefore, can serve as a possible biomarker to predict antiangiogenic treatment efficacy.

    View details for DOI 10.1002/stem.1170

    View details for Web of Science ID 000307820200006

    View details for PubMedID 22782858

  • Enhanced anti-tumor activity and safety profile of targeted nano-scaled HPMA copolymer-alendronate-TNP-470 conjugate in the treatment of bone malignances BIOMATERIALS Segal, E., Pan, H., Benayoun, L., Kopeckova, P., Shaked, Y., Kopecek, J., Satchi-Fainaro, R. 2011; 32 (19): 4450-4463

    Abstract

    Bone neoplasms, such as osteosarcoma, exhibit a propensity for systemic metastases resulting in adverse clinical outcome. Traditional treatment consisting of aggressive chemotherapy combined with surgical resection, has been the mainstay of these malignances. Therefore, bone-targeted non-toxic therapies are required. We previously conjugated the aminobisphosphonate alendronate (ALN), and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. HPMA copolymer-ALN-TNP-470 conjugate exhibited improved anti-angiogenic and anti-tumor activity compared with the combination of free ALN and TNP-470 when evaluated in a xenogeneic model of human osteosarcoma. The immune system has major effect on toxicology studies and on tumor progression. Therefore, in this manuscript we examined the safety and efficacy profiles of the conjugate using murine osteosarcoma syngeneic model. Toxicity and efficacy evaluation revealed superior anti-tumor activity and decreased organ-related toxicities of the conjugate compared with the combination of free ALN plus TNP-470. Finally, comparative anti-angiogenic activity and specificity studies, using surrogate biomarkers of circulating endothelial cells (CEC), highlighted the advantage of the conjugate over the free agents. The therapeutic platform described here may have clinical translational relevance for the treatment of bone-related angiogenesis-dependent malignances.

    View details for DOI 10.1016/j.biomaterials.2011.02.059

    View details for Web of Science ID 000291171700015

    View details for PubMedID 21429572

  • Antiangiogenic Antitumor Activity of HPMA Copolymer-Paclitaxel-Alendronate Conjugate on Breast Cancer Bone Metastasis Mouse Model MOLECULAR PHARMACEUTICS Miller, K., Eldar-Boock, A., Polyak, D., Segal, E., Benayoun, L., Shaked, Y., Satchi-Fainaro, R. 2011; 8 (4): 1052-1062

    Abstract

    Polymer therapeutics have shown promise as tumor-targeted drug delivery systems in mice. The multivalency of polymers allows the attachment of different functional agents to a polymeric backbone, including chemotherapeutic and antiangiogenic drugs, as well as targeting moieties, such as the bone-targeting agent alendronate (ALN). We previously reported the conjugation of ALN and the chemotherapeutic drug paclitaxel (PTX) with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. The in vitro physicochemical properties, cancer cytotoxicity and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate were extensively characterized. The reported results warranted in vivo evaluations of the conjugate. In this manuscript, we evaluated the in vivo anticancer and antiangiogenic activity of HPMA copolymer-PTX-ALN conjugate. The conjugate exhibited an antiangiogenic effect by decreasing microvessel density (MVD), and inducing apoptotic circulating endothelial cells (CEC) following treatment of the mice. Using intravital imaging system and mCherry-labeled breast cancer cell lines, we were able to monitor noninvasively the progression of orthotopic metastatic tumors injected into the tibia of the mice. HPMA copolymer-PTX-ALN conjugate showed the greatest antitumor efficacy on mCherry-labeled 4T1 mammary adenocarcinoma inoculated into the tibia, as compared with PTX alone or in combination with ALN. Treatment with the bone-targeted polymeric conjugate demonstrated improved efficacy, was better tolerated, and was more easily administered intravenously than the clinically used PTX formulated in Cremophor/ethanol.

    View details for DOI 10.1021/mp200083n

    View details for Web of Science ID 000293307400008

    View details for PubMedID 21545170

  • Real-time monitoring of drug release CHEMICAL COMMUNICATIONS Weinstain, R., Segal, E., Satchi-Fainaro, R., Shabat, D. 2010; 46 (4): 553-555

    Abstract

    A new prodrug system, assembled using a distinctive coumarin linker, was demonstrated to report real-time activation and drug release in vitro.

    View details for DOI 10.1039/b919329d

    View details for Web of Science ID 000273485600008

    View details for PubMedID 20062859

  • Design and development of polymer conjugates as anti-angiogenic agents ADVANCED DRUG DELIVERY REVIEWS Segal, E., Satchi-Fainaro, R. 2009; 61 (13): 1159-1176

    Abstract

    Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is one of the central key steps in tumor progression and metastasis. Consequently, it became an important target in cancer therapy, making novel angiogenesis inhibitors a new modality of anticancer agents. Although relative to conventional chemotherapy, anti-angiogenic agents display a safer toxicity profile, the vast majority of these agents are low-molecular-weight compounds exhibiting poor pharmacokinetic profile with short half-life in the bloodstream and high overall clearance rate. The "Polymer Therapeutics" field has significantly improved the therapeutic potential of low-molecular-weight drugs and proteins for cancer treatment. Drugs can be conjugated to polymeric carriers that can be either directly conjugated to targeting proteins or peptides or derivatized with adapters conjugated to a targeting moiety. This approach holds a significant promise for the development of new targeted anti-angiogenic therapies as well as for the optimization of existing anti-angiogenic drugs or polypeptides. Here we overview the innovative approach of targeting tumor angiogenesis using polymer therapeutics.

