Targeted Therapy

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Novel strategies for targeted therapy in NETs

Novel strategies for targeted therapy in NETs

Die palliative Therapie von fortgeschrittenen inoperablen NETs umfasst verschiedenen Systemtherapieansätze wie Biotherapie mit Somatostatin-Analoga und Interferon-alpha, Peptid Rezeptor Radionuklid Therapie (PRRT), Chemo- therapie oder molekular zielgerichtete Therapieoptionen . In den letzten Jahren wurden signifikante Verbesserungen bezüglich der Tumorkontrolle in der Sys- temtherapie von NET erreicht, jedoch besteht weiterhin ein Bedarf die molekular- biologischen Mechanismen der Tumorzelle vertieft zu verstehen und neuartige Behandlungsstrategien für eine weiter verbesserte Systemtherapie von NET zu entwickeln. Vor diesem Hintergrund wurden im Rahmen der hier vorgelegten Dissertationsarbeit zwei neue Strategien der ―targeted therapy‖ in humanen NET Zelllinien in vitro untersucht:
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Anti-Epidermal Growth Factor Receptor (EGFR) Antibodies Overcome Resistance of Ovarian Cancer Cells to Targeted Therapy and Natural Cytotoxicity

Anti-Epidermal Growth Factor Receptor (EGFR) Antibodies Overcome Resistance of Ovarian Cancer Cells to Targeted Therapy and Natural Cytotoxicity

Abstract: The poor outcome of advanced ovarian cancer under conventional therapy stimulated the exploration of new strategies to improve therapeutic efficacy. In our preclinical in vitro study we investigated a combination of targeted therapy and immunotherapy. Combination treatment with the anti-EGFR-antibody Cetuximab, related tyrosine kinase inhibitors (TKI) and cytolytic NK cells was tested against different ovarian cancer cell lines and primary tumour cells cultured from patient ascites. We found that selected ovarian cancer cells were susceptible to cetuximab and anti-EGFR-TKI-treatment, while the majority of cell lines were resistant to single or combination treatment with both substances. In addition, most ovarian cancer cells displayed low susceptibility to natural cytotoxicity of unstimulated NK cells. Notably, NK cytotoxicity against resistant ovarian cancer cells could be effectively enhanced by addition of Cetuximab mediating antibody-dependent cellular cytotoxicity (ADCC). Neither natural cytotoxicity nor ADCC of NK cells were negatively affected by the presence of TKIs. ADCC could be further increased when NK cells were pre-stimulated with monocytes and the immunostimulatory mycobacterial protein PstS-1. Our data suggest that targeted antibody therapy could be beneficial even against resistant tumour cells by augmenting supplementary cytolytic NK
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Recent developments and translational aspects in targeted therapy for metastatic breast cancer

Recent developments and translational aspects in targeted therapy for metastatic breast cancer

approaches where well-established or novel pathways are being targeted with the aim of prolonged disease control. 7–9 Besides the ER, targeting HER2 is today regarded as the best established targeted treatment approach in MBC. HER2 is a transmembrane growth factor receptor of the ERBB family; HER2 protein overexpression and/or HER2/neu gene ampli fication result in an aggressive BC phenotype with high recurrence rates and poor outcome. 10 Of note, before the avail- ability of targeted treatment options, median overall survival (OS) in HER2-positive MBC was low at around 20 months. 11 Addition of trastuzumab, a humanised monoclonal anti- body targeting the extracellular domain of HER2, to chemotherapy signi ficantly pro- longed progression-free survival (PFS) and OS over chemotherapy alone. 11 12 Still, sec- ondary resistance to trastuzumab will eventu- ally evolve and patients initially responding to HER2-targeted therapy will usually progress within 18 months, 13 indicating the need for further alternative treatment approaches.
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Preclinical in vitro investigation to evaluate novel molecular targeted therapy options for neuroendocrine neoplasms

Preclinical in vitro investigation to evaluate novel molecular targeted therapy options for neuroendocrine neoplasms

