Receptors & Clinical Investigation (E-Journal - Smart Science & Technology)
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Activation of necroptosis to overcome drug resistance in leukemia
Get PDFThe understanding of cell death mechanisms is crucial for the development and application of novel anti-cancer therapies to avoid or circumvent drug-resistance in refractory malignancies. Impairment of apoptotic cell death plays a major role in therapy resistance and relapse of acute lymphoblastic leukemia (ALL) patients. Therefore, efforts are being directed at new agents reactivating apoptosis or inducing alternative cell death pathways such as necroptosis, a regulated form of necrosis. In a recent study published in Science Translational Medicine we show that the IAP (inhibitor of apoptosis proteins) inhibitor birinapant potently induces cell death in patient-derived ALL cells in vitro and in vivo through a receptor-interacting protein kinase 1- (RIP1) dependent mechanism. To define the cell death modality induced downstream of RIP1, we used a multicolor lentiCRISPR approach that allows simultaneous knockout of multiple genes. We observed that apoptosis and necroptosis are induced simultaneously as the inhibition of both pathways is required to restore cell viability upon birinapant treatment. This induction of dual cell death makes birinapant and other IAP inhibitors interesting agents for the treatment of refractory or drug resistant malignancies. 
How missense mutations in receptors tyrosine kinases impact constitutive activity and alternate drug sensitivity: insights from molecular dynamics simulations
Get PDFThe fundamental oncology-related research is required for a deeper understanding of the molecular mechanisms associated with the normal and/or abnormal protein functions, which are closely related with structure and dynamics of the macromolecules involved in these process. The most common origin of oncogenic events is related to missense mutations. Mutation-induced structural effects promoted by oncogenic mutations in receptor tyrosine kinases (RTKs), are not yet fully characterized. Computational biology completes and enriches experimental data, producing a novel vision of molecular mechanisms governing RTKs activity. In series of our papers, we studied the structural and dynamical features of native and mutated RTKs from III family (KIT and CSF-1R), yielding a detailed description of their mechanisms of activation, ligand-depend for the native proteins and constitutive for the distinct mutants. The mechanisms of RTKs activation are described in terms of allosteric regulation between coupled regulating fragments of the protein, juxta-membrane region (JMR) and activation (A-) loop. As some mutations promote resistance to the clinically-used drugs, we analyzed the affinity of imatinib to these therapeutic targets. The computationally-obtained (in silico) data were correlated with in vivo and in vitro observations, thus validating our numerically-based accounts. Going forward, clinical validation of cancer-related models and simulations are cornerstones key of translation of in silico data into biomedical research, at clinical and pharmacological levels
The hypothyroid brain
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The thyroid gland is controlled by a feedback system, the hypothalamus-pituitary-thyroid axis, and produces thyroid hormone (TH), which plays a critical role in growth, development and cellular metabolism. Diseases of the thyroid are well defined clinically and biochemically and diseases affecting thyroid function can cause both clinical hypothyroidisms, the most common cause of thyroid dysfunction, occurs when there is a decrease in the production of thyroid hormones, and hyperthyroidism, when there is an increase in hormone production. Common systemic manifestations of hypothyroidism include fatigue, dry skin, weight gain, hair loss, cold intolerance, hoarseness and constipation. Patients affected by this condition present a number of central and peripheral signs in the nervous system that may be neurological manifestations that occur along with the systemic disease. The conversion of thyroid hormone in the target tissue is done by three distinct deiodinases: type I, type II and type III. Each deiodinase has a different function in order to maintain thyroid hormone homeostasis in the tissues. Other proteins important for thyroid state are the TH transporters. MCT8, OATP1C1 and LAT1 and 2 transporters regulate T4 and T3 flow in the cells. The action of THs depends on the interaction of several proteins that are specialized in the control of thyroid hormone homeostasis not only in the brain but also in various tissues. THs are important for the maturation of the brain from the intrauterine period and remain important to adulthood. When there is some disturbance in the control mechanisms for the state of thyroid hormone, the consequences to the tissues, especially the CNS, can range from mild damage to severe impairment in neuronal development
