Nuclear epidermal growth factor receptor as a therapeutic target

Epidermal growth factor receptor (EGFR) is one of the most well-studied oncogenes with roles in proliferation, growth, metastasis, and therapeutic resistance. This intense study has led to the development of a range of targeted therapeutics including small-molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and nanobodies. These drugs are excellent at blocking the activation and kinase function of wild-type EGFR (wtEGFR) and several common EGFR mutants. These drugs have significantly improved outcomes for patients with cancers including head and neck, glioblastoma, colorectal, and non-small cell lung cancer (NSCLC). However, therapeutic resistance is often seen, resulting from acquired mutations or activation of compensatory signaling pathways. Additionally, these therapies are ineffective in tumors where EGFR is found predominantly in the nucleus, as can be found in triple negative breast cancer (TNBC). In TNBC, EGFR is subjected to alternative trafficking which drives the nuclear localization of the receptor. In the nucleus, EGFR interacts with several proteins to activate transcription, DNA repair, migration, and chemoresistance. Nuclear EGFR (nEGFR) correlates with metastatic disease and worse patient prognosis yet targeting its nuclear localization has proved difficult. This review provides an overview of current EGFR-targeted therapies and novel peptide-based therapies that block nEGFR, as well as their clinical applications and potential for use in oncology

Stapled EGFR peptide reduces inflammatory breast cancer and inhibits additional HER-driven models of cancer

Background: The human epidermal growth factor receptor (HER) family of transmembrane tyrosine kinases is overexpressed and correlates with poor prognosis and decreased survival in many cancers. The receptor family has been therapeutically targeted, yet tyrosine kinase inhibitors (TKIs) do not inhibit kinase-independent functions and antibody-based targeting does not affect internalized receptors. We have previously demonstrated that a peptide mimicking the internal juxtamembrane domain of HER1 (EGFR; EJ1) promotes the formation of non-functional HER dimers that inhibit kinase-dependent and kinase-independent functions of HER1 (ERBB1/EGFR), HER2 (ERBB2) and HER3 (ERBB3). Despite inducing rapid HER-dependent cell death in vitro, EJ1 peptides are rapidly cleared in vivo, limiting their efficacy. Method: To stabilize EJ1 activity, hydrocarbon staples (SAH) were added to the active peptide (SAH-EJ1), resulting in a 7.2-fold increase in efficacy and decreased in vivo clearance. Viability assays were performed across HER1 and HER2 expressing cell lines, therapeutic-resistant breast cancer cells, clinically relevant HER1-mutated lung cancer cells, and patient-derived glioblastoma cells, in all cases demonstrating improved efficacy over standard of care pan-HER therapeutics. Tumor burden studies were also performed in lung, glioblastoma, and inflammatory breast cancer mouse models, evaluating tumor growth and overall survival. Results: When injected into mouse models of basal-like and inflammatory breast cancers, EGFRvIII-driven glioblastoma, and lung adenocarcinoma with Erlotinib resistance, tumor growth is inhibited and overall survival is extended. Studies evaluating the toxicity of SAH-EJ1 also demonstrate a broad therapeutic window. Conclusions: Taken together, these data indicate that SAH-EJ1 may be an effective therapeutic for HER-driven cancers with the potential to eliminate triple negative inflammatory breast cancer.Arizona Cancer Therapeutics; Ginny L Clements Breast Cancer Research Fund; NIH [NIH 1R41CA203353]; NCI [P30 CA023074]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Inferred Biomolecular Interaction Server—a web server to analyze and predict protein interacting partners and binding sites

IBIS is the NCBI Inferred Biomolecular Interaction Server. This server organizes, analyzes and predicts interaction partners and locations of binding sites in proteins. IBIS provides annotations for different types of binding partners (protein, chemical, nucleic acid and peptides), and facilitates the mapping of a comprehensive biomolecular interaction network for a given protein query. IBIS reports interactions observed in experimentally determined structural complexes of a given protein, and at the same time IBIS infers binding sites/interacting partners by inspecting protein complexes formed by homologous proteins. Similar binding sites are clustered together based on their sequence and structure conservation. To emphasize biologically relevant binding sites, several algorithms are used for verification in terms of evolutionary conservation, biological importance of binding partners, size and stability of interfaces, as well as evidence from the published literature. IBIS is updated regularly and is freely accessible via http://www.ncbi.nlm.nih.gov/Structure/ibis/ibis.html

