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The role of MMP10 in non-small cell Lung cancer, and pharmacological evaluation of its potential as a target for therapeutic intervention. Investigation of the role of MMP10 in the tumour microenvironment of non-small cell lung cancer using gene, protein and mass spectrometry approaches to determine MMP10’s potential in drug development strategiesBin Saeedan, Abdulaziz S.A. January 2014 (has links)
Non-Small Cell Lung Cancer (NSCLC), which accounts for 80% of all lung cancer cases, is associated with resistance to chemotherapy and poor prognosis. Exploitation of NSCLC-upregulated pathways that can either be targeted by novel therapeutics or used to improve the tumour-delivery of current chemotherapeutics are required. Among the matrix metalloproteinases (MMPs) that are essential for tumour development, MMP10 is a potential candidate as a therapeutic target based on its expression and contribution to NSCLC development. This research aims to explore the expression and functions of MMP10 in the tumour microenvironment of NSCLC and evaluate the potential of MMP10 as a target for therapeutic intervention. Herein, MMP10 expression at gene and protein levels were analysed in a panel of NSCLC cell lines using RT-PCR and Western blotting analysis. To determine MMP10 functional relevance, an in vitro angiogenesis assay using cell conditioned media was carried out. To identify specific peptide sequences for the design of prodrugs rationalised to be MMP10 activated, in vitro substrate cleavage studies were performed using a mass spectrometry approach to differentiate between MMP10 and the structurally similar MMP3. This study demonstrates that MMP10 is highly expressed in NSCLC and that high levels of MMP10 are associated with induction of angiogenesis, a crucial process supporting tumour growth. In addition to the achievement of having been able to differentiate between closely similar MMP3 and MMP10 through carefully monitoring the hydrolysis rate of compound 444259 (a known MMP substrate), data generated herein provides the basis for further studies to exploit MMP10 as a prodrug-activator. / Full text was made available at the end of the embargo period, 12th Dec 2019
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Exprese markerů imunogenní buněčné smrti na buňkách karcinomu plic / Expression of immunogenic cell death markers on lung cancer cellsKobosilová, Linda January 2014 (has links)
Immunogenic cell death (ICD) is characterized by presence of specific molecules including surface exposed calreticulin (CRT) and the heat shock proteins HSP70 and HSP90. Release of ATP and high- mobility group box protein 1 (HMGB1) belongs to other typical characteristics. For induction of ICD in lung cancer cells high-hydrostatic pressure (HHP) was used. Treatment by HHP induces expression of immunogenic markers CRT, HSP70 and HSP90 on the cell surface. HHP also induces secretion of ATP to the extracellular milieu. Dendritic cells (DC) pulsed with HHP-treated tumor cells showed fenotypic maturation characterized by upregulation of maturation molecule CD83, costimulation molecules CD80 and CD86, chemokine receptor CCR7 and MHC class II molecule HLA-DR. Pulsed DCs have also higher rate of phagocytosis of HHP-treated tumor cells and they induce lower numbers of regulatory T cells compared to immature DCs. Moreover, activation of caspases (-8, -9, -3) and other proteins (phosphorylation of eIF2α) which are crucial in ER-stress mediated apoptotic pathway, was observed after HHP treatment. Using wide range of methods it was confirmed that HHP treatment is able to induce ICD in lung cancer cell lines, fenotypic and functional characteristics were described and the decreased induction of regulatory T-lymphocytes...
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Molekulargenetische Veränderungen in nicht kleinzelligen Bronchialkarzinomen, detektiert durch komparative genomische Hybridisierung (CGH) / Molecular genetic changes in non small cell lung cancer, detected by comparative genomic hybridization (CGH)Hellms, Timo 22 January 2013 (has links)
No description available.
