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תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Tel Hashomer Medical Research Infrastructure and Services Ltd. Novel Therapeutics for Human Diseases Contact : Sylvie Luria PhD. Technology Transfer and Business & Development Manager Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Cell: 052-6667277 [email protected] http://research.sheba.co.il/e/ 1 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Cancer Therapy Targeting the SIL Regulator Gene The STIL (SIL) gene, SCL (Stem Cell Leukemia TAL1 Interrupting Locus), located on chromosome 1, was cloned from the most common chromosomal rearrangement in T cell Acute Lymphoblastic Leukemia. It encodes a 150 kDa cytosolic and centrosomal protein conserved in vertebrates. STIL is tightly regulated during the cell cycle. It is expressed only in proliferating cells, reaching a peak in mitosis during which the protein is phosphorylated and then degraded upon entrance to the next cell cycle. The critical requirement of STIL for cell growth, proliferation and survival during embryonic development, and its regulation during the cell cycle suggest that STIL might have a role in tumorogenesis. We have demonstrated increased expression of STIL RNA and protein in a wide variety of cancers. Further analysis revealed that genes with expression patterns similar to STIL were mitotic checkpoint genes regulated by the transcription factor E2F1 known to be activated in proliferating cells. The mitotic index is increased with expression of STIL and its expression in epithelial cancers is associated with metastases and poor prognosis. Inhibition of STIL expression by a specific anti STIL siRNA in colon cancer cells was established and demonstrated - STIL blocks mitotic entry and causes apoptosis of this colon cancer cells in-vitro and in-vivo. Similar results have been obtain on a variety of cancer cells representing the most common types of human cancer (Cervical, lung, breast, prostate, gliomas and renal cancer) using anti STIL siRNA oligonucleotides. The lethal effect of the knockdown of the human SIL is completely rescued by transfection of the murine STIL, demonstrating the specificity of the siRNA mediated approach. STIL is not necessary, however, for survival of all normal proliferating cells as we have mouse embryonic stem cells and fibroblasts that are negative for the STIL gene. We conclude that STIL is a good target for treating abnormal proliferation and cancer. Anti STIL activity was demonstrated to be effective in inhibiting tumor cell development in vitro and in vivo models for variety of human cancer models. 2 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Methods of Predicting Clinical Course and Treating Multiple Sclerosis Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS) affecting young adults (disease onset between 20 to 40 years of age) and is the third leading cause for disability after trauma and rheumatic diseases, with an estimated annual cost 34,000 USD per patient (total life time cost of 2.2 million USD per patient). The disease is characterized by destruction of myelin, associated with death of oligodendrocytes and axonal loss. The main pathologic finding in MS is the presence of infiltrating mononuclear cells, predominantly T lymphocytes and macrophages, which surpass the blood brain barrier and induce an active inflammation within the brain and spinal cord. The neurological symptoms that characterize MS include complete or partial vision loss, diplopia, sensory symptoms, motor weakness that can worsen to complete paralysis, bladder dysfunction and cognitive deficits, which eventually may lead to a significant disability. The associated multiple inflammatory foci lead to myelin destruction, plaques of demyelination, gliosis and axonal loss within the brain and spinal cord and are the reasons contribute to the clinical manifestations of neurological disability. The etiology of MS is not fully understood. The disease develops in genetically predisposed subjects exposed to yet undefined environmental factors and the pathogenesis involves autoimmune mechanisms associated with autoreactive T cells against myelin antigens. It is well established that not one dominant gene determines genetic susceptibility to develop MS, but rather many genes, each with different influence, are involved. We have discovered a unique gene set for Prediction and Diagnosis of Benign Multiple Sclerosis – New target for MS drug . Using high throughput gene expression analysis we have identified and characterized one of the major junctions involved in the determination of disease course amongst MS patients. Furthermore, we used the promoters and transcripts of these genes to generate reporter cell