Adaptive Value of Phenological Traits in Stressful Environments: Predictions Based on Seed Production and Laboratory Natural Selection

Phenological traits often show variation within and among natural populations of annual plants. Nevertheless, the adaptive value of post-anthesis traits is seldom tested. In this study, we estimated the adaptive values of pre- and post-anthesis traits in two stressful environments (water stress and interspecific competition), using the selfing annual species Arabidopsis thaliana. By estimating seed production and by performing laboratory natural selection (LNS), we assessed the strength and nature (directional, disruptive and stabilizing) of selection acting on phenological traits in A. thaliana under the two tested stress conditions, each with four intensities. Both the type of stress and its intensity affected the strength and nature of selection, as did genetic constraints among phenological traits. Under water stress, both experimental approaches demonstrated directional selection for a shorter life cycle, although bolting time imposes a genetic constraint on the length of the interval between bolting and anthesis. Under interspecific competition, results from the two experimental approaches showed discrepancies. Estimation of seed production predicted directional selection toward early pre-anthesis traits and long post-anthesis periods. In contrast, the LNS approach suggested neutrality for all phenological traits. This study opens questions on adaptation in complex natural environment where many selective pressures act simultaneously

Opera and Hypnosis: Victor Maurel’s Experiments with Verdi’s Otello

One day in his private home on the avenue Bugeaud, in Paris’s sixteenth arrondissement, the famous baritone Victor Maurel hosted a meeting which combined music with hypnotism of a young woman

Vocal Culture in the Age of Laryngoscopy

For several months beginning in 1884, readers of Life, Science, Health, the Atlantic Monthly and similar magazines would have encountered half-page advertisements for a newly patented medical device called the ‘ammoniaphone’ (Figure 2.1). Invented and promoted by a Scottish doctor named Carter Moffat and endorsed by the soprano Adelina Patti, British Prime Minister William Gladstone and the Princess of Wales, the ammoniaphone promised a miraculous transformation in the voices of its users. It was recommended for ‘vocalists, clergymen, public speakers, parliamentary men, readers, reciters, lecturers, leaders of psalmody, schoolmasters, amateurs, church choirs, barristers, and all persons who have to use their voices professionally, or who desire to greatly improve their speaking or singing tones’. Some estimates indicated that Moffat sold upwards of 30,000 units, yet the ammoniaphone was a flash in the pan as far as such things go, fading from public view after 1886

Unsound Seeds

With this image of a curtain hiding and at the same time heightening some terrible secret, Max Kalbeck began his review of the first Viennese performance of Richard Strauss’s Salome. Theodor W. Adorno picked up the image of the curtain in the context of Strauss’s fabled skill at composing non-musical events, when he identified the opening flourish of Strauss’s Salome as the swooshing sound of the rising curtain. If this is so, the succès de scandale of the opera was achieved, in more than one sense, as soon as the curtain rose at Dresden’s Semperoper on 10 December 1905. Critics of the premiere noted that the opera set ‘boundless wildness and degeneration to music’; it brought ‘high decadence’ onto the operatic stage; a ‘composition of hysteria’, reflecting the ‘disease of our time’, Salome is ‘hardly music any more’.The outrage did not end there

Science, Technology and Love in Late Eighteenth-Century Opera

It is a tale told by countless operas: young love, thwarted by an old man’s financially motivated marriage plans, triumphs in the end thanks to a deception that tricks the old man into blessing the young lovers’ union. Always a doddering fool, the old man is often also an enthusiast for knowledge. Such is the case, for instance, in Carlo Goldoni’s comic opera libretto Il mondo della luna (1750), in which Buonafede’s interest in the moon opens him to an elaborate hoax that has him believe he and his daughters have left Earth for the lunar world; and also in the Singspiel Die Luftbälle, oder der Liebhaber à la Montgolfier (1788), wherein the apothecary Wurm trades Sophie, the ward he intended to marry himself, for a technological innovation that will make him a pioneering aeronaut

Operatic Fantasies in Early Nineteenth-Century Psychiatry

In his celebrated essay on insanity in the Dictionnaire des sciences médicales (1816), French psychiatrist Étienne Esquirol marvelled at the earlier custom of allowing asylum inmates to attend theatrical productions at Charenton