Critical roles for EPH receptor (EPH)-ephrin signalling in a range of chronic and regenerative diseases are increasingly being recognized. In particular, the complex roles of EPHs and ephrins in ...tumour growth and progression, and in nerve injury and regeneration have been studied extensively. This has led to considerable progress in developing strategies for their therapeutic targeting, with some anticancer agents already in clinical trials. Promising leads for non-malignant diseases are also emerging, with compelling preclinical data encouraging clinical development. We discuss this rapidly developing area of drug discovery, highlighting the associated challenges and limitations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Significant endeavor has been applied to identify functional therapeutic targets in glioblastoma (GBM) to halt the growth of this aggressive cancer. We show that the receptor tyrosine kinase EphA3 is ...frequently overexpressed in GBM and, in particular, in the most aggressive mesenchymal subtype. Importantly, EphA3 is highly expressed on the tumor-initiating cell population in glioma and appears critically involved in maintaining tumor cells in a less differentiated state by modulating mitogen-activated protein kinase signaling. EphA3 knockdown or depletion of EphA3-positive tumor cells reduced tumorigenic potential to a degree comparable to treatment with a therapeutic radiolabelled EphA3-specific monoclonal antibody. These results identify EphA3 as a functional, targetable receptor in GBM.
► EphA3 is overexpressed on mesenchymal GBM and inhibits terminal differentiation ► EphA3 maintains the tumor-forming cell population in GBM ► EphA3 negatively regulates mitogen-activated protein kinase signaling in GBM ► EphA3 is a targetable tumor antigen for the treatment of GBM
Low-passage, serum-free cell lines cultured from patient tumour tissue are the gold-standard for preclinical studies and cellular investigations of glioblastoma (GBM) biology, yet entrenched, ...poorly-representative cell line models are still widely used, compromising the significance of much GBM research. We submit that greater adoption of these critical resources will be promoted by the provision of a suitably-sized, meaningfully-described reference collection along with appropriate tools for working with them. Consequently, we present a curated panel of 12 readily-usable, genetically-diverse, tumourigenic, patient-derived, low-passage, serum-free cell lines representing the spectrum of molecular subtypes of IDH-wildtype GBM along with their detailed phenotypic characterisation plus a bespoke set of lentiviral plasmids for bioluminescent/fluorescent labelling, gene expression and CRISPR/Cas9-mediated gene inactivation. The cell lines and all accompanying data are readily-accessible via a single website, Q-Cell (qimrberghofer.edu.au/q-cell/) and all plasmids are available from Addgene. These resources should prove valuable to investigators seeking readily-usable, well-characterised, clinically-relevant, gold-standard models of GBM.
Upregulation and activation of developmental axon guidance molecules, such as semaphorins and members of the Eph receptor tyrosine kinase family and their ligands, the ephrins, play a role in the ...inhibition of axonal regeneration following injury to the central nervous system. Previously we have demonstrated in a knockout model that axonal regeneration following spinal cord injury is promoted in the absence of the axon guidance protein EphA4. Antagonism of EphA4 was therefore proposed as a potential therapy to promote recovery from spinal cord injury. To further assess this potential, two soluble recombinant blockers of EphA4, unclustered ephrin-A5-Fc and EphA4-Fc, were examined for their ability to promote axonal regeneration and to improve functional outcome following spinal cord hemisection in wildtype mice. A 2-week administration of either of these blockers following spinal cord injury was sufficient to promote substantial axonal regeneration and functional recovery by 5 weeks following injury. Both inhibitors produced a moderate reduction in astrocytic gliosis, indicating that much of the effect of the blockers may be due to promotion of axon growth. These studies provide definitive evidence that soluble inhibitors of EphA4 function offer considerable therapeutic potential for the treatment of spinal cord injury and may have broader potential for the treatment of other central nervous system injuries.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Since the mid-1980s, Eph receptors have evolved from being regarded as orphan receptors with unknown functions and ligands to becoming one of the most complex "global positioning systems" that ...regulates cell traffic in multicellular organisms. During this time, there has been an exponentially growing interest in Ephs and ephrin ligands, coinciding with important advances in the way biological function is interrogated through mapping of genomes and manipulation of genes. As a result, many of the original concepts that used to define Eph signaling and function went overboard. Clearly, the need for progress in understanding Eph-ephrin biology and the underlying molecular principles involved has been compelling. Many cell-positioning programs during normal and oncogenic development-in particular, the patterning of skeletal, vascular, and nervous systems-are modulated in some way by Eph-ephrin function. Undeniably, the complexity of the underlying signaling networks is considerable, and it seems probable that systems biology approaches are required to further improve our understanding of Eph function.
Intracranial mesenchymal tumors with FET‐CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely ...FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET‐CREB fusion by next‐generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4–70). Tumors were uniformly extra‐axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1‐ATF1 fusion, seven had EWSR1‐CREB1, four had EWSR1‐CREM, and one had FUS‐CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1‐CREB1 fusions more often featured stellate/spindle cell morphology, mucin‐rich stroma, and hemangioma‐like vasculature compared to tumors with EWSR1‐ATF1 fusions that most often featured sheets of epithelioid cells with mucin‐poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression‐free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1‐ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET‐CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma‐like neoplasms.