lines for high throughput drug discovery system. The promoters and transcripts of genes that participate in a certain pathway can serve as reporters for cellular drug discovery screening system for that particular pathway. The cell based functional drug discovery system based on analysis the signature map in human cells before and after drug treatment have two laboratory applications: 1) Primary cultured PBMS from MS patients or test cell culture treated with variety of drug candidates followed by multiplex assay to analyze expression of related genes: 2) Mammalian cells stably transfected with plasmids containing the promoters of BMS-specific genes coupled to variety of reporter genes for detection and drug discovery. Both assays combined with simultaneous multiplex analysis of wide range of MS related inflammatory related proteins such as cytokines, adhesion molecules and nerodegeneration factors in cultured media. Assay enables the discovery of potential drug to treat MS and variety of Inflammatory diseases. 3 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Novel Therapy for anti-phospholipid syndrome - APS Anti-phospholipid syndrome (APS) is an antibody-mediated autoimmune disease. APS, is a life threatening blood-clotting disorder, also known as Hughes’ syndrome, is characterized by the presence of anti-phospholipid (aPL) beta-2-glycoprotein-I (2GPI)–dependent antibodies or lupus anticoagulant associated with thromboembolic phenomena, thrombocytopenia, recurrent fetal loss, CNS, heart and other organs involvement. The diverse clinical manifestations are associated with elevated titers of circulating anti-beta-2glycoprotein-I (b2GPI ) antibodies (Abs), and lupus anticoagulant. This autoimmune disease afflicts up to two million patients, including many lupus patients, in the United States and Europe. Unlike the typical stroke patient, these patients often experience their first stroke, heart attack or miscarriage in their 20s and 30s and have twice the probability of a recurrence. We have identified unique peptides corresponding to 2GPI that were able to prevent anti2GPI related endothelial cell activation in-vitro and induction of experimental APS in an animal model. Antibodies specific to these synthetic peptides, induced by common bacteria and passively transferred into naïve mice, induced experimental APS. Previously, our studies were based on neutralization of anti-2GPI Ab function by specific synthetic peptides. And recently we have developed a methodology that addresses specific clone death induce apoptosis of the B cells which express the anti-2GPI immunoglobulin or the mature B cell population which secret the pathogenic autoantibody. There results were further analyzed in -2GPI in-vitro system and in experimental APS animal model. In addition, The results suggest a novel therapeutic approach in which B cells that will secrete pathogenic antibodies are targeted specifically. This strategy might also be applicable in the treatment of other diseases that are humorally mediated by antigen-specific antigen 4 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Rejuvenation of Myocardial Scarring The human heart has little or no capacity to regenerate. This is a major medical problem, because inadequate regeneration contributes to myocardial scarring, heart failure, arrhythmia, and death. As a single cause of death, ischemic heart disease is one of the leading causes of mortality worldwide among people ages. This disease results from occlusion of cardiac vessels leading to loss of cardiomyocytes causing million deaths every year. Scar thinning, enlargement and spherical deformation of the left ventricle with a concomitant increase in wall stress are key elements in the pathogenesis of adverse remodeling and heart failure after myocardial infarction (MI). It is suggested that left ventricular (LV) remodeling may contribute independently to the progression of heart failure and death. Thus, any intervention that will increase scar thickness and strength will reduce LV remodeling. Surgically, cardiac transplantation is a potential treatment for many patients. However, lack of donors combined with an increasing number of patients has led to the search for other surgical strategies. Patients with symptomatic large left ventricular aneurysms have been treated with resection of the aneurysm and closure of the left ventricle either directly or by implantation of a patch. Scar areas of the left ventricle have also been successfully treated by the latter method. According to the law of Laplace, large dilated ventricles have increased wall tension and thus increased oxygen consumption. Based on this fact, Batista and coworkers have reduced the volume of enlarged left ventricles in patients