Neuroendocrine tumors (NETs) of the gastroenteropancreatic (GEP) system are highly complex and heterogeneous tumors, regarding their physiologic and genetic make-up and originate from distinct cell precursors [1]. GEP-NETs are frequently metastasized at the time of diagnosis, due to an absence of symptoms and curative resection is often impossible [2-4]. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are after colorectal cancer the second most common gastrointestinal malignancy [4] with increasing incidence [5, 6]. Despite an increasing knowledge of the tumor biology, genetics, epigenetics and novel biomarkers, the overall outcome and survival of GEP- NETs has gained very little over the last decades [4, 7, 8]. Furthermore, systemic therapeutic approaches for GEP-NETs, such as biotherapy, chemotherapy, molecular targeted therapy and peptide receptor radionuclide therapy are limited in their efficiency [9-11]. The paucity of successful therapeutic agents in GEP-NET is mostly due to the complexity, the rarity, the intrinsic differences in malignant potential because of their heterogeneity and the dissimilar clinical presentation [1, 4]. Molecularly targeted therapies with the multi-tyrosine kinase inhibitor sunitinib or the mTORC1 inhibitor everolimus are approved for treatment of pancreatic NETs [12-14]. Everolimus has recently also been approved for treatment of lung and gastrointestinal NETs [15].
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Investigation of AML-specific FLT3 mutations – from next generation diagnostics to combined targeted therapy

Investigation of AML-specific FLT3 mutations – from next generation diagnostics to combined targeted therapy

In the BM and HSC niche, microenvironmental hypoxia (low oxygen particle pressure) also leads to cell cycle arrest of AML blasts and inhibition of apoptosis by inducing the expression of the X- linked inhibitor of apoptosis protein (XIAP) [472]. Of note, in some patients hypoxia is capable of downregulating FLT3 expression in AML blasts, independent of the FLT3 mutational state. The hypoxia-mediated FLT3 downregulation is proteasome-dependent and mediated by PI3K signalling. [473] This questions how effective the TKI-mediated FLT3 surface increase and thus induced antigen presentation for FLT3-targeted immunotherapy in a large cohort of AML patients will be. With regards to immune evasion, hypoxia-induced autophagy furthermore attenuates TCMC by upregulating miR-210 and subsequent silencing of protein tyrosine phosphatase non-receptor type 1 (PTPN1) and hypoxia inducible factor (HIF)-1α-dependent activation of STAT3 in target cells, demonstrated by experiments using non-small cell lung carcinoma cells [458, 474]. Consistently, overexpression of miR-210 as well as HIF-1 α is associated with a poor prognosis in AML [475, 476]. PTPN1 has just recently been discovered to act as a tumor suppressor in the myeloid lineage cells, with deficiency in PTPN1 being sufficient to drive AML in mice [477]. The generation of NOX-generated ROS by increased surface FLT3 as described above might additionally enforce autophagy in AML blasts. Hypoxia induced HIF-2α- dependent upregulation of Tec family kinase BMX is also known to mediate chemotherapeutic and TKI resistance by sustained STAT5 and AKT signalling [478]. Thus, AML blasts might not only evade chemotherapy but also FLT3-targeted therapy due to hypoxic conditions.
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Immunhistochemische Untersuchungen von Plattenepithelkarzinomen der Mundhöhle
und des Oropharynx in Hinblick auf Anwendungsmöglichkeiten einer innovativen
zielgerichteten Therapie ("targeted therapy")

Immunhistochemische Untersuchungen von Plattenepithelkarzinomen der Mundhöhle und des Oropharynx in Hinblick auf Anwendungsmöglichkeiten einer innovativen zielgerichteten Therapie ("targeted therapy")

In der modernen Tumordiagnostik spielt die Immunhistochemie eine immer größere Rolle. Es lassen sich mit Hilfe der immunhistochemischen Ergebnisse Rückschlüsse auf die Prognose einer Krebserkrankung ziehen. In den letzen Jahren wurden Medikamente entwickelt, die genau auf die Marker abgestimmt sind und eine zielgerichtete Therapie („targeted therapy“) zulassen. Da es durch die Hemmung von übergeordneten Regulatoren zur Inaktivierung nachgeschalteter Signalwege kommt, wird auch der Begriff der „Signalwegstherapie“ gebraucht. Solche Therapien werden derzeit schon bei malignen Erkrankungen anderer Körperregionen angewendet. Von besonderem Interesse für gezielte Therapieansätze sind molekulardiagnostische Methoden, die den Nachweis der entsprechenden Zielstrukturen ermöglichen. Ein derartiger Nachweis liefert nicht nur die Grundlage für die Nutzung dieser neuen Tumortherapeutika, sondern verhindert auch deren Anwendung an Patienten, die von einer solchen Therapie nicht profitieren können, da in ihren Tumoren die Zielstruktur nicht vorhanden ist.
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Novel cryptophycin analogues and conjugates for tumor targeted therapy