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PRONTOX – proton therapy to reduce acute normal tissue toxicity in locally advanced non-small-cell lung carcinomas (NSCLC): study protocol for a randomised controlled trialZschaeck, Sebastian, Simon, Monique, Löck, Steffen, Troost, Esther G. C., Stützer, Kristin, Wohlfahrt, Patrick, Appold, Steffen, Makocki, Sebastian, Bütof, Rebecca, Richter, Christian, Baumann, Michael, Krause, Mechthild 17 March 2017 (has links) (PDF)
Background
Primary radiochemotherapy with photons is the standard treatment for locally advanced-stage non-small cell lung cancer (NSCLC) patients. Acute radiation-induced side effects such as oesophagitis and radiation pneumonitis limit patients’ quality of life, and the latter can be potentially life-threatening. Due to its distinct physical characteristics, proton therapy enables better sparing of normal tissues, which is supposed to translate into a reduction of radiation-induced side effects.
Methods/design
This is a single-centre, prospective, randomised controlled, phase II clinical trial to compare photon to proton radiotherapy up to 66 Gy (RBE) with concomitant standard chemotherapy in patients with locally advanced-stage NSCLC. Patients will be allocated in a 1:1 ratio to photon or proton therapy, and treatment will be delivered slightly accelerated with six fractions of 2 Gy (RBE) per week.
Discussion
The overall aim of the study is to show a decrease of early and intermediate radiation-induced toxicity using proton therapy. For the primary endpoint of the study we postulate a decrease of radiation-induced side effects (oesophagitis and pneumonitis grade II or higher) from 39 to 12%. Secondary endpoints are locoregional and distant failure, overall survival and late side effects.
Trial registration
Registered at ClinicalTrials.gov with Identifier NCT02731001 on 1 April 2016.
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WISP1 and EMT-associated response and resistance to immune checkpoint blockadeGaudreau, Pierre-Olivier 09 1900 (has links)
Les immunothérapies de type immune checkpoint blockade (ICB) ont révolutionné les
approches thérapeutiques en oncologie médicale et ont largement contribué au fait que
l’immunothérapie est maintenant considérée comme le quatrième pilier des traitements anticancer,
aux côtés d’approches traditionnelles telles que la chirurgie, la radiothérapie et la
chimiothérapie. Malgré les résultats encourageants des études cliniques évaluant ce type
d’immunothérapie, la majorité des patients décèderont des suites de leur maladie.
Conséquemment, le domaine de recherche visant à comprendre les mécanismes de résistance aux
immunothérapies est en expansion constante. Plusieurs stratégies visant à améliorer les issues
cliniques ont été proposées, parmi lesquelles figurent: 1) la recherche de nouvelles cibles
thérapeutiques dans le microenvironnement immun tumoral et; 2) les études de combinaisons
thérapeutiques où une immunothérapie est jumelée à d’autres types de modalités thérapeutiques
potentiellement synergiques. Chacune des études présentées dans cette thèse de recherche
s’apparente à l’une ou l’autre de ces stratégies.
Dans le cadre de notre première étude, nous démontrons que la protéine WISP1
représente une cible prometteuse à l’intérieur du microenvironnement de plusieurs types de
tumeurs solides étant donné son association avec différentes variables pronostiques et proinflammatoires,
ainsi qu’avec un programme épigénétique complexe, la transition épithélialemésenchymateuse
(Epithelial-Mesenchymal Transition; EMT). De plus, nous démontrons que
les niveaux d’expression de WISP1 sont significativement plus élevés au sein des tumeurs
démontrant une résistance primaire aux immunothérapies de type ICB, particulièrement lorsque
qu’une signature reliée à l’EMT peut être retrouvée de façon concomitante. Pour notre deuxième
étude, nous avons utilisé des modèles murins in vivo de cancer pulmonaire non à petites cellules
KRAS-mutés afin de tester différentes combinaisons thérapeutiques jumelant une thérapie dite
ciblée (i.e., un inhibiteur de MEK) a différentes immunothérapies de type ICB. Nos résultats
démontrent que l’ajout d’une immunothérapie anti-CTLA-4 à l’inhibiteur de MEK AZD6244
(selumetinib) et une immunothérapie anti-PD-L1 augmente significativement la survie, et que
ces bénéfices sont associés à une diminution de marqueurs reliés à l’EMT.