    View details for DOI 10.1016/j.addr.2009.06.005

    View details for Web of Science ID 000271769600005

    View details for PubMedID 19699248

  • Enhanced cytotoxicity of a polymer-drug conjugate with triple payload of paclitaxel BIOORGANIC & MEDICINAL CHEMISTRY Erez, R., Segal, E., Miller, K., Satchi-Fainaro, R., Shabat, D. 2009; 17 (13): 4327-4335

    Abstract

    The development of targeting approaches to selectively release chemotherapeutic drugs into malignant tissue is a major challenge in anticancer therapy. We have synthesized an N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymer-drug conjugate with an AB(3) self-immolative dendritic linker. HPMA copolymers are known to accumulate selectively in tumors. The water-soluble polymer-drug conjugate was designed to release a triple payload of the hydrophobic drug paclitaxel as a result of cleavage by the endogenous enzyme cathepsin B. The polymer-drug conjugate exhibited enhanced cytotoxicity on murine prostate adenocarcinoma (TRAMP C2) cells in comparison to a classic monomeric drug-polymer conjugate.

    View details for DOI 10.1016/j.bmc.2009.05.028

    View details for Web of Science ID 000266822900009

    View details for PubMedID 19482477

  • Targeting Angiogenesis-Dependent Calcified Neoplasms Using Combined Polymer Therapeutics PLOS ONE Segal, E., Pan, H., Ofek, P., Udagawa, T., Kopeckova, P., Kopecek, J., Satchi-Fainaro, R. 2009; 4 (4)

    Abstract

    There is an immense clinical need for novel therapeutics for the treatment of angiogenesis-dependent calcified neoplasms such as osteosarcomas and bone metastases. We developed a new therapeutic strategy to target bone metastases and calcified neoplasms using combined polymer-bound angiogenesis inhibitors. Using an advanced "living polymerization" technique, the reversible addition-fragmentation chain transfer (RAFT), we conjugated the aminobisphosphonate alendronate (ALN), and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer through a Glycine-Glycine-Proline-Norleucine linker, cleaved by cathepsin K, a cysteine protease overexpressed at resorption sites in bone tissues. In this approach, dual targeting is achieved. Passive accumulation is possible due to the increase in molecular weight following polymer conjugation of the drugs, thus extravasating from the tumor leaky vessels and not from normal healthy vessels. Active targeting to the calcified tissues is achieved by ALN's affinity to bone mineral. METHODS AND FINDING: The anti-angiogenic and antitumor potency of HPMA copolymer-ALN-TNP-470 conjugate was evaluated both in vitro and in vivo. We show that free and conjugated ALN-TNP-470 have synergistic anti-angiogenic and antitumor activity by inhibiting proliferation, migration and capillary-like tube formation of endothelial and human osteosarcoma cells in vitro. Evaluation of anti-angiogenic, antitumor activity and body distribution of HPMA copolymer-ALN-TNP-470 conjugate was performed on severe combined immunodeficiency (SCID) male mice inoculated with mCherry-labeled MG-63-Ras human osteosarcoma and by modified Miles permeability assay. Our targeted bi-specific conjugate reduced VEGF-induced vascular hyperpermeability by 92% and remarkably inhibited osteosarcoma growth in mice by 96%.This is the first report to describe a new concept of a narrowly-dispersed combined polymer therapeutic designed to target both tumor and endothelial compartments of bone metastases and calcified neoplasms at a single administration. This new approach of co-delivery of two synergistic drugs may have clinical utility as a potential therapy for angiogenesis-dependent cancers such as osteosarcoma and bone metastases.

    View details for DOI 10.1371/journal.pone.0005233

    View details for Web of Science ID 000265513800009

    View details for PubMedID 19381291

  • Targeting Bone Metastases with a Bispecific Anticancer and Antiangiogenic Polymer-Alendronate-Taxane Conjugate ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Miller, K., Erez, R., Segal, E., Shabat, D., Satchi-Fainaro, R. 2009; 48 (16): 2949-2954

    Abstract

    A polymer therapeutic designed for combination anticancer and antiangiogenic therapy inhibited the proliferation of prostate carcinoma cells and the proliferation, migration, and tube-formation of endothelial cells. The nanoconjugate was formed from an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, the bisphosphonate alendronate (for bone targeting), and the chemotherapy agent paclitaxel (PTX), which is cleaved by cathepsin B (see scheme).

    View details for DOI 10.1002/anie.200805133

    View details for Web of Science ID 000265230900025

    View details for PubMedID 19294707

  • Remarkable drug-release enhancement with an elimination-based AB(3) self-immolative dendritic amplifier BIOORGANIC & MEDICINAL CHEMISTRY Sagi, A., Segal, E., Satchi-Fainaro, R., Shabat, D. 2007; 15 (11): 3720-3727

    Abstract

    Self-immolative dendritic prodrugs, activated through a single catalytic reaction by a specific enzyme, could offer significant advantages in inhibition of tumor growth relative to monomeric prodrug, especially if the targeted or secreted enzyme exists at relatively low levels in the malignant tissue. We have designed and synthesized new AB(3) self-immolative dendritic prodrug system that releases three active drugs by a single cleavage of the enzyme penicillin-G-amidase. The cleavage signal is transferred from the dendron focal point to its periphery through fast elimination reactions and the design leads to three-fold signal amplification. In cell-growth inhibition assays, the elimination-based AB(3) self-immolative dendritic prodrug was significantly more effective than a cyclization-based AB(3) dendritic prodrug.

    View details for DOI 10.1016/j.bmc.2007.03.054

    View details for Web of Science ID 000246649000013

    View details for PubMedID 17416532

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