in terminal heart failure by removing a wedge of myocardium from the apex of the heart towards the base of the left ventricular free wall. This method is currently not recommended for treatment of heart failure because of high surgical failure rates. After MI, failure of extracellular (ECM) support has been associated with LV wall thinning and slippage of myocyte fascicles. This adverse remodeling process has been termed "infarct expansion" and occurs in the absence of additional myocyte injury or alterations in LV loading conditions. This post-MI remodeling process is a clinically significant problem in that it can lead to LV dilation and dysfunction, the progression to heart failure. Indeed, this post-MI remodeling process, which includes changes in ECM structure and composition, is an independent predictor of morbidity and mortality. It has been postulated that an acceleration of ECM degradation occurs within the scar and the myocardium surrounding the MI (border zone) and facilitates the infarct expansion process in this later phase of postMI remodeling. We have developed a unique approach to rejuvenate and strength an old scar after MI. The rational for this is that collagen matrix play a central role in the remodeling of the infarct zone and the ultimate transition to cardiac decompensation. Our experiments suggest the stimulation of new collagen and elastic fibers growth remodeling of the failing myocardium. Our preliminary results also suggest that this approach is safe and might recruit cardiac stem cells to the site having a functional synergistic positive effect. 5 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Elimination of Clonal Responses to Biological therapeutics Biological drugs have opened new therapeutic horizons for treating human diseases, but have also brought with them issues related to immunogenicity, long-term efficacy, safety and cost. During treatment with biopharmaceutical proteins, including insulin, growth hormone, granulocyte-macrophage colony-stimulating factor, factor VIII, erythropoietin, antibodies and interferons, there is an immune response to the biopharmaceutical agent, including the generation of anti-drug antibodies (ADAs) and hypersensitivity reactions. ADAs may reduce the clinical efficacy of these agents by blocking or neutralizing their biologic activity and may have other biologic effects. The potential to induce ADAs after treatment with biologics is a safety issue that has become an important consideration in the development of biologics and a critical aspect of regulatory filings. For example, antibodies develop in 20 % to 40% of patients with severe hemophilia treated with human factor VIII; the presence of these antibodies can result in tolerance to the clotting effects of this agent. Similarly, a proportion of patients treated with interferon alpha develop antibodies, which inhibit its therapeutic effects. Therefore, it is important to test for neutralizing antibodies during treatment with these agents, particularly in patients who are unresponsive to treatment or have breakthrough disease. Concurrent immunosuppressive drugs and pre-infusion steroids can decrease antibody formation to biological drugs. We have discovered a composition and methods for reducing undesired immune response to biological drugs and autoimmune antigens using unique combination therapy. Our initial studies demonstrated their efficacy in several applications. The global market for biopharmaceuticals, which is currently valued over US$ 50 billion, has been growing at an impressive compound annual growth rate of 19% over the previous five years. With over one third of all pipe-line products in active development are biopharmaceuticals, this segment is set to continue outperforming the total pharmaceutical market and could easily reach US$100 billion by the end of the decade. 6 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Novel Treatment for Neuro-developmental Disorders Neurodevelopment disorders are now recognized to be the result of abnormalities in brain development due to both genetic and environmental/biological causes. In total, these conditions affect approximately 1-3% of the population, frequently resulting in substantial economic, physical and emotional burdens to individuals, families, and society. Therefore, research into the pathogenesis and treatment of these disorders, aimed at the cure and amelioration of their effects on individuals, families, and society, is of considerable importance. Because of the brain disruption which is at the root of all neurodevelopmental disorders, there are several common features across the variety of disorders in this group. Some of these include difficulties with motor development, sensory integration