Novel cryptophycin analogues and conjugates for tumor targeted therapy

Cryptophycins are naturally occurring cytotoxins with great potential for chemotherapy. Since targeted therapy provides new perspectives for treatment of cancer, new potent analogues of cytotoxic agents containing functional groups for conjugation to homing devices are required. We describe the design, synthesis and biological evaluation of three new unit B cryptophycin ana- logues. The O-methyl group of the unit B D-tyrosine analogue was replaced by an O-(allyloxyethyl) moiety, an O-(hydroxyethyl) group, or an O-(((azidoethoxy)ethoxy)ethoyxethyl) substituent. While the former two maintain cytotoxicity in the subnanomolar range, the attachment of the triethylene glycol spacer with a terminal azide results in a complete loss of activity. Docking studies of the novel cryptophycin analogues to β-tubulin provided a rationale for the observed cytotoxicities.
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Macrophage-Targeted Therapy : CD64-Based Immunotoxins for Treatment of Chronic Inflammatory Diseases

Macrophage-Targeted Therapy : CD64-Based Immunotoxins for Treatment of Chronic Inflammatory Diseases

strategies up to now failed to significantly reduce immunogenicity. Vascular leak syndrome triggered by binding of toxins to endothelial cells represents another disadvantage of chimeric IT. As counter-measures, receptor mutation, inhibitors preventing the binding to endothelial cells and administration of anti-inflammatory agents have been taken [38]. Low or non-killing concentrations of such IT have also been reported to induce an enhanced inflammatory response via activation of innate immune sensors [39–41]. This fact is especially relevant in the context of treating inflammatory diseases as it would oppose the desired effect of resolving inflammation. A far more promising approach is presented by the generation of fully human cytolytic fusion proteins (hCFP). Fully human antibodies fused to human proteins, which are capable of directly or indirectly inducing apoptosis, are now gaining attention due to their safety. A dozen successfully applied hCFP already exist. Human RNases like RNase 1, 2, 3 and 5 (angiogenin), which degrade RNA and induce apoptosis by inhibition of protein synthesis, have been used to replace the non-human toxins [42]. Huhn et al. were able to show specific cytotoxicity of the human angiogenin to CD30 overexpressing Hodgkin lymphoma-derived cell lines delivered by a CD30 ligand (CD30L) [43]. Another hCFP CD30L-based IT was generated by Tur et al. who showed specific cytotoxicity of the human death associated protein kinase 2 towards several Hodgkin lymphoma cells in vitro [44,45]. Proapoptotic proteins such as Bik, Bak, Bax, DNA fragmentation factor 40, FAS-ligand, and TNF-related apoptosis-inducing ligand proofed effective in melanoma, renal cancer, cutaneous T cell lymphoma, and AML [46]. A novel IT composed of a scFv against CTLA4 and perforin was shown to kill CTLA-positive cell lines in vitro [47]. Although most of the IT were tested for toxicity on cancer cells, hCFP presenting a safe and non-immunogenic profile would allow for their application in diseases other than cancer. One interesting and, at the same time, challenging class of diseases which often lack effective and specific therapy are chronic inflammatory disorders. As macrophages are strongly involved in inflammation, they have been suggested to represent a suitable target for therapy.
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Macrophage-Targeted Therapy : CD64-Based Immunotoxins for Treatment of Chronic Inflammatory Diseases

Macrophage-Targeted Therapy : CD64-Based Immunotoxins for Treatment of Chronic Inflammatory Diseases

