Paula Ofek

Tel Aviv University | TAU · Department of Physiology and Pharmacology

Glioblastoma (GB) is an aggressive type of brain cancer with a high mortality rate. It is a highly angiogenic tumor exhibiting an extremely invasive nature. As such, its brain microenvironment plays a crucial role in its progression. Microglia are the brain resident immune cells that have been shown to facilitate GB cell invasion and immune suppres...

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...

Development of resistance to chemo- and immuno- therapies often occurs following treatment of melanoma brain metastasis (MBM). In this scenario, astrocytes cooperate towards MBM progression by upregulating secreted-factors, amongst which we found that monocyte chemoattractant protein-1 (MCP-1) and its receptors, CCR2 and CCR4, are overexpressed in...

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 proce...

Colorectal 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 prima...

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 tumo...

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...

Glioblastoma (GB) is an aggressive type of brain cancer with high mortality rate. It is a highly angiogenic tumor exhibiting an extremely invasive nature. As such, its brain microenvironment plays a crucial role in its progression. Microglia are the brain resident immune cells which have been shown to facilitate GB cell invasion and immune suppress...

p>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 pro...

The complexity and diversity of the biochemical processes that occur during tumorigenesis and metastasis are frequently over-simplified in the traditional in vitro cell cultures. Two-dimensional cultures limit researchers’ experimental observations and frequently give rise to misleading and contradictory results. Therefore, in order to overcome the...

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavi...

Glioblastoma (GBM) is the most aggressive form of glioma, with poor prognosis exhibited by most patients, and a median survival time of less than 2 years. We assemble a cohort of 87 GBM patients whose survival ranges from less than 3 months and up to 10 years and perform both high-resolution mass spectrometry proteomics and RNA sequencing (RNA-seq)...

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 th...

Glioblastoma (GB) is the most lethal type of primary tumor in the central nervous system. Current treatments include surgical resection followed by chemotherapy and radiotherapy. With this therapeutic regimen, the median survival is less than two years. However, these treatments do not much improve the overall survival of GB patients. GBs are highl...

Glioblastoma (GBM) is the most aggressive form of glioma, with poor prognosis exhibited by most patients, and a median survival time of less than two years. To examine survival-associated patterns, we assembled a cohort of 87 GBM patients whose survival ranges from less than 3 months and up to 10 years, most of which are not bearing isocitrate-dehy...

Background: Trastuzumab is a monoclonal antibody which demonstrates efficacy for HER2 positive breast cancer patients. Recently, an increased incidence of brain metastasis in trastuzumab-treated patients has been reported. The reason for this may be the effectiveness of systemic trastuzumab allowing patients to survive longer thus providing time f...

Glioblastoma is an aggressive and invasive brain malignancy with high mortality rates despite current treatment modalities. In this study, we show that a 7-gene signature, previously found to govern the switch of glioblastomas from dormancy to aggressive tumor growth, correlates with improved overall survival of patients with glioblastoma. Using gl...

Introduction Glioblastoma is the most common and lethal type of brain cancer with a median survival of under fifteen months. It is a highly angiogenic tumour exhibiting an extremely invasive nature. It is well-known that the brain microenvironment plays a crucial role in glioblastoma progression although the large multitude of interactions between...

Introduction Globally, colorectal cancer (CRC) is common cause of cancer-related deaths. The high mortality rate of patients with colon cancer is due to cancer cell invasion and metastasis. Initiation of the epithelial-to-mesenchymal transition (EMT) is essential for the tumorigenesis. Peroxiredoinxs (PRX1-6) have been reported to be overexpressed...

The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Here we show a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors. Using proteomic-...

RNAi therapeutics carried a great promise to the area of personalized medicine: the ability to target "undruggable" oncogenic pathways. Nevertheless, their efficient tumor targeting via systemic administration had not been resolved yet. Amphiphilic alkylated poly(α)glutamate amine (APA) can serve as a cationic carrier to the negatively-charged olig...

Raw data of U-87 MG proliferation assay following short-term exposure to treatments.

Raw data of Kaplan-Meier survival curve.

Raw data of blood count and biochemistry analysis.

Raw data of mice Rotarod experiments.

Raw data of U-87 MG, U251 and HUVEC proliferation assays.

Raw data of the fluorescent signal of mCherry labeled U-87 MG intracranial tumors.

Glioblastoma is a highly aggressive brain tumor. Current standard-of-care results in a marginal therapeutic outcome, partly due to acquirement of resistance and insufficient blood-brain barrier (BBB) penetration of chemotherapeutics. To circumvent these limitations, we conjugated the chemotherapy paclitaxel (PTX) to a dendritic polyglycerol sulfate...

Since the approval of bevacizumab as antiangiogenic therapy in 2004 by the FDA, an array of angiogenesis inhibitors have been developed and approved. However, results were disappointing with regards to their therapeutic efficacy. RNA interference approaches offer the possibility of rational design with high specificity, lacking in many current drug...

Supplementary materials.

Glioblastoma Multiforme (GBM) is one of the most aggressive forms of all cancers. The median survival with current standard-of-care radiation and chemotherapy is about 14months. GBM is difficult to treat due to heterogeneity in cancer cell population. MicroRNA-based drugs have rapidly become a vast and burgeoning field due to the ability of a micro...

s: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; February 11-14, 2016; New Orleans, LA Glioblastoma multiforme is a very heterogeneous tumor, highly infiltrative, angiogenic and resistant to standard therapeutic intervention. Experimental models currently used in research are mostly based on cance...