difficulties, speech and language delays and a range of cognitive difficulties including learning disabilities, poor organizational skills, poor self regulation and behavioral difficulties. We are studying the Rett syndrome, a genetic neurodevelopmental disorder affecting mainly females. The genetic cause for most of the cases are mutations in the X-linked MECP2 gene. Mecp2 protein is a transcription regulator of several known and still unknown genes. One of the main affected genes is the BDNF gene .The level of BDNF is decreased in MECP2 mutated and deficient mice. It was already shown that BDNF null mice have clinical features which resemble the MECP2 deficient mice and over expression of BDNF in MECP2 deficient mice causes delay and partial rescue of the clinical phenotype of these mice. Copaxone is an immune modulator but lately one of his major effects was found to be elevation of BDNF in EAE mice and in MS patients. It is a safe drug to use with very mild side effects. We have found a compound to be given to Rett syndrome girls and cause elevation of BDNF protein expression in their brains, and potentially relief Rett symptoms. Neurodevelopmental disorders are thought of as beginning before birth, and many such as Down syndrome clearly do. Clinically, however, other such disorders may unfold over months such as Mental Retardation, Autism, Rett Syndrome or years as Asperger Syndrome, Fragile X and Dyslexia. These applications are candidate to be analyzed with this compound. 7 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Novel Pharmaceutical composition to treat Breast Cancer. Breast cancer is the most common cancer among women. Despite recent advances, treatment of breast cancer is still unsatisfactory and the median survival of patients with metastatic disease is about two years. Moreover, current chemotherapies used to treat breast cancer are associated with severe side effects. The identification of novel and less toxic therapies is of major importance. We have identified a peptide hormone GLP-1, which is secreted from endocrine L cells, located in the distal ileum and colon. The hormone is secreted in response to food intake, stimulates insulin secretion and sensitivity and inhibits glucagon secretion. In addition, GLP-1 promotes pancreatic β-cell proliferation. GLP-1 also appears to be a physiological regulator of appetite and food intake. These actions are mediated mainly through GLP-1 receptor (GLP-1R), a seven transmembrane G-protein coupled receptor. Due to these actions, GLP-1 or GLP-1 receptor are targets for the therapy of type 2 diabetes. GLP-1 is a 31-amino acids long peptide, with a short half-life in the circulation (less than 2 minutes), which is rapidly inactivated by the ubiquitous proteolytic enzyme dipeptidyl peptidase-4 (DPP-4). Therefore, the use of GLP-1, and GLP-1R analogues with a prolonged half life are currently being evaluated. As both diabetes and obesity are associated with breast cancer, and as GLP-1 induces insulin sensitivity, we studied the effects of the analogues on breast cancer cells. Our results show that the analogues, which are already approved to treat type 2 diabetes, are potent and selective inhibitors of breast cancer cell proliferation, and can enhance the activity of doxorubicin. 8 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Novel Pharmaceutical composition in the treatment of pancreatic cancer. Klotho is a transmembrane protein, which is expressed in the brain and kidneys, as well as in the pancreas. Klotho can be shed and act as a hormone, and has been identified previously as an inhibitor of the insulin growth factor (IGF)-1 pathway in hepatocytes and muscle cells. The IGF-1 pathway is known to play a major role in the development of pancreatic cancer. Pancreatic cancer is a fatal disease and the 5 years survival of patients who suffer from advanced disease is less than 10%. Current treatment for metastatic pancreas cancer consists of chemotherapy and is unsatisfactory, with a median survival following chemotherapy of about 6 months. We studied the effects of klotho on pancreatic cancer cell lines and identified, for the first time, growth inhibitory activity of klotho on the pancreatic cancer cell lines PANC-1, miapaca and Colo-357. Growth was inhibited by either over-expression of klotho or treatment of the cells with soluble klotho, where soluble klotho inhibited PANC-1 cells growth up to 50%. We also found additive effects of klotho and various chemotherapy agents and noted more than 70% inhibition of PANC-1 cells by the combination of klotho and low dose of chemotherapy. Thus, our in vitro and in vivo data suggest klotho, for the first time, as a novel therapy for pancreatic and breast cancer and indicate a possible