Browsing by Subject "targeted therapy"

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  • Filippou, Artemis; Pehkonen, Henna; Karhemo, Piia-Riitta; Väänänen, Juho; Nieminen, Anni I.; Klefström, Juha; Grenman, Reidar; Mäkitie, Antti; Joensuu, Heikki; Monni, Outi (2021)
    Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that derive from the mucosal epithelium of the upper aerodigestive tract and present high mortality rate. Lack of efficient targeted-therapies and biomarkers towards patients' stratification are caveats in the disease treatment. Anoctamin 1 (ANO1) gene is amplified in 30% of HNSCC cases. Evidence suggests involvement of ANO1 in proliferation, migration, and evasion of apoptosis; however, the exact mechanisms remain elusive. Aim of this study was to unravel the ANO1-dependent transcriptional programs and expand the existing knowledge of ANO1 contribution to oncogenesis and drug response in HNSCC. We cultured two HNSCC cell lines established from primary tumors harboring amplification and high expression of ANO1 in three-dimensional collagen. Differential expression analysis of ANO1-depleted HNSCC cells demonstrated downregulation of MCL1 and simultaneous upregulation of p27Kip1 expression. Suppressing ANO1 expression led to redistribution of p27Kip1 from the cytoplasm to the nucleus and associated with a cell cycle arrested phenotype. ANO1 silencing or pharmacological inhibition resulted in reduction of cell viability and ANO1 protein levels, as well as suppression of pro-survival BCL2 family proteins. Collectively, these data provide insights of ANO1 involvement in HNSCC carcinogenesis and support the rationale that ANO1 is an actionable drug target.
  • Kurppa, Kari J.; Caton, Javier; Morgan, Peter R.; Ristimaki, Ari; Ruhin, Blandine; Kellokoski, Jari; Elenius, Klaus; Heikinheimo, Kristiina (2014)
  • Grünewald, Thomas G. P.; Alonso, Marta; Avnet, Sofia; Banito, Ana; Burdach, Stefan; Cidre-Aranaz, Florencia; Di Pompo, Gemma; Distel, Martin; Dorado-Garcia, Heathcliff; Garcia-Castro, Javier; Gonzalez-Gonzalez, Laura; Grigoriadis, Agamemnon E.; Kasan, Merve; Koelsche, Christian; Krumbholz, Manuela; Lecanda, Fernando; Lemma, Silvia; Longo, Dario L.; Madrigal-Esquivel, Claudia; Morales-Molina, Alvaro; Musa, Julian; Ohmura, Shunya; Ory, Benjamin; Pereira-Silva, Miguel; Perut, Francesca; Rodriguez, Rene; Seeling, Carolin; Al Shaaili, Nada; Shaabani, Shabnam; Shiavone, Kristina; Sinha, Snehadri; Tomazou, Eleni M.; Trautmann, Marcel; Vela, Maria; Versleijen-Jonkers, Yvonne M. H.; Visgauss, Julia; Zalacain, Marta; Schober, Sebastian J.; Lissat, Andrej; English, William R.; Baldini, Nicola; Heymann, Dominique (2020)
    Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.
  • Närhi, Katja; Nagaraj, Ashwini S.; Parri, Elina; Turkki, Riku; van Duijn, Petra W.; Hemmes, Annabrita; Lahtela, Jenni; Uotinen, Virva; Mäyränpää, Mikko I.; Salmenkivi, Kaisa; Räsänen, Jari; Linder, Nina; Trapman, Jan; Rannikko, Antti; Kallioniemi, Olli; Af Hällström, Taija M.; Lundin, Johan; Sommergruber, Wolfgang; Anders, Simon; Verschuren, Emmy W. (2018)
    A key question in precision medicine is how functional heterogeneity in solid tumours informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signalling and therapy response can be modelled in precision-cut slices from Kras-driven non-small-cell lung cancer with varying histopathologies. Unexpectedly, profiling of in situ tumours demonstrated that signalling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma, and mitogen-activated protein kinase (MAPK) activity in adenocarcinoma. In addition, high intertumour and intratumour variability was detected, particularly of MAPK and mammalian target of rapamycin (mTOR) complex 1 activity. Using short-term treatment of slice explants, we showed that cytotoxic responses to combination MAPK and phosphoinositide 3-kinase-mTOR inhibition correlate with the spatially defined activities of both pathways. Thus, whereas genetic drivers determine histopathology spectra, histopathology-associated and spatially variable signalling activities determine drug sensitivity. Our study is in support of spatial aspects of signalling heterogeneity being considered in clinical diagnostic settings, particularly to guide the selection of drug combinations. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
  • Schönefeldt, Susann; Wais, Tamara; Herling, Marco; Mustjoki, Satu; Bekiaris, Vasileios; Moriggl, Richard; Neubauer, Heidi A. (2021)
    Simple Summary:& nbsp;gamma delta T cells play important roles in cancer immunity. Their rapid activation and cytotoxic nature make them promising candidates for use in cell-based immunotherapies; however, under certain conditions, they can induce pro-tumour functions. Furthermore, upon transformation, gamma delta T cells can develop into aggressive lymphomas with a poor prognosis and no curative therapeutic options. Here, we provide a comprehensive summary of our current knowledge on the complex roles of gamma delta T cells in cancer. We discuss their anti- and pro-tumour functions in both solid and blood cancers, highlighting the key subsets involved and their potential utility in anti-cancer immunotherapy. We also discuss the mechanisms of gamma delta T-cell transformation, summarising the resulting gamma delta T-cell leukaemia/lymphoma entities and their genetic and molecular profiles, as well as current and future treatment strategies.& nbsp;gamma delta T cells are unique players in shaping immune responses, lying at the intersection between innate and adaptive immunity. Unlike conventional alpha beta T cells, gamma delta T cells largely populate non-lymphoid peripheral tissues, demonstrating tissue specificity, and they respond to ligands in an MHC-independent manner. gamma delta T cells display rapid activation and effector functions, with a capacity for cytotoxic anti-tumour responses and production of inflammatory cytokines such as IFN-gamma or IL-17. Their rapid cytotoxic nature makes them attractive cells for use in anti-cancer immunotherapies. However, upon transformation, gamma delta T cells can give rise to highly aggressive lymphomas. These rare malignancies often display poor patient survival, and no curative therapies exist. In this review, we discuss the diverse roles of gamma delta T cells in immune surveillance and response, with a particular focus on cancer immunity. We summarise the intriguing dichotomy between pro- and anti-tumour functions of gamma delta T cells in solid and haematological cancers, highlighting the key subsets involved. Finally, we discuss potential drivers of gamma delta T-cell transformation, summarising the main gamma delta T-cell lymphoma/leukaemia entities, their clinical features, recent advances in mapping their molecular and genomic landscapes, current treatment strategies and potential future targeting options.