EGFR/EGFRvIII-targeted immunotoxin therapy for the treatment of glioblastomas via convection-enhanced delivery
Get PDFGlioblastoma is the most aggressive malignant brain tumor among all primary brain and central nervous system tumors. The median survival time for glioblastoma patients given the current standard of care treatment (surgery, radiation, and chemotherapy) is less than 15 months. Thus, there is an urgent need to develop more efficient therapeutics to improve the poor survival rates of patients with glioblastoma. To address this need, we have developed a novel tumor-targeted immunotoxin (IT), D2C7-(scdsFv)-PE38KDEL (D2C7-IT), by fusing the single chain variable fragment (scFv) from the D2C7 monoclonal antibody (mAb) with the Pseudomonas Exotoxin (PE38KDEL). D2C7-IT reacts with both the wild-type epidermal growth factor receptor (EGFRwt) and EGFR variant III (EGFRvIII), two onco-proteins frequently amplified or overexpressed in glioblastomas. Surface plasmon resonance and flow cytometry analyses demonstrated a significant binding capacity of D2C7-IT to both EGFRwt and EGFRvIII proteins. In vitro cytotoxicity data showed that D2C7-IT can effectively inhibit protein synthesis and kill a variety of EGFRwt-, EGFRvIII-, and both EGFRwt- and EGFRvIII-expressing glioblastoma xenograft cells and human tumor cell lines. Furthermore, D2C7-IT exhibited a robust anti-tumor efficacy in orthotopic mouse glioma models when administered via intracerebral convection-enhanced delivery (CED). A preclinical toxicity study was therefore conducted to determine the maximum tolerated dose (MTD) and no-observed-adverse-effect-level (NOAEL) of D2C7-IT via intracerebral CED for 72 hours in rats. Based on this successful rat toxicity study, an Investigational New Drug (IND) application (#116855) was approved by the Food and Drug Administration (FDA), and is now in effect for a Phase I/II D2C7-IT clinical trial (D2C7 for Adult Patients with Recurrent Malignant Glioma, https://clinicaltrials.gov/ct2/show/NCT02303678). While it is still too early to draw conclusions from the trial, results thus far are promising
Zero to one: normal derived human ER+ cells in culture-proliferating
Get PDFCell culture technology is used to model structural and functional properties of human organs under normal and pathological conditions “in a dish”. The most obvious reason to culture human breast-derived cells is our fundamental desire to understand and ultimately treat breast cancer. Highly reproducible serum-free formulations for long-term propagation of normal human breast epithelial cells have existed for more than three decades and have served to complement the insight gained from a vast number of established breast cancer cell lines. The unspoken dichotomy in the experimental approach, however, has lied in the puzzling fact that normal-derived cells show a more myoepithelial expression profile, while breast cancer cells show more of a luminal profile making these difficult to compare experimentally. Moreover, normal estrogen receptor positive (ER+) luminal cells, thought to be equivalents to the most frequent form of human breast cancer, the ER+ subtype, completely fail to grow under standard culture conditions. One might choose to ignore this fact since breast homeostasis relies on a stem cell hierarchy and stem cells reside in the myoepithelial compartment which, if given the right conditions, can differentiate into ER+ luminal cells. The problem with this is that myoepithelial cells in culture, for unknown reasons, fail to behave like myoepithelial cells in vivo. This review summarizes some of the progress that has been made in the field with regard to the ER+ luminal breast epithelial lineage, especially within a human context, and its relevance to human breast cancer
Functional consequences of genetic polymorphisms in the NKG2D receptor signaling pathway and putative gene interactions