additive effect for klotho when administered with standard chemotherapy. Our data suggest high levels of klotho protein expression in normal breast samples and normal pancreatic cells, but very low expression in cancerous breast cells or cancerous pancreatic cells. In addition, noted inhibition of breast cancer cell growth following overexpression of klotho protein, and growth enhancement of klotho protein-expressing cells following klotho protein knock-down; and revealed modulation of the IGF-1 and the insulin pathways by klotho protein. Taken together, the results suggest klotho protein as a novel breast cancer tumor suppressor. Moreovere, we have found additive effects of klotho and various chemotherapy agents and noted more than 70% inhibition of PANC-1 cells by the combination of klotho and low dose of chemotherapy. Animal studies demonstrate a therapeutic effect of Klotho. Treatment of mice with Klotho protein resulted in a significant dose response inhibition of tumor growth. The present invention relates to the use of the klotho protein for the treatment and diagnosis of cancer, such as breast cancer and pancreatic cancer as well as other IGF-1 dependent cancers. 9 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 New approach for gene silencing for treatment of psoriasis microRNAs (miRNA), are a group of hairpin shaped gene transcripts whose function and mechanism of action is being recently revealed. These molecules are transcribed in the nucleus, transported to the cytoplasm, transformed by a series of enzymes to the active short double stranded RNA duplexes which exert their suppressive effect on the translation of multiple mRNAs. As compared to artificial short interfering RNAs (siRNA), miRNAs exert their effects with less than full sequence homology, thus they are able to inhibit the translation of multiple downstream genes, thus acting as master genes. Few hundreds of such genes were discovered, and their essential role in the control of cell growth and differentiation and their aberrant expression in acquired and genetic disorders is being revealed. The therapeutic implication of miRNA discovery resides in the understanding of their downstream targets and the possibility to predict siRNA sequences that will be effective in interfering with the expression of the miRNA or it target. In addition, we are developing a novel platform technology approach for gene silencing (psiRNA). The study involves the synthesis of unique siRNAs conjugated to target promoter sequences of genes that are essential for cell survival and/or proliferation. We have developed a biological system for psoriasis, including animal models bearing human psoriatic affected skin. We have discovered several miRNAs, differs significantly between psoriatic uninvolved a normal skin for their expression. Analysis of the role and downstream possible targets of these miRNAs showed the involvement in controlling the expression of specific genes. Among those genes, bFGFR is associated with keratinocyte hyperproliferation and was found to be overexpressed in psoriasis and IRAK2 which is part of the IL-1 pathway that is strongly related to psoriasis. The platform psiRNA approace is currently validated in cell models of cancer and psoriasis. 10 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 FZD7 for targeting tumor stem cells FZD7 is a member of the 'frizzled' gene family, encoding 7-transmembrane domain receptors for Wnt signaling proteins. Binding of Wnt proteins to the FZD7 receptor results in activation of the canonical Wnt pathway which usually leads to cell proliferation and survival. FZD7 is known to be over expressed in several malignancies including Colon cancer, Esophageal cancer, Gastric cancer, Wilm's tumor and more, compared to the normal tissue from which each tumor develops. It is becoming clear that many, if not most, malignancies arise from a population of cells that exclusively maintain the ability to self-renew and sustain the tumor via the expression of tumor-progenitor genes. These ‘‘cancer stem cells’’ are often biologically distinct from the differentiated cancer cells that comprise most of the tumor bulk. Since cancer stem cells are believed to be primarily responsible for tumor initiation as well as resistance to chemo- and radiotherapy, their persistence after such treatments may account for relapsing disease and metastasis in many malignancies. Taking into account the Wnt pathway established role in enabling stem cell properties ('stemness') as well as FZD7 over expression in multiple cancers in which the Wnt pathway is deranged, FZD7 is a potential therapeutic target for numerous malignancies both as a biomarker for cancer stem cells and as a target for attenuating Wnt signaling in these