Intracranial mesenchymal tumors with FET‐CREB fusion comprise a group of neoplasms that have been variably described as intracranial angiomatoid fibrous histiocytoma and intracranial myxoid mesenchymal tumor. Our investigation reveals that these tumors occur in a wide age range with a female predominance, usually have extra‐axial or intraventricular location, typically have solid and cystic growth pattern with enhancement after contrast administration, and demonstrate a propensity for local recurrence and occasionally dissemination or metastasis leading to mortality. These tumors demonstrate a broad range of histologic features, with those harboring CREB1 or CREM as the fusion partner enriched for stellate/spindle cell morphology and mucin‐rich stroma, versus those with ATF1 as the fusion partner enriched for epithelioid/rhabdoid morphology and mucin‐poor stroma.
The detection and characterization of young planetary systems offer a direct path to study the processes that shape planet evolution. We report on the discovery of a sub-Neptune-sized planet orbiting ...the young star HD 110082 (TOI-1098). Transit events we initially detected during TESS Cycle 1 are validated with time-series photometry from Spitzer. High-contrast imaging and high-resolution, optical spectra are also obtained to characterize the stellar host and confirm the planetary nature of the transits. The host star is a late-F dwarf (M⁎ = 1.2Mꙩ) with a low-mass, M dwarf binary companion (M⁎ = 0.26Mꙩ) separated by nearly one arcminute (∼6200 au). Based on its rapid rotation and Lithium absorption, HD 110082 is young, but is not a member of any known group of young stars (despite proximity to the Octans association). To measure the age of the system, we search for coeval, phase-space neighbors and compile a sample of candidate siblings to compare with the empirical sequences of young clusters and to apply quantitative age-dating techniques. In doing so, we find that HD 110082 resides in a new young stellar association we designate MELANGE-1, with an age of 250(+50, -70) Myr. Jointly modeling the TESS and Spitzer light curves, we measure a planetary orbital period of 10.1827 days and radius of R(p) = 3.2 ± 0.1Rꚛ. HD 110082 b’s radius falls in the largest 12% of field-age systems with similar host-star mass and orbital period. This finding supports previous studies indicating that young planets have larger radii than their field-age counterparts.
Eph receptors and their ephrin ligands constitute the largest subfamily of receptor tyrosine kinases and are components of the cell signaling pathways involved during development. Eph and ephrin ...overexpression have been documented in a variety of human cancers including gastrointestinal malignancies and in particular colorectal malignancies. EphB and ephrin B proteins have been implicated in the homeostasis of the gastrointestinal tract where EphB2‐ and EphB3‐ephrin B signaling regulates cell sorting in the mature epithelium. These proteins are also reported to be upregulated in colon carcinomas. The EphA/ephrin A system has also been implicated in epithelial tissue structure and function. More recently, EphA receptors and their corresponding ligands have been implicated in numerous malignancies. Of these, EphA2 in particular has been intensively investigated and has been proposed as a therapeutic target. An interesting observation emerging from these studies is the role for Ephs and ephrins in critical aspects of cell adhesion, migration and positioning, and a crucial role in tumor progression and metastasis. However, the underlying role of Ephs and ephrins in these processes has generally been studied on individual Eph or ephrin genes. Given the multiplicity of Eph expression on gut epithelial cells, a more global approach is needed to define the precise role of Eph–ephrin interaction in malignant transformation. Here, we will review the recent advances on the role of Eph–ephrin signaling in colorectal malignancies.
•Monoclonal antibody therapy is a successful therapeutic strategy in many cancers.•High expression of Eph receptors is found in hematopoietic malignancies.•High specificity of Eph receptors is found ...on malignant hematopoietic cells.•Eph receptors can be used as a target for antibody therapy in hematological malignancies.
The use of monoclonal antibodies (mAbs) and molecules derived from them has achieved considerable attention and success in recent years, establishing this mode of therapy as an important therapeutic strategy in many cancers, in particular hematological tumors. mAbs recognize cell surface antigens expressed on target cells and mediate their function through various mechanisms such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, or immune system modulation. The efficacy of mAb therapy can be improved when they are conjugated to a highly potent payloads, including cytotoxic drugs and radiolabeled isotopes. The Eph family of proteins has received considerable attention in recent years as therapeutic targets for treatment of both solid and hematological cancers. High expression of Eph receptors on cancer cells compared with low expression levels in normal adult tissues makes them an attractive candidate for cancer immunotherapy. In this review, we detail the modes of action of antibody-based therapies with a focus on the Eph family of proteins as potential targets for therapy in hematological malignancies.
Abstract
Acute myeloid leukemia (AML) blasts express high levels of interlekin-3 (IL-3) receptor-α (CD123). CSL360 is a recombinant, chimeric immunoglobulin G1 (IgG1), anti-CD123 monoclonal antibody ...(MoAb) that neutralizes IL-3 and demonstrates anti-leukemic activity in vitro. This phase 1 study assessed safety, pharmacokinetics and bioactivity of weekly intravenous CSL360 for 12 weeks in 40 patients with advanced AML across five dose levels (0.1-10.0 mg/kg). Other than mild infusion reactions, CSL360 was well tolerated. The maximal tolerated dose was not reached. The half-life was 4.9 days, and the area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with dose. Doses ≥ 3.0 mg/kg resulted in complete saturation and down-regulation of CD123 and abolition of ex vivo proliferative responsiveness to IL-3, indicating adequate blockade of IL-3 signaling. Two patients responded, with one remaining in complete remission after 17 doses. CSL360 bound CD123 specifically, but did not induce anti-leukemic activity in most patients. While safe, MoAb blockade of CD123 function is insufficient as a therapeutic strategy.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
PDF
