Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

The somatic genomic landscape of glioblastoma

Glioblastoma multiforme (GBM) is one of the most malignant types of central nervous system tumors. Despite advances in treatment modalities it remains largely incurable. The objective of our review is to provide a holistic picture of GBM epidemiology, etiology, pathogenesis, clinical findings and treatment. A literature search was conducted for GBM at PubMed and Google Scholar, with relevant key words like glioblastoma multiforme, pathogenesis, signs and symptoms, treatment etc., and papers published until 2015 were reviewed. It was found that radiation and certain genetic syndromes are the only risk factors identified to date for GBM. Depending on the tumor site patients may present to the clinic with varying symptoms. To confirm the presence and the extent of tumor, various invasive and non-invasive imaging techniques require employment. The literature survey revealed the pathogenesis to involve aberrations of multiple signaling pathways through multiple genetic mutations and altered gene expression. Although several treatment options are available, including surgery, along with adjuvant chemo- and radio-therapy, the disease has a poor prognosis and patients generally succumb within 14 months of diagnosis.

http://journal.waocp.org/article_42593_ac801aaa3721f49b0f79bc0c790bfac0.pdf

Glioblastoma Multiforme: A Review of its Epidemiology and Pathogenesis through Clinical Presentation and Treatment

The National Library of Medicine.

The SARS-CoV-2 virus is more transmissible than previous coronaviruses and causes a more serious illness than influenza. The SARS-CoV-2 receptor binding domain (RBD) of the spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) receptor as a prelude to viral entry into the cell. Using a naive llama single-domain antibody library and PCR-based maturation, we have produced two closely related nanobodies, H11-D4 and H11-H4, that bind RBD (KD of 39 and 12 nM, respectively) and block its interaction with ACE2. Single-particle cryo-EM revealed that both nanobodies bind to all three RBDs in the spike trimer. Crystal structures of each nanobody-RBD complex revealed how both nanobodies recognize the same epitope, which partly overlaps with the ACE2 binding surface, explaining the blocking of the RBD-ACE2 interaction. Nanobody-Fc fusions showed neutralizing activity against SARS-CoV-2 (4-6 nM for H11-H4, 18 nM for H11-D4) and additive neutralization with the SARS-CoV-1/2 antibody CR3022.

/pdf/neutralizing-nanobodies-bind-sars-cov-2-spike-rbd-and-block-58rno0e04b.pdf

Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2.

Today, bio-medical efforts are entering the subcellular level, which is witnessed with the fast-developing fields of nanomedicine, nanodiagnostics and nanotherapy in conjunction with the implementation of nanoparticles for disease prevention, diagnosis, therapy and follow-up. Nanoparticles or nanocontainers offer advantages including high sensitivity, lower toxicity and improved safety—characteristics that are especially valued in the oncology field. Cancer cells develop and proliferate in complex microenvironments leading to heterogeneous diseases, often with a fatal outcome for the patient. Although antibody-based therapy is widely used in the clinical care of patients with solid tumours, its efficiency definitely needs improvement. Limitations of antibodies result mainly from their big size and poor penetration in solid tissues. Nanobodies are a novel and unique class of antigen-binding fragments, derived from naturally occurring heavy-chain-only antibodies present in the serum of camelids. Their superior properties such as small size, high stability, strong antigen-binding affinity, water solubility and natural origin make them suitable for development into next-generation biodrugs. Less than 30 years after the discovery of functional heavy-chain-only antibodies, the nanobody derivatives are already extensively used by the biotechnology research community. Moreover, a number of nanobodies are under clinical investigation for a wide spectrum of human diseases including inflammation, breast cancer, brain tumours, lung diseases and infectious diseases. Recently, caplacizumab, a bivalent nanobody, received approval from the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for treatment of patients with thrombotic thrombocytopenic purpura.

/pdf/the-therapeutic-potential-of-nanobodies-hwswliidrp.pdf

The Therapeutic Potential of Nanobodies

Cancer is a heterogeneous disease, which provides a broad field for investigation, while simultaneously reducing the chances for a universal treatment. Malignant gliomas are the most common type of primary brain tumors. The heteroge- neity of gliomas regarding clinical presentation, pathology and response to treatment makes this type of tumor a challenging area of research. As the clinical symptoms may be unspecific (e.g., seizures and headaches) it is often difficult to diagnose a patient in the early stages of the disease. Thus far, there are no known genetic patterns of inheritance of this disease. Currently, the treatment of glioblastoma involves surgery, whenever possible, followed by radiation and chemotherapy. Experimental procedures, such as passive and active immu- notherapy, use of angiogenesis inhibitors in combination with chemotherapeutics and gene/antibody therapy, are additional treatment options. However, as the brain is difficult to access due to the presence of the blood‑brain barrier (BBB), none of the above-mentioned therapies have been successful in curing this disease. The lack of knowledge regarding the mechanisms underlying the development and progression of gliomas further adds to the difficulties . Currently, investigations are focused on the development of novel methods for improving the outcome of this disease. However, despite the extensive investigations, 88% of all glioblastoma multiforme (GBM) patients succumb to the disease within 3 years. GBM remains one of the most challenging malignancies worldwide.