Glioblastoma multiforme (GBM) is the most common and aggressive primary neoplasm of the brain. Poor prognosis is mainly attributed to tumor heterogeneity, invasiveness, and drug resistance. microRNA-based therapeutics represent a promising approach due to their ability to inhibit multiple targets. In this work, we aim to restore the oncosuppressor...

The presence of dormant, microscopic cancerous lesions possesses a major obstacle for the treatment of metastatic and recurrent cancers. While it is well-established that microRNAs play a major role in tumorigenesis, their involvement in tumor dormancy has yet to be fully elucidated. We established and comprehensively characterized dormant and fast...

There is an increasing interest in elucidating the mechanisms of the earlier stages in tumor progression, the point at which a dormant tumor acquires the ability to grow and metastasize. Although the tumor dormancy phenomenon has important implications for early detection and treatment of cancer, its biology and genetic characteristics are poorly u...

Glioblastoma multiforme (GBM) is an aggressive primary neoplasm of the brain that exhibit notable refractivity to standard treatment regimens. Recent large-scale molecular profiling has revealed deregulated molecular networks as potential targets for therapeutic development. MicroRNAs (miRNAs) are noncoding RNA molecules which act as post-transcrip...

The ability to specifically silence genes using RNA interference (RNAi) has wide therapeutic applications for the treatment of disease. Numerous studies have demonstrated global gene and protein signatures distinguishing malignant and nonmalignant tissues. This worldwide pursuit of optimal cancer targets has so far provided a wide list of potential...

New targets for RNA interference (RNAi)-based cancer therapy are constantly emerging from the increasing knowledge on the molecular pathways involved in carcinogenesis. Nevertheless, in vivo delivery of small interfering RNA (siRNA) remains a crucial challenge for its therapeutic success. SiRNAs on their own are not taken-up by most mammalian cells...

There is an increasing interest in elucidating the mechanisms of the earlier stages in tumor progression, the point at which a dormant tumor acquires the ability to grow and metastasize. Although the tumor dormancy phenomenon has important implications for early detection and treatment of cancer, its biology and genetic characteristics are poorly u...

Based on clinical necessity for improved anticancer drugs and the importance of understanding the mechanism underlying the angiogenic switch phenomenon, we designed a targeted drug delivery system for the treatment of bone-related angiogenesis-dependent malignances. Using multidisciplinary approaches involving novel chemistry and molecular imaging,...

Polymer conjugation is an efficient approach to improve the delivery of drugs and biological agents, both by protecting the body from the drug (by improving biodistribution and reducing toxicity) and by protecting the drug from the body (by preventing degradation and enhancing cellular uptake). This review discusses the journey that polymer therape...

Doxorubicin (DOX) is extensively used in cancer therapy; however, it is cardiotoxic in cumulative doses and chemoresistance can evolve with prolonged use. Conjugation of a chemotherapeutic agent to a water-soluble polymeric carrier prolongs the circulation life of the drug, promotes its accumulation at the tumor site due to the enhanced permeabilit...

Although anti-angiogenic agents offer great therapeutic potential, preclinical and clinical studies suggest that these agents, used as monotherapies, have a delayed onset of activity and may have only limited effects on advanced malignancies. Multimodality targeted polymer therapeutics that include anti-angiogenic agents and chemotherapeutics offer...

The cover picture shows the extravasation of polymer therapeutics from angiogenic hyperpermeable vessels and their accumulation in a diseased target site, enabled by the Enhanced Permeability and Retention (EPR) phenomenon. The multivalency of polymers, highlighted in this stylized representation, is what makes possible their ability to be conjugat...

New targets for RNA interference (RNAi)-based cancer therapy are constantly emerging from the increasing knowledge on key molecular pathways that are paramount for carcinogenesis. Nevertheless, in vivo delivery of small interfering RNA (siRNA) remains a crucial challenge for therapeutic success. siRNAs on their own are not taken up by most mammalia...

Scheme 1 Synthesis of HPMA copolymer-ALN-TNP470 conjugate. (1.47 MB TIF)

Chemotherapeutic treatment of neoplastic diseases is often restricted by adverse systemic toxicity, which limits the dose of drug that can be administered, or by the appearance of drug resistance. Therefore, novel targeted therapeutic approaches are being developed to improve current conventional therapy in order to increase specificity and biocomp...

Background: 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 pol...

Protein phosphatase 2C (PP2C) dephosphorylates a broad range of substrates, regulating stress response and growth-related pathways in both prokaryotes and eukaryotes. We now demonstrate that PP2Cα, a major mammalian isoform, inhibits cell growth and activates the p53 pathway. In 293 cell clones, in which PP2Cα expression is regulated by a tetracycl...

The chapter presents a system that enables to study properties of protein phosphatase 2Cα (PP2Cα) expression in 293 cells.PP2Cα (also referred as PPM1A) is the most characterized member of the PP2C group. It is a monomeric enzyme of about 42 kDa that shows broad substrate specificity. The catalytic domain, of 300 amino acid residues, in the N termi...