Il existe donc un lien commun entre ces deux études qui repose sur l’importance de
l’EMT comme facteur favorisant la résistance thérapeutique aux immunothérapies. De plus, nous
démontrons pour la première fois que les bénéfices associés à la triple combinaison
thérapeutique susmentionnée peuvent être corrélés à une diminution d’expression de marqueurs
liés à l’EMT. Par conséquent, nos résultats sont discutés en tant que base potentielle pour de
futures études visant à réduire la résistance thérapeutique reliée à l’EMT. Nous discutons
également de la valeur translationnelle de nos résultats à travers le développement d’une étude
clinique. / Immune checkpoint blockade (ICB) has revolutionized therapeutic approaches in the
field of medical oncology and has largely contributed to the fact that immunotherapy is now
being regarded as the fourth pillar of cancer treatment alongside surgery, radiotherapy and
chemotherapy. Despite encouraging results from clinical trials using ICB, most patients
ultimately relapse or succumb to their disease. Therefore, the field of immunotherapeutic
resistance research is rapidly expanding. Many strategies to improve ICB responses have been
undertaken, including: 1) the search for novel, actionable targets in the immune tumor
microenvironment (TME) and; 2) therapeutic combination studies where an ICB backbone is
combined with different, synergistic treatment modalities. Each of the studies presented in this
research thesis embraces one of these strategies.
In our first study, we show that WISP1 represents a promising TME target in multiple
solid tumor types by demonstrating its association with prognostic and pro-inflammatory
variables, as well as to a complex epigenetic program termed Epithelial-Mesenchymal Transition
(EMT). Furthermore, we show that increased WISP1 expression is associated to primary
resistance to ICB, particularly when EMT-related signatures are found concomitantly. In our
second study, we used in vivo mouse models of KRAS-mutant Non-Small Cell Lung Cancer
(NSCLC) to test different therapeutic combinations of targeted therapies (i.e., MEK inhibitor)
and ICB. We found that the addition of anti-CTLA-4 ICB to MEK inhibitor AZD6244
(selumetinib) and anti-PD-L1 ICB increases survival, and that these benefits are associated with
the downregulation of EMT-related markers.
Therefore, there exists a common link between these studies, which relies on the
significance of EMT as a detrimental factor within the TME and its association with ICB
resistance. Moreover, we show for the first time that the benefits of ICB combination therapy can
be associated to the downregulation of EMT markers in vivo. Consequently, we discuss how our
results may constitute the basis for future work aiming at reducing EMT-mediated therapeutic
resistance, as well as the translational relevance of our pre-clinical results through the
development of a clinical trial.
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PRONTOX – proton therapy to reduce acute normal tissue toxicity in locally advanced non-small-cell lung carcinomas (NSCLC): study protocol for a randomised controlled trialZschaeck, Sebastian, Simon, Monique, Löck, Steffen, Troost, Esther G. C., Stützer, Kristin, Wohlfahrt, Patrick, Appold, Steffen, Makocki, Sebastian, Bütof, Rebecca, Richter, Christian, Baumann, Michael, Krause, Mechthild 17 March 2017 (has links)
Background
Primary radiochemotherapy with photons is the standard treatment for locally advanced-stage non-small cell lung cancer (NSCLC) patients. Acute radiation-induced side effects such as oesophagitis and radiation pneumonitis limit patients’ quality of life, and the latter can be potentially life-threatening. Due to its distinct physical characteristics, proton therapy enables better sparing of normal tissues, which is supposed to translate into a reduction of radiation-induced side effects.
Methods/design
This is a single-centre, prospective, randomised controlled, phase II clinical trial to compare photon to proton radiotherapy up to 66 Gy (RBE) with concomitant standard chemotherapy in patients with locally advanced-stage NSCLC. Patients will be allocated in a 1:1 ratio to photon or proton therapy, and treatment will be delivered slightly accelerated with six fractions of 2 Gy (RBE) per week.
Discussion
The overall aim of the study is to show a decrease of early and intermediate radiation-induced toxicity using proton therapy. For the primary endpoint of the study we postulate a decrease of radiation-induced side effects (oesophagitis and pneumonitis grade II or higher) from 39 to 12%. Secondary endpoints are locoregional and distant failure, overall survival and late side effects.
Trial registration
Registered at ClinicalTrials.gov with Identifier NCT02731001 on 1 April 2016.
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