Sortilin-related receptor is a druggable therapeutic target in breast cancer

In breast cancer, the currently approved anti-receptor tyrosine-protein kinase erbB-2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2-related therapeutic targets could offer a means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin-related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2-targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti-SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumab in vitro and in ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cell density in a mouse xenograft model of HER2-positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient-derived explant three-dimensional cultures. These results provide, for the first time, proof of principle that SorLA is a druggable target in breast cancer.Peer reviewe

Metformiini ja syöpä

Metformiini on tyypin 2 diabeteksen peruslääke, mutta viimeaikaisten epidemiologisten tutkimusten perusteella metformiinissa voi piillä myös syöpää estäviä vaikutuksia. Tarkastelemme väitettä kriittisesti uusimman kliinisen tiedon valossa ja pureudumme metformiinin vaikutuksiin syöpäsoluissa, joiden aineenvaihduntakontrolli on perustavasti erilainen kuin terveissä soluissa. Metformiini estää mitokondrioiden hengitysketjun kompleksi I:n toimintaa, mikä lamaa solujen adenosiinitrifosfaatin (ATP) tuotantoa ja sitruunahappokierron toimintaa. Terveet solut sopeutuvat vähäisempään energiantuotantoon ja sitruunahappokierron lamaan, mutta kasvunhallintansa menettäneet syöpäsolut kohtaavat metformiinin vaikutusten alla vakavan energiakriisin. Konsepti luo mielekkään pohjan tutkia metformiinia syöpäsoluja valikoivasti tappavana yhdisteenä. Syöpälääkkeeksi metformiinista on kuitenkin vasta sitten, kun sen vaikutusmekanismit syöpäsoluissa, tehoa ennustavat merkkiaineet ja soveltuvuus yhdistelmähoitoihin on paremmin tutkittu.Peer reviewe

A critical perspective on the administrative approach to crime prevention: The case of labour trafficking

Building on empirical data from Finnish enforcement agencies, we reflect on the challenges of the administrative approach to crime prevention. At the operational level, we identify explicit legal and implicit extra-legal limitations for using the administrative approach, that we call (1) ‘tunnel view’, (2) ‘structural siloes’, (3) ‘double role’, and (4) ‘blurred lines’. At the conceptual level, we consider the challenges of using the administrative approach in the context of labour trafficking. We argue that the initial set-up of the administrative approach that stresses the serious and organised crime paradigm limits understanding of the habitual and pervasive nature of labour trafficking. Nevertheless, administrative cooperation has the potential to contribute to full ‘labour justice’ as a governance framework that coordinates the efforts of public authorities and their multidimensional strategies to account for the entire labour exploitation spectrum.</p

Sortilin-related receptor is a druggable therapeutic target in breast cancer

In breast cancer, the currently approved anti-receptor tyrosine-protein kinase erbB-2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2-related therapeutic targets could offer a means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin-related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2-targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti-SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumab in vitro and in ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cell density in a mouse xenograft model of HER2-positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient-derived explant three-dimensional cultures. These results provide, for the first time, proof of principle that SorLA is a druggable target in breast cancer

A Potential Novel Spontaneous Preterm Birth Gene, AR, Identified by Linkage and Association Analysis of X Chromosomal Markers

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Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy

Correction: Volume: 10 Article Number: 932 DOI: 10.1038/s41467-019-08956-x Published: FEB 20 2019 Accession Number: WOS:000459099300001Elevated MYC expression sensitizes tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK strongly synergizes with BCL-2/BCL-X-L inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-X-L co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with navitoclax or venetoclax efficiently inhibited tumor growth, conferred survival benefits and induced tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re-growth with presentation of PD-1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by adjuvant metformin+venetoclax+anti-PD-1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance.Peer reviewe

Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer

Few patients with triple negative breast cancer (TNBC) benefit from immune checkpoint inhibitors with complete and durable remissions being quite rare. Oncogenes can regulate tumor immune infiltration, however whether oncogenes dictate diminished response to immunotherapy and whether these effects are reversible remains poorly understood. Here, we report that TNBCs with elevated MYC expression are resistant to immune checkpoint inhibitor therapy. Using mouse models and patient data, we show that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, mice experience tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and when strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors. The oncoprotein c-Myc is often overexpressed in triple negative breast cancer and has a role in tumor progression and resistance to therapy. Here the authors show that elevated MYC expression is correlated with low immune infiltration, diminished MHC-I pathway expression and that CpG/aOX40 treatment could overcome resistance to PD-L1 blockade in MYC-high breast tumors.Peer reviewe

MYC and AMPK-Save Energy or Die!

Peer reviewe