Browsing by Subject "Melanoma"

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  • Aly, Ashraf A.; El-Sheref, Essmat M.; Bakheet, Momtaz E. M.; Mourad, Mai A. E.; Bräse, Stefan; Ibrahim, Mahmoud A. A.; Nieger, Martin; Garvalov, Boyan K.; Dalby, Kevin N.; Kaoud, Tamer S. (2019)
    Approximately 60% of human cancers exhibit enhanced activity of ERK1 and ERK2, reflecting their multiple roles in tumor initiation and progression. Acquired drug resistance, especially mechanisms associated with the reactivation of the MAPK (RAF/MEK/ERK) pathway represent a major challenge to current treatments of melanoma and several other cancers. Recently, targeting ERK has evolved as a potentially attractive strategy to overcome this resistance. Herein, we report the design and synthesis of novel series of fused naphthofuro[3,2-c] quinoline-6,7,12-triones 3a-f and pyrano[3,2-c]quinoline-6,7,8,13-tetraones 5a,b and 6, as potential ERK inhibitors. New inhibitors were synthesized and identified by different spectroscopic techniques and X-ray crystallography. They were evaluated for their ability to inhibit ERK1/2 in an in vitro radioactive kinase assay. 3b and 6 inhibited ERK1 with IC50s of 0.5 and 0.19 mu M, and inhibited ERK2 with IC50s of 0.6 and 0.16 mu M respectively. Kinetic mechanism studies revealed that the inhibitors are ATP-competitive inhibitors where 6 inhibited ERK2 with a K-i of 0.09 mu M. Six of the new inhibitors were tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Compound 3b and 6 were the most potent against most of the human tumor cell lines tested. Moreover, 3b and 6 inhibited the proliferation of the BRAF mutant A375 melanoma cells with IC50s of 3.7 and 0.13 mu M, respectively. In addition, they suppressed anchorage-dependent colony formation. Treatment of the A375 cell line with 3b and 6 inhibited the phosphorylation of ERK substrates p-90RSK and ELK-1 and induced apoptosis in a dose dependent manner. Finally, a molecular docking study showed the potential binding mode of 3b and 6 within the ATP catalytic binding site of ERK2.
  • Wouters, Michel W.; Michielin, Olivier; Bastiaannet, Esther; Beishon, Marc; Catalano, Orlando; del Marmol, Veronique; Delgado-Bolton, Roberto; Dendale, Remi; Trill, Maria Die; Ferrari, Andrea; Forsea, Ana-Maria; Kreckel, Hannelore; Lövey, Jozsef; Luyten, Gre; Massi, Daniela; Mohr, Peter; Oberst, Simon; Pereira, Philippe; Paiva Prata, Joao Paulo; Rutkowski, Piotr; Saarto, Tiina; Sheth, Sapna; Spurrier-Bernard, Gilly; Vuoristo, Meri-Sisko; Costad, Alberto; Naredi, Peter (2018)
    Background ECCO essential requirements for quality cancer care (ERQCC) are explanations and descriptions of challenges, organisation and actions that are necessary to give high-quality care to patients who have a specific type of cancer. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. Melanoma: essential requirements for quality care: Melanoma, the most-deadly skin cancer, is rising in incidence among fair-skinned people in Europe. Increasing complexity of care for advanced disease in clinical areas such as staging and new therapies requires attention to a number of challenges and inequalities in a diverse patient group. Care for advanced melanoma must only be carried out in, or in collaboration with, specialist melanoma centres which have both a core multidisciplinary team and an extended team of allied professionals, and which are subject to quality and audit procedures. Access to such units is far from universal in all European countries. It is essential that, to meet European aspirations for high-quality comprehensive cancer control, healthcare organisations implement the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis to treatment and follow-up, to improve survival and quality of life for patients. Conclusion: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality service for melanoma. The ERQCC expert group is aware that it is not possible to propose a 'one size fits all' system for all countries, but urges that access to multidisciplinary teams and specialised treatments is guaranteed to all patients with melanoma.