cells which in turn is likely to lead to cancer cell death. Wilms tumor (WT), a pediatric kidney cancer can serve as an excellent model for studying malignant renal stem cells leading to tumor initiation and progression. An important link between aberrant Wnt signaling and WT formation has been established. We have observed frizzled7 (FZD7) up regulation in WT compared to normal kidney and showed FZD7 protein expression on a subset of WT cells. Unexpectedly, incubation of WT cells with anti-FZD7 Ab resulted in apoptosis and cancer cell death, suggesting possible manipulation of the tumor with antibody therapy. Further analysis of additional WTs has identified tumours from which a viable FZD7(+) cell population can be isolated, which enabled characterization of these cells as potential Wilm’s tumor stem cells. These novel observations highlight the Wnt pathway and especially FZD7 as a therapeutic target in Wilm’s tumor and possibly in additional FZD7 over-expressing cancers. 11 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Exendin-4 and related active pharmaceutical ingredients such as glucagonlike peptide-1 hormone, derivatives or analogues, in the treatment of cancer Breast cancer is the most common cancer among women. Despite recent advances, treatment of breast cancer is still unsatisfactory and the median survival of patients with metastatic disease is about two years. Moreover, current chemotherapies used to treat breast cancer are associated with severe side effects. Glucagon-like peptide 1 (GLP-1) is a hormone secreted from endocrine L cells in the distal ileum and colon in response to food intake. It stimulates insulin secretion and sensitivity and inhibits glucagon secretion. In addition, GLP-1 promotes pancreatic β-cell proliferation and differentiation. These actions are mediated mainly through GLP-1 receptor (GLP-1R), a seven-pass transmembrane Gprotein coupled receptor. Due to these actions, GLP-1 or GLP-1 receptor are targets for the therapy of type 2 diabetes. GLP-1 is a 31-amino acids long peptide, with a very short halflife in the circulation, and it is rapidly inactivated by the proteolytic enzyme dipeptidyl peptidase-4. Therefore, GLP-1 analogs with a prolonged half life were sought. One of these analogs is exendin-4 (Ex4), which is isolated from Heloderma suspectum (Gila monster lizard) venom and is a potent GLP-1R agonist. Ex4 has been approved by the FDA for type 2 diabetes treatment. As both diabetes and obesity are associated with breast cancer, and as GLP-1 induces insulin sensitivity and is a differentiation factor, we studied extensively the effects and mechanism of action of Ex4 on breast cancer cells. Exendin-4 almost completely inhibited proliferation of human breast cancer cells but not of human primary liver cells. Moreover, Ex4 enhanced the activity of doxorubicin, a commonly used chemotherapy for breast cancer, on breast cancer cells. Ex4 treatment induced elevation of the tumor suppressors p53 and p21 in breast cancer cells, but down-regulated it in human primary liver cultures. Also, Ex4 treatment increased apoptosis of breast cancer cells, as evidenced by increased PARP cleavage, whereas it decreased apoptosis in primary liver cells. Our detailed cellular and biochemical analysis and results indicate Ex4 is a potent and selective inhibitor of breast cancer cell proliferation. Moreover, Ex4 can enhance the activity of standard chemotherapy drugs. 12 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Anti-Microbial and Anti-Adherent polypeptides from Sea Species Different aquatic species, such as sea anemones, are natural targets for microbial colonization. To prevent that, they developed defensive polypeptides, which prevent the adhesion of a wide range of biofilms. Biofilms consist of diverse microorganisms linked to a surface by substances they secrete. Biofilms formed on edible plants, water supply and medical equipment (especially catheters and other indwelling devices) are a major source of infection and contamination. Bacteria in biofilms often outlive antibiotic treatment. Our invention comprises a large set of proteins and polypeptides derived from sea species which prevent bacterial adhesion. Such compounds provide innovative ways for the prevention of microbial biofilm development on a variety of surfaces, such as orthopaedic implants, stents, catheters. In addition they may be used for sanitation of food preparation areas, plant protection againt yeast and moulds, and targeted therapy for preventing or reducing biofilm formation in various human diseases such as infectious kidney stones, cystitis, dental caries, chronic otitis media, bacterial endocarditis, osteomyelitis, wounds, and acne. These polypeptides are resistant to organic solvents, lyophilization and high ambient temperatures. Currently, we have identified and characterised several proteins and peptides that tested for their ability to prevent and reduce biofilm formation. The know-how includes the isolation methods as well as methods for assessing the beneficial properties of the compounds obtained. We are developing several medical and cleantech applications using these peptides. 