However, clinical management consisting of blocking pro-inflammatory cytokines target the amplification loop of inflammation by depleting secondary inflammatory signals (e.g., TNF-Į). Beyond that, depletion of specific subsets of antigen specific T cells is associated with the undesirable reduction of the immune systems diversity. An intervention in processes that do not amplify, but rather cause the imbalance of pro- and anti-inflammatory cytokines would potentially result in a more rational approach to suppress chronic inflammation. One suitable target for this approach are macrophages which substantially contribute to chronicity by production of pro-inflammatory soluble mediators. To allow specific targeting of these cells, a surface molecule had to be selected to act as an entrance mediator. Screening of surface expression revealed FcȖRI, also referred to as CD64, to be up-regulated in macrophages. Compared to the other three FcȖ receptors (i.e., FcȖRII (CD32), FcȖRIII (CD16) and neonatal FcȖR), CD64 displays several exclusive properties: (1) high affinity; (2) ability to bind and internalize monomeric IgG [100]; and (3) constitutive expression only on macrophages, monocytes and their progenitors [101–103]. These properties make CD64 a suitable target molecule for a selective therapy directed against macrophages. First evidence for the success of this strategy was given by Thepen et al. in 2000, when elimination of CD64-positive macrophages using the IT H22-RicinA was demonstrated to resolve chronic skin inflammation in transgenic mice within 24 h [104]. In addition, Thepen et al. also showed by histological examination that other inflammatory cells disappeared from the site of inflammation and clinical parameters like vascular leakage and increased temperature were restored. Six years later, the same laboratory showed the inhibition of progression of arthritis
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Molecularly targeted therapy on a new preclinical mouse model for gastric neuroendocrine tumors

Molecularly targeted therapy on a new preclinical mouse model for gastric neuroendocrine tumors

The results of the molecularly targeted therapies on CEA424-SV40 TAg transgenic mouse model system, especially the successful experience with mTOR inhibitor RAD001, raised some obvious questions. RAD001 treatment inhibited tumor development and significantly prolonged the survival time. However, the anti-tumor effect achieved was not strong enough to kill all the tumor cells and cure the mice. RAD001 treated mice still developed highly proliferative tumor mass and presented similar behavior when the cancer progressed, like losing weight. Thus, we tried to find possible escape mechanism of tumor cells from RAD001 treatment for even more efficient treatment protocols. Possible hypothesis were the selection of cells by the mTOR inhibition, or the change in differentiation. Besides, the feed back activation of PI3K-Akt pathway was also evaluated because this side effect induced by single RAD001 treatment has been reported on other neuroendocrine cell lines.
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Characterization and targeted therapy of stem cell-like side population cells in pancreatic cancer and esophageal cancer

Characterization and targeted therapy of stem cell-like side population cells in pancreatic cancer and esophageal cancer

A number of existing drugs and natural compounds have been identified as inhibitors and/or modulators of Wnt/β-catenin signaling pathway (Takahashi-Yanaga and Kahn 2010). Aspirin is cheap and easy to handle in clinical application, especially, daily use of aspirin has already been considered as an effective cancer prevention strategy. Aspirin or other NASIDs affect cell proliferation, angiogenesis and metastasis and induced cell apoptosis in colorectal cancer (Ricchi et al 1997, Yao et al 2005). COX-2 elevation was observed in cancer cells and correlated with increased prostaglandin PGE2 production (Yoshida et al 2003). PEG2 can efficiently prevent β-catenin degradation by interfering with both GSK3-β and Axin2 function. In an esophageal cancer model, Navtej S et al has shown that either selective or non- selective COX-2 inhibitors can inhibit inflammation, COX-2 activity, and the development of adenocarcinoma induced by reflux (Buttar et al 2002). COX-2 contributes to P-glycoprotein- mediated multidrug resistance via JNK pathway (Sui et al 2011), which suggested that modulation of COX-2 might regulate SP cells associated chemoresistance. In our study, under aspirin treatment, we firstly observed a significant inhibition of SP cells that also show comparable sensitive to aspirin (Figure IV.35). The reduction was strengthened in SP enriched chemoresistant cells that could be associated with decreased COX-2 mRNA expression. The cell adhesion protein family member-CD44 regulates growth, survival, differentiation and migration and is thereby prone to be involved in tumor progression and metastasis. Furthermore, CD44 was identified as CSC marker in various cancer, for instance, homing of leukemia cancer stem cells is dependent on CD44 (Jin et al 2006). CD44 expression is up regulated in esophageal epithelial cells undergoing EMT (Le Bras et al 2011) and associated with acquirement of 5-FU resistance in ESCC cell lines (Zhao et al 2011). We found higher CD44 expression in OE19-SP cells than OE19-NSP cells, and could be down regulated by aspirin in resistant cells (Table IV.7). Other Wnt target genes, growth factors such as BMP4 is important in cell development and differentiation, for example, enquired for CD133 + CSCs maintenance (Zhang et al 2012). Cell cycle related genes-SOX2, CCND1, COX-2 and adhesion or migration genes MMP7, NRCAM were all down regulated under aspirin therapy.
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SABCS 2017: update on chemotherapy, targeted therapy, and immunotherapy

