Carboxypeptidase E (CPE), a novel Wnt inhibitor

Research

Jun 22nd, 2015
The Wnt Signaling Pathway and Colorectal Cancer

Prof. Rosin-Arbesfeld, Ph.D.
Department of Clinical Microbiology and Immunology

The Wnt signaling pathway is involved in virtually every aspect of human development, as well as in adult homeostasis. Hyperactivation of this pathway has been linked to a wide range of cancers and especially colorectal cancer. Our aim is to understand the molecular events underlying Wnt signal transduction, as well as develop novel therapeutic strategies to fight colorectal cancer.

 

Current projects in the lab include:

  1. Identifying and characterizing new Wnt signaling components.
  2. Developing new anti-colorectal cancer treatment strategies.
3D reconstruction of a single red blood cell

Research

Jun 22nd, 2015
Interaction of Nanomaterials and Electromagnetic Fields with Cells

Prof. Rafi Korenstein, Ph.D.
Department of Physiology and Pharmacology

The research activity addresses the following lines of research:

  • Absorption and uptake of nanoparticles by cells in relation to drug delivery and toxicity
  • Enhancement of uptake by electrical and chemical means 
  • Treatment of cancer by electrochemical based approach
  • Assessment of genetic and epigenetic risks following in-vitro exposure to electromagnetic fields associated with cell phone communication.
  • Physiological regulation and underlying mechanism of cell membrane-cortical skeleton nanoscale mechanical fluctuations.

Research methods used include routine cell biology and biochemical methodologies with emphasis on special cutting edge light microscopies possessing nanometric resolution such as Digital Holographic Microscopy.

 

Prof. Yona Keisari

Research

Jun 22nd, 2015
Development of Cancer Treatments Integrating Radiotherapy or Electrochemical

Prof. Yona Keisari, Ph.D.
Department of Clinical Microbiology and Immunology

Cancer is currently the most devastating chronic disease affecting humankind. Today solid malignant tumors are mainly treated by surgery and/or radiotherapy to eradicate the local primary lesion, and chemotherapy, that is administered mainly to destroy remaining local or distant malignant cells. In spite of the advancement in preventing and treating cancer, morbidity and mortality remain high, especially in cases when tumors are highly metastatic, or cannot be completely removed. The main goal of our research projects is to develop in situ tumor ablation treatments of primary tumors and incorporate them with systemic chemotherapy and immuno-stimulatory agents, into combined treatment protocols.

 

In order to achieve efficient primary tumor ablation we developed two novel and powerful treatment modalities for solid cancer, which can be used instead or in combination with surgery. The first treatment, developed with Prof. Rafi Korenstein (Dept. Physiology & Pharmacology), is base on the use of intratumoral unipolar pulsed electric currents for the ablation (ECTA) of solid primary tumors. ECTA can be enforced by the concomitant use of chemotherapeutic agents in the treatment of tumors. The second cancer treatment, developed with Prof. Itzhak Kelson (School of Physics & Astronomy), is based on insertion into the tumor of radioactive wires that spread in the tumor alpha emitting atoms and can also be augmented by chemotherapy.

 

Our teams proved that these treatment modalities effectively destroy primary tumors, and reduce the metastatic load in experimental animal and human cancer models of melanoma, breast, colon, prostate, pancreas, lung, and squamous cell carcinomas. We found that in situ ablation of primary antigenic tumors led to the activation of immunological reactions, destroying remaining malignant cells in the primary tumor as well as in distant metastases.

 

Immunopharmacological methods aimed to stimulate the patient’s immune response against the cancer after local tumor ablation can make use of several approaches and we currently study the following:

  1. Immunostimulation by adjuvants such as the oligonucleotides, CpG, which enforce weak immune reactions.
  2. Inhibition of immunosuppressive mechanisms such as T-regulatory and Myeloid Derived Suppressor cells (MDSC).
  3. Combination with inhibitors of immunological checkpoints such as anti CTLA-4 or anti PDL1/PD1.

 

Carboxypeptidase E (CPE), a novel Wnt inhibitor

Research

Jun 22nd, 2015
Basic and Translational Research of Childhood Malignancies and Leukemia

Prof. Shai Izraeli, M.D

Division of Pediatric Hematology and Oncology, Schneider Children's Medical Center;

Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine

We focus on patient-driven basic research into the pathogenesis of childhood leukemia and cancer. We harness advanced molecular and cellular biology technologies utilizing in-vitro and in-vivo models with the ultimate goal of improving the care of children with cancer.

 

Our research is divided into two major topics:

  1. Basic, translational and clinical research of leukemia.
  2. The role of SIL (STIL) protein in mitosis, centrosomal biology and cancer.

 

Cancer is the deadliest disease of children and leukemia is the most common childhood cancer. We are interested in the fundamental question how normal blood development is diverted into leukemia. What are the genetic and biochemical abnormalities that block cell differentiation, enhance proliferation and survival and confer the unique stem cell properties of self renewal to leukemia stem cells? We focus on chromosome 21 because of the mysterious association of leukemia with Down Syndrome. We utilize advanced genomic technologies, cell based assays of transformation of primary human and mouse stem cells, mouse models including transgenic, transplantation and explants of human leukemia. Our recent discoveries of the major involvement of the TSLP-IL7R-JAK2 pathway in leukemogenesis have lead to clinical trials with novel inhibitors of this pathway for high-risk leukemias in children and adults. The spread of leukemia to the brain is a major clinical problem as preventive therapy to the brain consistingof chemotherapy or irradiation causes long term side effects. We are therefore studying how leukemia cells spread to the central nervous system and developing mouse models to study this challenging problem.