13 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Melanoma Diagnosis and Treatment by CEACAM-1 Antibodies Carcinoembryonic Antigen Cell Adhesion Molecule -1 (CEACAM1) is a transmembranal glycoprotein that belongs to the carcinoembryonic antigen family and to the larger immunoglobulin superfamily. CEACAM1 is expressed on various normal cells of epithelial and endothelial origins, as well as on activated lymphocytes. Various functions are attributed to CEACAM1, including regulation of cell proliferation, immune modulation, angiogenesis, insulin clearance and organization of 3D tissue structure. A retrospective study revealed a very strong association between the presence of CEACAM1 on primary skin melanoma lesions and the development of metastatic disease with poor prognosis. Over a time course of 10 years, almost 80% of the patients with CEACAM1-positive primary tumor died, as compared to only 25% of the patients with CEACAM1-negative primary tumors. The predictive value of CEACAM1 as a single prognostic marker surpassed the most widely accepted marker, and is regarded as the strongest predictive marker in melanoma. A similar prognostic association was reported in non small-cell lung cancer, particularly lung adenocarcinoma. CEACAM1 is not expressed by normal melanocytes. We have demonstrated that CEACAM1 protects melanoma cells from elimination by NK cells and by antigen-restricted T cells in vitro. Melanoma cells employ CEACAM1 to inhibit effector functions such as killing and secretion of interferon-gamma. Blocking of CEACAM1 did not induce non-specific killing of HLA-mismatched melanoma cells by antigen-restricted T cells. Furthermore, we showed that melanoma cells are able to actively elevate CEACAM1 expression, in response to interferon-gamma secreted from attacking lymphocytes, to enhance their resistance to subsequent immune attack. Our novel observations support the immune protective role of CEACAM1 in melanoma cells and implies that the majority of metastatic melanoma patients might benefit from CEACAM1-targeted therapy. We have generated a monoclonal antibody to CEACAM1 and demonstrated in vitro and in vivo its potential therapeutic effect in various assays. 14 תל השומר מחקרים תשתיות ושירותים רפואיים בע"מ Tel Hashomer Medical Research, Infrastructure and Services Ltd. Tel: +972-3-5305998 Fax: +972-3-5305944 Restoration of p53 anti-tumor activity by Zinc IPK2 is a nuclear serine/threonine kinase that belong to a family of co-repressors of homeodomain transcription factors and is considered as a central switch in the targeting of cells toward apoptosis upon genotoxic stress by phosphorylating the oncosuppressor p53 at Ser46. We have shown recently that hypoxia-driven HIPK2 downregulation can be reversible. We found that zinc supplementation stabilizes and reactivates the hypoxiainhibited HIPK2, leading to repression of the HIF-1 pathway and restored p53-Ser46 phosphorylation and apoptotic activity. Our study demonstrated that HIPK2-mediated transcription regulation includes inhibition of HIF-1 whereas HIPK2 knockdown induced upregulation of HIF-1 pathway leading to angiogenesis, chemoresistance and tumor growth in vivo. Additionally, it has been shown that hypoxia-driven mechanisms inhibit HIPK2, creates a negative regulatory loop between HIPK2 and HIF-1 that affects the multiple pathways regulated by both proteins, including p53 and VEGF pathways. Zinc supplementation rescues p53Ser46 phosphorylation and apoptotic activity as well as HIPK2 activity. Our finding suggest a novel and unexpected way to reactivate hypoxiainhibited HIPK2 in cancer cells, and to exert its dual role in restraining tumor growth through (i) inhibition of HIF-1 pathway, and (ii) through p53 activation in response to drug. Furthermore, we provided evidence that this function may have an in vivo relevance by improving chemotherapy response in treatment of tumor xenografts. We have demonstrated that Intragastical Zinc chloride (ZnCl2) decreased tumor volume in nude mice xenografts. Zinc restored p53 phosphorylation, conformation, and switches its recruitment from oncogene to oncosuppressor genes in cell cultures. The invention relates to methods for treating cancer by zinc compositions. Zinc supplementation in vitro and in vivo reverses p53 phosphorylation and restores its tumor suppressor activity. 15