SABCS 2017: update on chemotherapy, targeted therapy, and immunotherapy

The phase Ib/II PANACEA trial (KEYNOTE-014) evaluated the combination of trastuzumab with the immune-checkpoint inhibitor pembrolizumab in metastatic breast cancer patients progressing on prior HER2-directed therapy [ 12 ]. The study was based upon preclinical data suggesting that this combina- tion may offer the chance to overcome trastuzumab resistance [ 13 ]; safety and efficacy of trastuzumab plus pembrolizumab in HER2-positive metastatic breast cancer patients with PD-L1 expressing tu- mours was defined as the primary study endpoint. A second, smaller, PD-L1 negative cohort was in- cluded as well. Overall, 58 patients were accrued; all had received prior trastuzumab-containing therapy and 51 additional anti-HER2 therapy as well (includ- ing pertuzumab and T-DM1). Overall response rate (ORR) in the PD-L1 positive cohort was 15% (90% CI 7–29) and an encouraging disease-control rate (DCR; CR + PR + SD ≥ 6 months) of 25% (90% CI 14–49) was reported, while no relevant activity was seen in PD-L1 negative subjects. Median progression-free survival (PFS) in the PD-L1 positive cohort was only 2.7 months but patients responding to treatment experienced prolonged disease control.
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Immunokinases, a novel class of immunotherapeutics for targeted cancer therapy

Immunokinases, a novel class of immunotherapeutics for targeted cancer therapy

Typical treatment strategies for cancer include surgery, chemotherapy and radiotherapy, but success is limited by the concurrent killing of nonmalignant cells, which can result in serious and often life- threatening side effects. Many tumor cells also become resistant to drugs, which substantially reduces the response to treatment and results in a poor prognosis. Surgical resection of primary tumors leads to high relapse rates reflecting the incomplete removal of tumor cells as well as the ineffective control of metastatic disease. Therefore, there is a strong demand for more potent and selective treatment options. Targeted immunotherapeutic approaches for the specific elimination of malignant cells have the potential to meet these criteria. Immunotherapy generally involves the induction of several mechanisms that interfere with carcinogenesis and tumor cell proliferation, although active immunotherapy is a more specialized approach in which the immune system itself is stimulated to remove malignant cells [1,2]. Targeted therapy involves either the direct activation or inactivation of (soluble) enzymes, growth factors or surface receptors in signaling pathways that are necessary for tumor maintenance and proliferation (e.g., growth factor receptors such as EGFR (Epidermal Growth Factor Receptor), Her2, BRAF and Kit) or the indirect targeted delivery of effector molecules to tumor cells, leading to growth arrest or remission [3,4]. This may involve drugs that penetrate the tumor cell plasma membrane allowing the targeting of intracellular tumor antigens, or the use of monoclonal antibodies (mAbs) that target cell surface molecules.
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Immunokinases, a novel class of immunotherapeutics for targeted cancer therapy

Immunokinases, a novel class of immunotherapeutics for targeted cancer therapy

Typical treatment strategies for cancer include surgery, chemotherapy and radiotherapy, but success is limited by the concurrent killing of nonmalignant cells, which can result in serious and often life- threatening side effects. Many tumor cells also become resistant to drugs, which substantially reduces the response to treatment and results in a poor prognosis. Surgical resection of primary tumors leads to high relapse rates reflecting the incomplete removal of tumor cells as well as the ineffective control of metastatic disease. Therefore, there is a strong demand for more potent and selective treatment options. Targeted immunotherapeutic approaches for the specific elimination of malignant cells have the potential to meet these criteria. Immunotherapy generally involves the induction of several mechanisms that interfere with carcinogenesis and tumor cell proliferation, although active immunotherapy is a more specialized approach in which the immune system itself is stimulated to remove malignant cells [1,2]. Targeted therapy involves either the direct activation or inactivation of (soluble) enzymes, growth factors or surface receptors in signaling pathways that are necessary for tumor maintenance and proliferation (e.g., growth factor receptors such as EGFR (Epidermal Growth Factor Receptor), Her2, BRAF and Kit) or the indirect targeted delivery of effector molecules to tumor cells, leading to growth arrest or remission [3,4]. This may involve drugs that penetrate the tumor cell plasma membrane allowing the targeting of intracellular tumor antigens, or the use of monoclonal antibodies (mAbs) that target cell surface molecules.
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Validation of CCR2-targeted mesoporous silica nanoparticles for lung cancer therapy