 

We have discovered that SIL, a gene cloned from childhood leukemia, is required for centrosomal biogenesis and for survival of cancer cells. Targeting SIL by siRNA cause cancer cell death at mitotic entry in-vitro and in-vivo. Current research focuses on the fundamental role of the SIL protein in centrosome generation in normal and malignant cells and on developing approaches for its targeting for cancer therapy. 

 

Proteomics of Breast Cancer Progression

Research

Jun 22nd, 2015
Proteomics of Breast Cancer Progression

Prof. Tamar Geiger, Ph.D.
Department of Human Molecular Genetics and Biochemistry

Our main interest is to understand the mechanisms of breast cancer progression. We are using state-of-theart mass spectrometry-based proteomics to obtain a system-wide view of the tumor proteins. Analysis of the changes in protein levels and modifications that occur during tumor development is aimed to discover novel regulators of transformation.

 

Combination of the proteomics technology with biochemical and genetic methods will show the significance of these candidates to cancer development and may suggest novel drug targets and tumor markers.

 

K562 cancer cells

Research

Jun 22nd, 2015
Molecular Analysis of Cancer Immunoresistance

Prof. Zvi Fishelson, Ph.D.
Department of Cell and Developmental Biology

The long-term goal of our research is to develop a novel treatment for immune resistant cancers. Our research includes characterization of the mechanism of complement dependent cytotoxicity and of the basis for elevated resistance of cancer cells to cell death, and design of novel reagents that sensitize cancer cells to cell death. Research methods used include analyses of cell growth and death and mitochondrial activity, western blotting, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, confocal fluorescence microscopy, Fluorescence-activated Cell Sorting (FACS), peptide analysis by mass spectrometry, electon microscopy, and analysis of cancer growth in animal models.

 

Cancer Associated Fibroblasts

Research

Jun 22nd, 2015
Cancer Related Inflammation in Tumor Progression and Metastasis

Prof. Neta Erez, Ph.D.
Department of Pathology

The main goal of our laboratory is to uncover stromal pathways that contribute to tumorigenesis and metastasis. In particular, we combine transgenic mouse models of cancer as well as clinical data to study the role of inflammation and cancer-associated fibroblasts in facilitating lung metastasis of breast cancer, and to uncover the role of neuroinflammation mediated by astrocytes in melanoma brain metastasis.

 

Extensive research has led to the understanding that tumors are more than just cancer cells: stromal cells in the tumor microenvironment play a crucial role in all stages of tumor initiation and progression, and cancer research is no longer focused only on the pathways inside tumor cells, but rather on tumors as multi-cellular organs.
 
 
The major cause of cancer mortality is metastasis to distant organs. Currently, metastatic cancers are incurable and available therapies can only prolong life to a limited extent. Therefore, uncovering the mechanisms that facilitate metastasis is an urgent and unmet clinical need. Nevertheless, changes in the metastatic microenvironment that enable the growth of disseminated tumor cells are poorly characterized,
and are the major focus of our research. 
 
Expanding our understanding of the early stages of metastatic growth is an essential prerequisite for the discovery of novel target molecules for the development of targeted therapeutics that may prevent, rather than try to cure, metastatic disease.
 
Cancer cell eradication

Research

Jun 22nd, 2015
PARP Proteins in Health and Disease

Prof. Malka Cohen-Armon, D.Sc.
Dept. of Physiology & Pharmacology and the Neufeld Cardiac Research Institute
 

The general focus of our research is on signal transduction mechanisms implicating PARP (polyADP-ribose polymerase) proteins. PARPs are highly conserved proteins that are involved in a variety of processes, including epigenetic mechanisms, DNA repair, cell cycle and gene expression. PARP-1, the most abundant PARP protein, is activated by binding to single strand DNA breaks. Activated PARP-1 recruits ligazes to the lesion, promoting DNA repair.

 

One of our contributions to this field was the discovery of alternative mechanisms activating PARP-1 in the absence of DNA breaks. This unveiled a variety of extra-nuclear signals activating PARP proteins in a variety of processes regulating gene expression.

 

We found that PARP-1 is a target of signal transduction mechanisms activated by intracellular Ca2+ mobilizition or by the MEK-ERK phosphorylation cascade. Moreover, we found that ERK activity in the nucleus is highly up-regulated by activated PARP-1, implicating PARP-1 in ERK-dependent gene expression. Up-regulation of immediate early genes underlying long-term memory formation may underlie the pivotal role of PARP-1 in long-term memory formation during learning. Regulation of gene expression, controlling cell growth and development, may underlie the role of PARP-1 in neuronal remodeling and cardiomyocytes growth.

 

Recently, we found that a phenanthrene derived PARP inhibitor acts as an extra-centrosomes de-clustering agent, exclusively and efficiently eradicating human cancer cells by ‘mitotic catastrophe’ cell death, without impairing normal cells. Since many human cancer cells depend on extra-centrosomes clustering for their survival, this molecule is now used for developing a novel cancer targeting therapy.

 

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