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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.

Natural Killer (NK) cells can target and destroy cancer cells, yet tumor microenvironments typically suppress NK cell recruitment and cytotoxicity. The epidermal growth factor receptor (EGFR) is a potent oncogene that can activate survival, migration, and proliferation pathways, and clinical data suggests it may also play an immunomodulating role in cancers. Recent work has demonstrated a novel role for nuclear EGFR (nEGFR) in regulating transcriptional events unique from the kinase domain. Using a novel peptide therapeutic (cSNX1.3) that inhibits retrograde trafficking of EGFR and an EGFR nuclear localization mutant, we discovered that nEGFR suppresses NK cell recruitment and cytotoxicity. RNA-Seq analysis of breast cancer cells treated with cSNX1.3 or modified to lack a nuclear localization sequence (EGFR ΔNLS ) revealed the EGF-dependent induction of NK activating receptor ligands, while kinase inhibition by erlotinib did not impact these genes. NanoString analysis of tumor-bearing WAP-TGFα transgenic mice treated with cSNX1.3 demonstrated an increase in immune cell populations and activating genes. Additionally, immunohistochemistry confirmed an increase in NK cells upon cSNX1.3 treatment. Finally, cSNX1.3 treatment was found to enhance NK cell recruitment and cytotoxicity in vitro. Together, the data demonstrate a unique immunomodulatory role for nEGFR.

Overexpression and/or overactivation of the Epidermal Growth Factor Receptor (EGFR) is oncogenic in several tumor types yet targeting the kinase domain of wildtype EGFR has had limited success. EGFR has numerous kinase-independent roles, one of which is accomplished through the Sorting Nexin-dependent retrotranslocation of EGFR to the nucleus, which is observed in some metastatic cancers and therapeutically resistant disease. Here, we have utilized the BAR domain of Sorting Nexin 1 to create a peptide-based therapeutic (cSNX1.3) that promotes cell death in EGFR-expressing cancer. We evaluated the efficacy of cSNX1.3 in tumor-bearing WAP-TGFα transgenic mice (an EGFR-dependent model of breast cancer), where cSNX1.3 treatment resulted in significant tumor regression without observable toxicity. Evaluation of remaining tumor tissues found evidence of increased PARP cleavage, suggesting apoptotic tumor cell death. To evaluate the mechanism of action for cSNX1.3, we found that cSNX1.3 binds the C-terminus of the EGFR kinase domain at an interface site opposite the ATP binding domain with a Kd of ~4.0 µM. In vitro analysis found that cSNX1.3 inhibits the nuclear localization of EGFR. To determine specificity, we evaluated cancer cell lines expressing wildtype EGFR (MDA-MB-468, BT20 and A549), mutant EGFR (H1975) and non-transformed lines (CHO and MCF10A). Only transformed lines expressing wildtype EGFR responded to cSNX1.3, while mutant EGFR and normal cells responded better to an EGFR kinase inhibitor. Phenotypically, cSNX1.3 inhibits EGF-, NRG-, and HGF-dependent migration, but not HA-dependent migration. Together, these data indicate that targeting retrotranslocation of EGFR may be a potent therapeutic for RTK-active cancer.

EGFR is one of the most studied oncogenes in human biology with roles in proliferation, growth, and metastasis. This intense study has led to the development of a range of targeted therapeutics including small molecule tyrosine kinase inhibitors and monoclonal antibodies. These drugs are excellent at blocking activation and the kinase function of wtEGFR and many common EGFR mutants. These drugs have significantly improved patient outcomes with tumors including head and neck, glioblastoma, colorectal, and non-small cell lung cancer. However, these therapies are ineffective for the treatment of triple negative breast cancer (TNBC) even though about half of patients present with an overexpression of EGFR. 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. Previous work in our lab has demonstrated that blocking retrograde trafficking in TNBC cells significantly reduces EGFR driven oncogenic phenotypes. However, this retrograde trafficking inhibitor, Retro-2, blocks all retrograde trafficking with no specificity to EGFR. We then analyzed the retrograde trafficking of EGFR in TNBC and determined that the interaction between EGFR and SNX1 was a critical step for EGFR nuclear localization. We therefore developed a therapeutic peptide, cSNX1.3, that blocks the interaction of EGFR and SNX1 to inhibit the retrograde trafficking of EGFR. cSNX1.3 eliminates nuclear EGFR and reduces EGFR driven oncogenic phenotypes in vitro. Using a transgenic mouse model of EGFR driven breast cancer, we found that cSNX1.3 significantly reduced tumor growth and induces regression in several animals.