  • Vihinen, Pia; Mäkelä, Siru; Hernberg, Micaela; Tyynelä-Korhonen, Kristiina; Koivunen, Jussi (2017)
  • Hernberg, Micaela; Mäkelä, Siru; Vihinen, Pia (2017)
  • Peippo, Minna; Gardberg, Maria; Lamminen, Tarja; Kaipio, Katja; Carpen, Olli; Heuser, Vanina D. (2017)
    The functional properties of actin-regulating formin proteins are diverse and in many cases cell-type specific. FHOD1, a formin expressed predominantly in cells of mesenchymal lineage, bundles actin filaments and participates in maintenance of cell shape, migration and cellular protrusions. FHOD1 participates in cancer associated epithelial to mesenchymal transition (EMT) in oral squamous cell carcinoma and breast cancer. The role of FHOD1 in melanomas has not been characterized. Here, we show that FHOD1 expression is typically strong in cutaneous melanomas and cultured melanoma cells while the expression is low or absent in benign nevi. By using shRNA to knockdown FHOD1 in melanoma cells, we discovered that FHOD1 depleted cells are larger, rounder and have smaller focal adhesions and inferior migratory capacity as compared to control cells. Importantly, we found FHOD1 depleted cells to have reduced colony-forming capacity and attenuated tumor growth in vivo, a finding best explained by the reduced proliferation rate caused by cell cycle arrest. Unexpectedly, FHOD1 depletion did not prevent invasive growth at the tumor margins. These results suggest that FHOD1 participates in key cellular processes that are dysregulated in malignancy, but may not be essential for melanoma cell invasion.
  • Arasu, Uma Thanigai; Deen, Ashik Jawahar; Pasonen-Seppänen, Sanna; Heikkinen, Sami; Lalowski, Maciej; Kärnä, Riikka; Härkönen, Kai; Mäkinen, Petri; Lazaro-Ibañez, Elisa; Siljander, Pia R-M; Oikari, Sanna; Levonen, Anna-Liisa; Rilla, Kirsi (2020)
    Intercellular communication is fundamental to the survival and maintenance of all multicellular systems, whereas dysregulation of communication pathways can drive cancer progression. Extracellular vesicles (EVs) are mediators of cell-to-cell communication that regulate a variety of cellular processes involved in tumor progression. Overexpression of a specific plasma membrane enzyme, hyaluronan synthase 3 (HAS3), is one of the factors that can induce EV shedding. HAS3, and particularly its product hyaluronan (HA), are carried by EVs and are known to be associated with the tumorigenic properties of cancer cells. To elucidate the specific effects of cancerous, HAS3-induced EVs on target cells, normal human keratinocytes and melanoma cells were treated with EVs derived from GFP-HAS3 expressing metastatic melanoma cells. We found that the HA receptor CD44 participated in the regulation of EV binding to target cells. Furthermore, GFP-HAS3-positive EVs induced HA secretion, proliferation and invasion of target cells. Our results suggest that HAS3-EVs contains increased quantities of IHH, which activates the target cell hedgehog signaling cascade and leads to the activation of c-Myc and regulation of claspin expression. This signaling of IHH in HAS3-EVs resulted in increased cell proliferation. Claspin immunostaining correlated with HA content in human cutaneous melanocytic lesions, supporting our in vitro findings and suggesting a reciprocal regulation between claspin expression and HA synthesis. This study shows for the first time that EVs originating from HAS3 overexpressing cells carry mitogenic signals that induce proliferation and epithelial-to-mesenchymal transition in target cells. The study also identifies a novel feedback regulation between the hedgehog signaling pathway and HA metabolism in melanoma, mediated by EVs carrying HA and IHH.
  • Mattila, Kalle; Mäkelä, Siru; Hernberg, Micaela; Vihinen, Pia (2018)
    Immuuniaktivaation vapauttajat ovat uusia syöpälääkkeitä, joiden haittavaikutuksena voi ilmaantua tulehduksia. Jos päivystyspotilasta on hoidettu näillä lääkkeillä, hänen oireitaan tulee epäillä lääkkeen haittavaikutuksiksi, kunnes toisin on osoitettu. Samanaikainen infektio on mahdollinen.