Validation of CCR2-targeted mesoporous silica nanoparticles for lung cancer therapy

Lung cancer has one of the highest mortality rates worldwide and even though advancements in treatment schemes have been made over the last years, lung cancer stays on top of the list for causes of cancer related deaths with a 5-year survival rate of 15,9%. In addition, early diagnosis and thus early treatment for lung cancer has not been achieved yet. In the past years treating the cancer mi- croenvironment and especially tumor-associated macrophages has been a major field of discussion. In addition, an emphasis on new targeted therapy strategies for cancer treatment has been made. As the idea is to target only tumor cells, healthy tissue should be spared and hence side effects of the therapy should be reduced. One approach to actively target tumor cells and tumor-associated mac- rophages is with the help of nanoparticles. These nanometer size particles can consist of different materials and can, for example, encapsulate chemotherapeu- tics to release them at a specific stimulus. In addition, ligands can be attached to actively target cells expressing a fitting receptor.
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Targeted Combination Therapy: Discovery and Evaluation of Synergistic Anticancer Effects of Anti-HER2-Duocarmycin Antibody-Drug Conjugates Combined with ATR Inhibitors

Targeted Combination Therapy: Discovery and Evaluation of Synergistic Anticancer Effects of Anti-HER2-Duocarmycin Antibody-Drug Conjugates Combined with ATR Inhibitors

While the global cancer burden is still high with 10 million people being diagnosed with cancer and 6 million cancer-related deaths yearly, academia and industry are developing more and more sophisticated therapies to combat cancer. One recent development are antibody-drug conjugates (ADCs) which consist of an antibody portion that mediates tumor selectivity and a highly cytotoxic drug designed to efficiently kill cancer cells. The majority of ADCs in clinical trials today carries payloads targeting the cytoskeleton. However, microtubule- targeting agents often lack clinical efficacy and thus, drugs with other mode of actions are in focus of current ADC research. With Mylotarg and Besponsa for example two ADCs carrying DNA damaging agents are already approved and SYD985 an ADC carrying the DNA-alkylating agent duocarmycin is currently showing promising results in a clinical phase III study. Although ADCs have shown promising anticancer effects and often come along with a broadened therapeutic window compared to conventional chemotherapy, there is still room for improvement regarding e.g. saftey aspects. Establishment of combination therapy for ADCs might pose a strategy for increasing efficacy, diminish side-effects and slow down resistance development especially because single agent therapy has seldom been curative. This work aimed at the discovery of a synergistic drug combination that might enhance the efficacy of duocarmycin-based ADCs like the clinically evaluated ADC SYD985. Therefore, 17 DNA-damage response inhibitors (DDRis), potentially involved in the repair of duocarmycin-induced lesions, were selected based on literature and tested in in vitro models. HCC-1954 and MDA-MB-468 cancer cells were treated with a combination of the selected DDRis and duocarmycin and the antiproliferative effects of the combination treatment were compared to the effects of the single agents alone. These experiments clearly demonstrated that inhibitors of the kinase ATR, which plays a central role in the response to replication stress, synergistically enhanced the cytotoxic effects of duocarmycin. This observation was additionally confirmed by treatment of ATR Knock-down cells with duocarmycin. Further drug combination experiments revealed the impact of structural features of different duocarmycins and ATR inhibtors on the synergism level. Besides studying the combinatorial effects of the small molecules alone, it was demonstrated that this combination effect could be translated to a targeted therapy approach like antibody-drug conjugates. Several duocarmycin based ADCs showed strong synergistic effects in combination with different ATR inhibitors
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Autophagy in cancer therapy