Get PDFNKG2D (NK group 2, member D) is an activating natural killer (NK) receptor, which is expressed on NK and CD8+ T cells. On NK cells, NKG2D elicits cytotoxicity and release of cytokines. On CD8+ T cells, it functions as a co-stimulatory molecule. The receptor recognizes several ligands including the major histocompatibility complex (MHC) class I chain-related molecules A (MICA) and B (MICB) as well as the UL16-binding proteins (ULBP). The diversity of NKG2D ligands is further increased by a high degree of genetic variability of the ligands. Recently, an amino acid exchange from valine to methionine at position 129 in MICA has been found to be associated with the outcome of allogeneic hematopoietic stem cell transplantation (HSCT), and the functional consequences of this specific genetic variation have been elucidated. The clinical associations found after HSCT were explainable by the functional differences of the MICA-129 variants. Herein, we discuss how the genetic polymorphisms of NKG2D ligands and NKG2D itself interact and may affect the outcome of HSCT and the susceptibility to other diseases, which have been associated with polymorphisms in the NKG2D signaling pathway
Blockade of non-opioid excitatory effects of spinal Dynorphin A at bradykinin receptors
Get PDFDynorphin A (Dyn A) is an endogenous opioid peptide that produces neuroinhibitory (antinociceptive) effects via m, d, and k opioid receptors. However, under chronic pain conditions, up-regulated spinal Dyn A can also interact with bradykinin receptors (BRs) to promote hyperalgesia through a neuroexcitatory (pronociceptive) effect. These excitatory effects cannot be blocked by an opioid antagonist, and thus are non-opioid in nature. Considering the structural dissimilarity between Dyn A and endogenous BR ligands, bradykinin (BK) and kallidin (KD), this interaction could not be predicted, and provided an opportunity to discover a novel potential neuroexcitatory target. Systematic structure-activity relationship (SAR) studies discovered a minimum pharmacophore of Dyn A, [des-Arg7]-Dyn A-(4-11) LYS1044 for antagonist activity at the BRs, along with insights into the key structural features for BRs recognition, i.e., amphipathicity. The des-Tyr fragment of dynorphin does not bind to opioid receptors. Intrathecal administration of des-Tyr dynorphin produces hyperalgesia reminiscent of behaviors seen in peripheral neuropathic pain models and at higher doses, neurotoxicity. Our lead ligand LYS1044 blocked Dyn A-(2-13)-induced neuroexcitatory effects in naïve animals and reversed thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in animals with experimental neuropathic pain. Based on these results, ligand LYS1044 might inhibit abnormal pain states by blocking the neuroexcitatory effects of enhanced levels of Dyn A that are seen in experimental models of neuropathic pain and that likely promote excitation mediated by BRs in the spinal cord
CD73 in Autoimmune Arthritis
Get PDFAdenosine is a potent anti-inflammatory molecule that plays an important role in many diseases. Extracellular levels of adenosine are determined by a combination of membrane transporters and ecto-nucleotidases such as CD73. Therapeutic targeting of the adenosinergic pathway, such as administration of adenosine receptor agonists, could be a valuable approach in the treatment of rheumatoid arthritis(RA). Until recently, the role of CD73 in RA pathogenesis had not been established. Using CD73-deficient gene-targeted mice, we demonstrated that CD73 plays a critical protective role in collagen-induced arthritis (CIA) in mice. Our findings, together with the results of recently published human studies, thus suggests that enhancement of CD73 activity may be a novel therapeutic approach in RA
Biomimetic Scaffolds for Osteogenesis
Get PDFSkeletal regenerative medicine emerged as a field of investigation to address large osseous deficiencies secondary to congenital, traumatic, and post-oncologic conditions. Although autologous bone grafts have been the gold standard for reconstruction of skeletal defects, donor site morbidity remains to be a significant limitation. To address these limitations, contemporary bone tissue engineering research aims to target delivery of osteogenic cells and growth factors in a defined three dimensional space using scaffolding material. Using bone as a template, biomimetic strategies in scaffold engineering unite organic and inorganic components in an optimal configuration to both support osteoinduction as well as osteoconduction. This article reviews the various structural and functional considerations behind the development of effective biomimetic scaffolds for osteogenesis and highlights strategies for enhancing osteogenesis