Daniela Elise Tache

Biobanking in a constantly developing medical world.

Biobank is a very sophisticated system that consists of a programmed storage of biological material and corresponding data. Biobanks are created to be used in medical research, in clinical and translational medicine, and in healthcare. In the past 20 years, a large number of biobanks have been set up around the world, to support the modern research directions in medicine such as omix and personalized medicine. More recently, embryonic and adult stem cell banks have been developed. Stem cell banking was reported to be required for medical research as well as clinical transplant applications. The quality of the samples stored in a biobank is very important. The standardization is also important; the biological material stored in a biobank must be processed in a manner that allows compatibility with other biobanks that preserve samples in the same field. In this paper, we review some issues related to biobanks purposes, quality, harmonization, and their financial and ethical aspects.

Cancer Stem Cells: Biological Functions and Therapeutically Targeting

Almost all tumors are composed of a heterogeneous cell population, making them difficult to treat. A small cancer stem cell population with a low proliferation rate and a high tumorigenic potential is thought to be responsible for cancer development, metastasis and resistance to therapy. Stem cells were reported to be involved in both normal development and carcinogenesis, some molecular mechanisms being common in both processes. No less controversial, stem cells are considered to be important in treatment of malignant diseases both as targets and drug carriers. The efforts to understand the role of different signalling in cancer stem cells requires in depth knowledge about the mechanisms that control their self-renewal, differentiation and malignant potential. The aim of this paper is to discuss insights into cancer stem cells historical background and to provide a brief review of the new therapeutic strategies for targeting cancer stem cells.

Silencing of epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) via siRNA-induced cell death in glioblastoma.

ABSTRACT The failure of therapies targeting tumor angiogenesis may be caused by anti-angiogenic resistance mechanisms induced by VEGF and non-VEGF pathways alterations. Anti-angiogenic therapy failure is also attributed to immune system, acting by tumor-associated macrophages that release pro-angiogenic factors and a consequent increase of blood vessels. Recently, in a study by Rheal et al., a new angiogenic receptor, epidermal growth factor, latrophilin, and 7 trans-membrane domain-containing protein 1 on chromosome 1(ELTD1) has been identified as a promising glioma biomarker. In this study we aim to analyse whether this receptor may be used as a target molecule in glioblastoma therapy. Our results showed that small interfering RNA silencing ELTD1 caused cytotoxicity in glioblastoma cells. We also found that PDGFR, VEGFR, and their common PI3K/mTOR intracellular pathway inactivation-induced cytotoxicity in glioblastoma cells. Further, we found high percent of cytotoxicity in a low passage glioblastoma cell line after BEZ235 (a dual inhibitor of PI3K/mTOR pathway) treatment at nanomolar concentrations, compared to AG1433 (a PDGFR inhibitor) and SU1498 (a VEGFR inhibitor) that were only cytotoxic at micromolar ranges. In the future, these could prove as attractive therapeutic targets in single therapy or coupled with classic therapeutic approaches such as chemotherapy of radiotherapy.

Comparative effect of immunotherapy and standard therapy in patients with high grade glioma: a meta-analysis of published clinical trials

Immunotherapy holds great promise in the treatment of high grade glioma (HGG). We performed a comprehensive meta-analysis of clinical trials involving dendritic cell (DC) therapy and viral therapy (VT) for the treatment of HGG, in order to assess their clinical impact in comparison to standard treatments in terms of overall survival (OS) and progression-free survival (PFS). To our knowledge, this is the first meta-analysis to evaluate VT for the treatment of HGG, allowing comparison of different immunotherapeutic approaches. Thirteen eligible studies of 1043 cases were included in the meta-analysis. For DC vaccination, in terms of OS, both newly diagnosed patients (HR, 0.65) and patients who suffered from recurrent HGGs (HR = 0.63) presented markedly improved results compared to the control groups. PFS was also improved (HR = 0.49) but was not statistically significant (p = 0.1). A slight improvement was observed for newly diagnosed patients receiving VT in terms of OS (HR = 0.88) while PFS was inferior for patients in the experimental arm (HR = 1.16). Our results show that DC therapy greatly improves OS for patients with both newly diagnosed and recurrent HGGs. VT, however, did not provide any statistically significant improvements in terms of OS and PFS for patients with newly diagnosed HGGs.

Current and emerging EGFR therapies for glioblastoma

ABSTRACT Glioblastomas (GBMs) are the most lethal and hard to treat malignancies in clinical practice. The standard of care for treating GBM involving surgery and adjuvant radiotherapy and concomitant temozolomide (TMZ) has remained virtually unchanged in the past decade. Molecular targeted therapies against cancer-specific structures have reported mediocre results in the treatment of GBM, due to multiple factors such as the presence of the blood brain barrier or a vast array of molecular alterations which greatly hinder the action of the most therapeutic agents. One such therapy is directed against the epidermal growth factor (EGF) and its’ receptor (EGFR) using either monoclonal antibodies or tyrosine kinase inhibitors. Even though anti-EGF/EGFR treatment produced encouraging results in other forms of cancer it failed to present any clinical benefit for patients with GBM. Lately, immunotherapies that focus on using the host’s own immune system against cancer cells have gained popularity, with approaches like peptide vaccination being successfully used in clinical trials for different types of malignancies. These immune-based therapies could hold the key to improving both the prognosis and quality of life for patients suffering for cancers previously considered incurable, such as GBM.

epidermal growth factor, latrophilin, and seven transmembrane domain-containing protein 1 marker, a novel angiogenesis marker

Epidermal growth factor, latrophilin, and seven transmembrane domain-containing protein 1 on chromosome 1 (ELTD1), an orphan adhesion G-protein coupled receptor, was reported as a regulator of angiogenesis, also involved in cancer progression and development. More recently, ELTD1 was identified as a potential new tumor marker for high-grade glioma. ELTD1, belongs to the G-protein coupled receptor superfamily that comprises the biggest receptor family in the human genome. Following the discovery of ELTD1 almost a decade ago, only a few research groups have attempted to find its role in normal and tumor cells, important information about this receptor remaining still unknown. The ELTD1 ligand has not currently been identified and intracellular signaling studies have not yet been performed in normal or tumor cells. Although the current published data on ELTD1 function and structure are rather limited, this receptor seems to be very important, not only as biomarker, but also as molecular target in glioblastoma. This review summarizes and discusses the current knowledge on ELTD1 structure, function, and its role in both physiological and tumoral angiogenesis.

DNA Methylation, Stem Cells and Cancer

In the past few years ‘cancer stem cells’ (CSCs) area has become an interesting field of cancer research. In 19th century, Durante and Conheim [6] and after one hundred year Sell and Pierce [6, 7] issued the hypothesis that stem cells could induce cancer in all type of tissues. Unlike normal tissue stem cells, cancer stem cells are characterized by an abnormal differen‐ tiation rate, which can lead to tumor [8, 9].

Epigenetic Alteration of Receptor Tyrosine Kinases in Cancer

In the process of cellular carcinogenesis, genetic and epigenetic mechanisms contribute to abnormal expression of genes. Conrad Waddington introduced the term ‘‘epigenetics’’ in 1942 (Goldberg, Allis et al. 2007) to describe heritable changes in gene expression that have no connection with changes in DNA sequence (Yoo and Jones 2006; Goldberg, Allis et al. 2007). The molecular basis of epigenetics is complex and involves DNA methylation, histone modifications, chromatin remodeling and microRNAs (Esteller 2006).