Autophagy in cancer therapy

Keywords: autophagy, cell death, cancer, autophagic cell death, cancer therapy iNTRODUCTiON Autophagy is a basic cellular process that serves as a quality control checkpoint during physiological and pathophysiological conditions to cope with cellular stress. Autophagy regulates the turnover of damaged cellular elements that are degraded, for example, via lysosomal enzymes after engulfment into autophagosomes ( 1 , 2 ). There are different forms of autophagy including macroautophagy (hereafter referred to as autophagy), microautophagy, and chaperone-mediated autophagy ( 3 ). A panel of genes involved in the regulation of autophagy has been identified over the last decades illus- trating that autophagy represents a genetically controlled process ( 4 ). As far as cancer is concerned, autophagy may function as both a tumor suppressor and tumor promoter ( 5 ). One explanation is the dual function of autophagy being either cytoprotective or cytotoxic in a context-dependent fashion. By definition, autophagic cell death (ACD) refers to a mode of cell death that is inhibited via specific blockage of the autophagic pathway ( 6 ).
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Information and targeted spending

Information and targeted spending

Keywords. Local public goods, information, elections, targeted spending. JEL classification. D72, D82, H41. 1. I ntroduction During electoral campaigns, voters pay only limited attention to candidates’ policy pro- posals. In particular, they pay more attention to any proposal that directly affects them and their districts than to other proposals. As a result, voters end up with an information asymmetry: they are better informed about policy proposals targeted to their own dis- trict than about proposals targeted to other districts. For instance, U.S. survey data show that voters in Michigan were better informed about the 2008 bailout of the Michigan auto industry than voters in other states; similarly, voters in offshore drilling Louisiana were better informed about offshore drilling proposals; and voters in states bordering Mexico (TX, NM, AZ, and CA) were better informed about border control policies (see Appendix A.1 for details).
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Targeted Countercyclical Capital Buffers

Targeted Countercyclical Capital Buffers

This paper investigates the effect of broad-based versus sectoral capital requirements using a dynamic model of bank behaviour. We study the problem facing banks when determining their dividend policy and portfolio of long-term loans to the retail and corporate sector. The return on lending is uncertain, and capital requirements may be reduced when loan losses are high, in order to stabilise lending. We find that when shifting capital between sectors is difficult or very costly, targeted regulation, such as a sectoral buffer (SCCyB), can lead to more stable lending during a crisis than a broad-based CCyB, at a lower cost. This depends on the ability of the policymaker to foresee the type of crisis. A targeted requirement is ex-post an inefficient policy if crises occur in sectors where the buffer requirement is inactive, as the targeted policy cannot effectively stabilise credit. However, the consequences of policy "mistakes" depend on the degree of sectoral segmentation in the banking market. Banks that provide credit to both the retail and the corporate sector will endogenously reallocate capital to the constrained sector in a crisis, irrespective of the kind of regulatory buffer that is implemented, thereby dampening the consequences of such inefficient policy.
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Riboflavin-Targeted Drug Delivery

Riboflavin-Targeted Drug Delivery

RF seems to play an important role in cancer development and progression, as its carrier protein and transporters are highly overexpressed in several cancer tissues. Thus, RFVTs and RCP have the potential to be used as biomarkers for cancer detection. Furthermore, fast and efficient RF uptake also renders it a promising targeting ligand for cancer diagnostics and therapeutics. In this context, it can be advantageous that both tumor cells and cells of the tumor microenvironment (endothelial cells and macrophages) show enhanced RF internalization. However, the exploration of this interesting pathway is in its infancy, and it is unclear why different cells upregulate different RFVTs and how this influences targeting efficacy. Additionally, the mechanism of RF internalization, depending on the size and composition of the RF-targeted diagnostics and therapeutics, require extensive investigation. Furthermore, the reviewed literature clearly indicates that diagnostic and therapeutic RF-targeted probes require different design considerations. Diagnostic RF-targeted agents should be small molecules with fast exchange kinetics between the tumor compartments and rapid elimination from the body to display the RFVT status. RF-targeted therapeutics, on the other hand, should be larger molecules that strongly accumulate via the EPR but still be small enough to penetrate the tumor tissue and benefit from the enhanced RF-mediated internalization. Thus, if these aspects are taken into consideration, RFVTs may become powerful targets for various theranostic and tumor targeted drug delivery systems. Author Contributions: M.D. researched the data for the article and drafted the manuscript. N.D., T.L., and F.K. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research was supported by the Deutsche Forschungsgemeinschaft (DFG) in the framework of the Research Training Group 2375 “Tumor-targeted Drug Delivery” grant 331065168 and DFG FOR 2591 to F.K. Grant No. 321137804.
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