The genetics of plant variety Large-scale genome-wide association (GWA) studies have become an important tool in human genomics, mostly focused on disease but also on adaptive variations such as skin colour. The technique is now shown to be similarly useful in plants. Atwell et al . report a GWA study of over a hundred phenotypes in naturally occurring inbred lines of Arabidopsis thaliana . The results range from significant associations, usually for single genes, to more difficult-to-interpret findings that indicate confounding by complex genetics and population structure. The accompanying paper by Todesco et al . demonstrates the ability of this technique to detect major-effect gene loci. Using forward genetics and GWA analyses, they show that variation at a single locus ( ACD6 ) in Arabidopsis underlies phenotypic variation in vegetative growth as well as resistance to infection. The strong enhancement of resistance mediated by one of the alleles at this locus explains its persistence in natural populations throughout the world, despite it drastically reducing new leaf production. Here, large-scale genome-wide association studies were carried out with the naturally occurring inbred lines of Arabidopsis thaliana , which can be genotyped once and phenotyped repeatedly. The results range from significant associations, usually corresponding to single genes, to findings that are more difficult to interpret, because confounding by complex genetics and population structure makes it hard to distinguish true associations from false. Although pioneered by human geneticists as a potential solution to the challenging problem of finding the genetic basis of common human diseases 1 , 2 , genome-wide association (GWA) studies have, owing to advances in genotyping and sequencing technology, become an obvious general approach for studying the genetics of natural variation and traits of agricultural importance. They are particularly useful when inbred lines are available, because once these lines have been genotyped they can be phenotyped multiple times, making it possible (as well as extremely cost effective) to study many different traits in many different environments, while replicating the phenotypic measurements to reduce environmental noise. Here we demonstrate the power of this approach by carrying out a GWA study of 107 phenotypes in Arabidopsis thaliana , a widely distributed, predominantly self-fertilizing model plant known to harbour considerable genetic variation for many adaptively important traits 3 . Our results are dramatically different from those of human GWA studies, in that we identify many common alleles of major effect, but they are also, in many cases, harder to interpret because confounding by complex genetics and population structure make it difficult to distinguish true associations from false. However, a-priori candidates are significantly over-represented among these associations as well, making many of them excellent candidates for follow-up experiments. Our study demonstrates the feasibility of GWA studies in A. thaliana and suggests that the approach will be appropriate for many other organisms.

Knowledge based on science has been central to implementing community-based childhood obesity prevention interventions. The art of practitioner wisdom is equally critical to ensure locally relevant responses. In South Australia (SA), the OPAL (Obesity Prevention and Lifestyle) program has been implemented to reduce childhood obesity across 20 communities reaching nearly one quarter of the state’s population. Staff from across the State come together at regular intervals to share practice challenges and insights and refine the model of practice. Over a 3-year period 12 reflective practice workshops were held with OPAL staff (n = 46). OPAL staff were guided by an external facilitator using inquiring questions to reflect on their health promotion practice within local government. Three themes were identified as central within the reflections. The first theme is shared clarity through the OPAL obesity prevention model highlighting the importance of working to a clearly articulated, holistic obesity prevention model. The second theme is practitioner skill and sensitivity required to implement the model and deal with the ‘politics’ of obesity prevention. The final theme is the power of relationships as intrinsic to effective community based health promotion. Insights into the daily practices and reflections from obesity prevention practitioners are shared to shed light on the skills required to contribute to individual and social change. OPAL staff co-authored this paper.

Although pioneered by human geneticists as a potential solution to the challenging problem of finding the genetic basis of common human diseases1,2, genome-wide association (GWA) studies have, owing to advances in genotyping and sequencing technology, become an obvious general approach for studying the genetics of natural variation and traits of agricultural importance. They are particularly useful when inbred lines are available, because once these lines have been genotyped they can be phenotyped multiple times, making it possible (as well as extremely cost effective) to study many different traits in many different environments, while replicating the phenotypic measurements to reduce environmental noise. Here we demonstrate the power of this approach by carrying out a GWA study of 107 phenotypes in Arabidopsis thaliana, a widely distributed, predominantly self-fertilizingmodel plant known to harbour considerable genetic variation for many adaptively important traits3. Our results are dramatically different from those of human GWA studies, in that we identify many common alleles of major effect, but they are also, in many cases, harder to interpret because confounding by complex genetics and population structure make it difficult to distinguish true associations from false. However, a-priori candidates are significantly over-represented among these associations as well, making many of themexcellent candidates for follow-up experiments. Our study demonstrates the feasibility of GWA studies in A. thaliana and suggests that the approach will be appropriate for many other organisms.