  • Bolomsky, Arnold; Vogler, Meike; Köse, Murat C; Heckman, Caroline A; Ehx, Grégory; Ludwig, Heinz; Caers, Jo (BioMed Central, 2020)
    Abstract Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.
  • Bolomsky, Arnold; Vogler, Meike; Kose, Murat Cem; Heckman, Caroline A.; Ehx, Gregory; Ludwig, Heinz; Caers, Jo (2020)
    Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.
  • Vuoristo, Meri-Sisko; Mäkelä, Siru; Nores, Marja; Bouchard, Laura; Koulu, Leena (2017)
  • Koljonen, Virve; Palve, Johanna; Ilmonen, Suvi (2017)
    Moniammatilliset ihokasvainkokoukset tuovat hoidon suunnitteluun monen erikoisalan asiantuntemuksen samanaikaisesti. Valtaosa tapauksista käsitellään lähetteiden ja potilasasiakirjojen perusteella, ja siksi hyvä lähete on erityisen tärkeä.
  • Capasso, Cristian; Hirvinen, Mari; Garofalo, Mariangela; Romaniuk, Dmitrii; Kuryk, Lukasz; Sarvela, Teea; Vitale, Andrea; Antopolsky, Maxim; Magarkar, Aniket; Viitala, Tapani; Suutari, Teemu; Bunker, Alex; Yliperttula, Marjo; Urtti, Arto; Cerullo, Vincenzo (2016)
    The stimulation of the immune system using oncolytic adenoviruses (OAds) has attracted significant interest and several studies suggested that OAd´s immunogenicity might be important for their efficacy. Therefore, we developed a versatile and rapid system to adsorb tumor-specific major histocompatibility complex class I (MHC-I) peptides onto the viral surface to drive the immune response towards the tumor-epitopes. By studying the model epitope SIINFEKL we demonstrated that the peptide-coated OAd (PeptiCRAd) retains its infectivity and the cross-presentation of the modified-exogenous epitope on MHC-I is not hindered. We then showed that the SIINFEKL-targeting PeptiCRAd achieves a superior anti-tumor efficacy and increases the percentage of anti-tumor CD8+ T-cells and mature epitope-specific dendritic cells in vivo. PeptiCRAds loaded with clinically relevant tumor epitopes derived from tyrosinase-related protein 2 (TRP-2) and human gp100 could reduce the growth of primary-treated tumors and secondary-untreated melanomas, promoting the expansion of antigen-specific T-cell populations. Finally, we tested PeptiCRAd in humanized mice bearing human melanomas. In this model, a PeptiCRAd targeting the human melanoma-associated antigen A1 (MAGE-A1) and expressing granulocyte and macrophage colony-stimulating factor (GM-CSF) was able to eradicate established tumors and increased the human MAGE-A1-specific CD8+ T-cell population. Herein we show that the immunogenicity of OAds plays a key role in their efficacy and it can be exploited to direct the immune response system towards exogenous tumor epitopes. This versatile and rapid system overcomes the immunodominance of the virus and elicits a tumor-specific immune response, making PeptiCRAd a promising approach for clinical testing.
  • Isoherranen, Kirsi; Lagus, Heli; Keinonen, Anne; Koskenmies, Sari; Ylitalo, Leea; Övermark, Meri; Pitkänen, Sari (2020)
    • Kroonisen haavan taustalla on pahanlaatuinen kasvain noin 2–4 %:ssa tapauksista. • Kasvaimeen viittaavat haavan epätyypillinen sijainti, epäsäännölliset reunat, voimakas liikakasvu, herkästi vuotava haavan pohja, epätyypillinen pigmentaatio haavan reunalla sekä huono hoitovaste 4–12 viikon kuluessa. • Diagnoosi tehdään koepalasta. • Hoito valikoituu kasvaimen lajin mukaan, mutta ensisijainen hoito on kirurginen.
  • Kivelä, Tero; Turunen, Joni (2019)
  • Koskivuo, Ilkka; Jahkola, Tiina (2017)