Epigenomic perturbation of novel EGFR enhancers reduces the proliferative and invasive capacity of glioblastoma and increases sensitivity to temozolomide.

Background: Glioblastoma (GB) is the most aggressive of all primary brain tumours and due to its highly invasive nature, surgical resection is nearly impossible. Patients typically rely on radiotherapy with concurrent temozolomide (TMZ) treatment and face a median survival of ~ 14 months. Alterations in the Epidermal Growth Factor Receptor gene (EGFR) are common in GB tumours, but therapies targeting EGFR have not shown significant clinical efficacy.

Isolation of a Natural Killer Group 2D Small-Molecule Ligand from DNA-Encoded Chemical Libraries.

Natural Killer Group 2D (NKG2D) is a homo-dimeric transmembrane protein which is typically expressed on the surface of natural killer (NK) cells, natural killer T (NKT) cells, gamma delta T (γδT) cells, activated CD8 positive T-cells and activated macrophages. Bispecific molecules, capable of bridging NKG2D with a target protein expressed on the surface of tumor cells, may be used to redirect the cytotoxic activity of NK-cells towards antigen-positive malignant T-cells. In this work, we report the discovery of a novel NKG2D small molecule binder [K =(410±60) nM], isolated from a DNA-Encoded Chemical Library (DEL).

Evidence For Cannabidiol Modulation of Serotonergic Transmission in a Model of Osteoarthritis via PET Imaging and Behavioral Assessment.

Background: Preclinical studies indicate that cannabidiol (CBD), the primary nonaddictive component of cannabis, has a wide range of reported pharmacological effects such as analgesic and anxiolytic actions; however, the exact mechanisms of action for these effects have not been examined in chronic osteoarthritis (OA). Similar to other chronic pain syndromes, OA pain can have a significant affective component characterized by mood changes. Serotonin (5-HT) is a neurotransmitter implicated in pain, depression, and anxiety.

Identification and Validation of New Interleukin-2 Ligands Using DNA-Encoded Libraries.

Interleukin-2 (IL2) is a pro-inflammatory cytokine that plays a crucial role in immunity, which is increasingly being used for therapeutic applications. There is growing interest in developing IL2-based therapeutics which do not interact with the alpha subunit of the IL2 receptor (CD25) as this protein is primarily found on immunosuppressive regulatory T cells (T). Screenings of a new DNA-encoded library, comprising 669,240 members, provided a novel series of IL2 ligands, subsequently optimized by medicinal chemistry.

An Attenuated Targeted-TNF Localizes to Tumors In Vivo and Regains Activity at the Site of Disease.

Antibody-cytokine fusion proteins (immunocytokines) are gaining importance for cancer therapy, but those products are often limited by systemic toxicity related to the activity of the cytokine payload in circulation and in secondary lymphoid organs. Tumor necrosis factor (TNF) is used as a pro-inflammatory payload to trigger haemorrhagic necrosis and boost anti-cancer immunity at the tumor site. Here we describe a depotentiated version of TNF (carrying the single point mutation I97A), which displayed reduced binding affinity to its cognate receptor tumor necrosis factor receptor 1 (TNFR-1) and lower biocidal activity.

Chick fetal organ spheroids as a model to study development and disease.

Background: Organ culture models have been used over the past few decades to study development and disease. The in vitro three-dimensional (3D) culture system of organoids is well known, however, these 3D systems are both costly and difficult to culture and maintain. As such, less expensive, faster and less complex methods to maintain 3D cell culture models would complement the use of organoids.

Biomolecular Modeling and Simulation: A Prospering Multidisciplinary Field.

We reassess progress in the field of biomolecular modeling and simulation, following up on our perspective published in 2011. By reviewing metrics for the field's productivity and providing examples of success, we underscore the productive phase of the field, whose short-term expectations were overestimated and long-term effects underestimated. Such successes include prediction of structures and mechanisms; generation of new insights into biomolecular activity; and thriving collaborations between modeling and experimentation, including experiments driven by modeling.

Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade.

Introduction: Cytokine-based products are gaining importance for cancer immunotherapy. L19-TNF is a clinical-stage antibody-cytokine fusion protein that selectively accumulates to tumors and displays potent anticancer activity in preclinical models. Here, we describe an innovative approach to transiently inhibit off-target toxicity of L19-TNF, while maintaining antitumor activity.

S100A7: from mechanism to cancer therapy.

Within the tumor, malignant and stromal cells support each other by secreting a wide variety of growth factors and cytokines, allowing tumor growth and disease progression. The identification and regulation of those key factors in this crosstalk has opened the opportunity to develop new therapeutic strategies that not only act on the tumor cells but also on the stroma. Among these factors, S100A7 protein has gained interest in the last years.

S100P antibody-mediated therapy as a new promising strategy for the treatment of pancreatic cancer.

Despite progresses in diagnosis and treatment, pancreatic cancer continues to have the worst prognosis of all solid malignant tumors. Recent evidences suggest that the metastasis-promoting protein S100P stimulates pancreatic tumor proliferation, survival, invasion and metastasis progression through extracellular functions. Moreover, its expression is strongly correlated with poor prognosis in patients with several types of cancer although the entire molecular mechanism responsible for the diverse biological functions is not fully understood.

S100 to receptor for advanced glycation end-products binding assay: looking for inhibitors.

Secreted by tumor and stromal cells, S100 proteins exert their biological functions via the interaction with surface receptors. The most described receptor is the receptor for advanced glycation end-products (RAGE), thereby participating in the S100-dependent cell migration, invasion, tumor growth, angiogenesis and metastasis. Several approaches have been described for determining this interaction.

Polypurine reverse Hoogsteen hairpins as a gene therapy tool against survivin in human prostate cancer PC3 cells in vitro and in vivo.

As a new approach for gene therapy, we recently developed a new type of molecule called polypurine reverse Hoogsteen hairpins (PPRHs). We decided to explore the in vitro and in vivo effect of PPRHs in cancer choosing survivin as a target since it is involved in apoptosis, mitosis and angiogenesis, and overexpressed in different tumors. We designed four PPRHs against the survivin gene, one of them directed against the template strand and three against different regions of the coding strand.

Therapeutic targeting of tumor growth and angiogenesis with a novel anti-S100A4 monoclonal antibody.

S100A4, a member of the S100 calcium-binding protein family secreted by tumor and stromal cells, supports tumorigenesis by stimulating angiogenesis. We demonstrated that S100A4 synergizes with vascular endothelial growth factor (VEGF), via the RAGE receptor, in promoting endothelial cell migration by increasing KDR expression and MMP-9 activity. In vivo overexpression of S100A4 led to a significant increase in tumor growth and vascularization in a human melanoma xenograft M21 model.