/pdf/glioma-and-glioblastoma-how-much-do-we-not-know-review-4j6m5fovhl.pdf

Glioma and glioblastoma ‑ how much do we (not) know? (Review)

Advances in technology of the past decades led to development of new nanometer scale diagnosis and treatment approaches in cancer medicine leading to establishment of nanooncology. Inorganic and organic nanomaterials have been shown to improve bioimaging techniques and targeted drug delivery systems. Their favorable physico-chemical characteristics, like small sizes, large surface area compared to volume, specific structural characteristics, and possibility to attach different molecules on their surface transform them into excellent transport vehicles able to cross cell and/or tissue barriers, including the blood–brain barrier. The latter is one of the greatest challenges in diagnosis and treatment of brain cancers. Application of nanomaterials can prolong the circulation time of the drugs and contrasting agents in the brain, posing an excellent opportunity for advancing the treatment of the most aggressive form of the brain cancer—glioblastomas. However, possible unwanted side-effects and toxicity issues must be considered before final clinical translation of nanoparticles.

https://www.mdpi.com/1996-1944/12/10/1588/pdf

Nanotechnology Meets Oncology: Nanomaterials in Brain Cancer Research, Diagnosis and Therapy.

// Ivana Jovcevska 1 , Neja Zupanec 1 , Žiga Urlep 2 , Andrej Vranic 3 , Bostjan Matos 4 , Clara Limbaeck Stokin 5 , Serge Muyldermans 6 , Michael P. Myers 7 , Anton A. Buzdin 8, 9 , Ivan Petrov 10, 11 and Radovan Komel 1 1 Medical Center for Molecular Biology, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 2 Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Department of Neurosurgery, Foundation Rothschild, Paris, France 4 Department of Neurosurgery, University Clinical Center, Ljubljana, Slovenia 5 Institute of Histopathology, Charing Cross Hospital, London, United Kingdom 6 Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium 7 International Center for Genetic Engineering and Biotechnology, Trieste, Italy 8 First Oncology Research and Advisory Center, Moscow, Russia 9 National Research Center 'Kurchatov Institute', Center of Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow, Russia 10 Center for Biogerontology and Regenerative Medicine, IC Skolkovo, Moscow, Russia 11 Moscow Institute of Physics and Technology, Moscow, Russia Correspondence to: Radovan Komel, email: radovan.komel@mf.uni-lj.si Ivana Jovcevska, email: ivana.jovcevska@mf.uni-lj.si Keywords: glioblastoma multiforme, biomarkers, nanobodies, cancer biology, OncoFinder Received: September 14, 2016     Accepted: April 10, 2017     Published: April 24, 2017 ABSTRACT Glioblastoma multiforme is the most frequent primary malignancy of the central nervous system. Despite remarkable progress towards an understanding of tumor biology, there is no efficient treatment and patient outcome remains poor. Here, we present a unique anti-proteomic approach for selection of nanobodies specific for overexpressed glioblastoma proteins. A phage-displayed nanobody library was enriched in protein extracts from NCH644 and NCH421K glioblastoma cell lines. Differential ELISA screenings revealed seven nanobodies that target the following antigens: the ACTB/NUCL complex, VIM, NAP1L1, TUFM, DPYSL2, CRMP1, and ALYREF. Western blots showed highest protein up-regulation for ALYREF, CRMP1, and VIM. Moreover, bioinformatic analysis with the OncoFinder software against the complete “Cancer Genome Atlas” brain tumor gene expression dataset suggests the involvement of different proteins in the WNT and ATM pathways, and in Aurora B, Sem3A, and E-cadherin signaling. We demonstrate the potential use of NAP1L1 , NUCL , CRMP1 , ACTB , and VIM for differentiation between glioblastoma and lower grade gliomas, with DPYSL2 as a promising “glioma versus reference” biomarker. A small scale validation study confirmed significant changes in mRNA expression levels of VIM , DPYSL2 , ACTB and TRIM28 . This work helps to fill the information gap in this field by defining novel differences in biochemical profiles between gliomas and reference samples. Thus, selected genes can be used to distinguish glioblastoma from lower grade gliomas, and from reference samples. These findings should be valuable for glioblastoma patients once they are validated on a larger sample size.

Differentially expressed proteins in glioblastoma multiforme identified with a nanobody-based anti-proteome approach and confirmed by OncoFinder as possible tumor-class predictive biomarker candidates

Owing to the advancement of technology combined with our deeper knowledge of human nature and diseases, we are able to move towards precision medicine, where patients are treated at the individual level in concordance with their genetic profiles. Lately, the integration of nanoparticles in biotechnology and their applications in medicine has allowed us to diagnose and treat disease better and more precisely. As a model disease, we used a grade IV malignant brain tumor (glioblastoma). Significant improvements in diagnosis were achieved with the application of fluorescent nanoparticles for intraoperative magnetic resonance imaging (MRI), allowing for improved tumor cell visibility and increasing the extent of the surgical resection, leading to better patient response. Fluorescent probes can be engineered to be activated through different molecular pathways, which will open the path to individualized glioblastoma diagnosis, monitoring, and treatment. Nanoparticles are also extensively studied as nanovehicles for targeted delivery and more controlled medication release, and some nanomedicines are already in early phases of clinical trials. Moreover, sampling biological fluids will give new insights into glioblastoma pathogenesis due to the presence of extracellular vesicles, circulating tumor cells, and circulating tumor DNA. As current glioblastoma therapy does not provide good quality of life for patients, other approaches such as immunotherapy are explored. To conclude, we reason that development of personalized therapies based on a patient’s genetic signature combined with pharmacogenomics and immunogenomic information will significantly change the outcome of glioblastoma patients.

https://www.mdpi.com/1420-3049/25/3/490/pdf

Ivana Jovčevska

Papers

The Therapeutic Potential of Nanobodies

Glioma and glioblastoma ‑ how much do we (not) know? (Review)

Nanotechnology Meets Oncology: Nanomaterials in Brain Cancer Research, Diagnosis and Therapy.

Differentially expressed proteins in glioblastoma multiforme identified with a nanobody-based anti-proteome approach and confirmed by OncoFinder as possible tumor-class predictive biomarker candidates

Nanomedicine and Immunotherapy: A Step Further towards Precision Medicine for Glioblastoma