Treatment of chronic myelogenous leukemia – current status and future prospects

Wprowadzenie imatynibu do terapii przewlekłej białaczki szpikowej (PBSz) można już z perspektywy ponad dekady ocenić jako jedno z przełomowych wydarzeń w leczeniu nowotworów i w historii onkologii. Drobnocząsteczkowy inhibitor swoiście hamujący aktywność onkogennej kinazy tyrozynowej BCR/ABL, odpowiedzialnej za transformację nowotworową komórki macierzystej krwiotworzenia, okazał się zaskakująco skuteczny u większości chorych i zrewolucjonizował terapię PBSz. Niestety znacząca grupa chorych z powodu wystąpienia oporności lub nietolerancji nie odnosi spodziewanych korzyści terapeutycznych, co powoduje, że jednym z głównych celów badań stało się poszukiwanie nowych, jeszcze skuteczniejszych leków. W ostatnich 5 latach do terapii wprowadzono inhibitory drugiej generacji (dasatynib, nilotynib, bosutynib), trwają badania kliniczne nad inhibitorami trzeciej generacji (np. ponatynib hamujący zmutowaną kinazę BCR/ABL z mutacją T315I) oraz inhibitorami allosterycznymi, które hamują kinazę w innym mechanizmie, nie wiążąc się z jej centrum aktywnym. Żaden z dotychczas badanych leków nie eliminuje macierzystych komórek białaczkowych będących źródłem choroby, dlatego obecnie uważa się, że leczenie musi być kontynuowane dożywotnio. Ponieważ celem dla terapii powinno być całkowite wyleczenie chorego i możliwość przerwania leczenia, trwają badania nad możliwością całkowitej eradykacji białaczki, przez zastosowanie terapii łączonych. Można mieć nadzieję, że tak jak sukces imatynibu w terapii PBSz wyznaczył nowy kierunek w onkologii, tak samo osiągnięcie celu w postaci całkowitego wyleczenia pomoże w znalezieniu skutecznej terapii w innych nowotworach.Introduction of imatinib to the treatment of chronic myelogenous leukemia (CML) more than a decade ago may be considered as one of the milestones in the history of cancer treatment and oncology. Small molecule inhibitor, which specifically inhibits BCR/ABL oncogenic tyrosine kinase, responsible for malignant transformation of hematopoietic stem cell proved to be unexpectedly effective in the majority of patients and has revolutionized CML therapy. Unfortunately, a significant group of patients develops resistance or is intolerant to the drug which necessitate search for new better drugs. In the last 5 years 2nd generation inhibitors have been approved (dasatinib, nilotinib and bosutinib), clinical trials are ongoing with 3rd generation inhibitors (among them ponatinib, active against BCR/ABL with T315I mutation) and allosteric inhibitors. None of the available drugs eliminates leukemia stem cells, which are the roots of the disease, therefore therapy must be continued indefinitely. Since ultimate goal is to cure the disease there are number of trials to eradicate the disease with combination therapies. We may expect that such like imatinib opened new therapeutic horizons in oncology, complete eradication of CML will help to find cure other cancers

Statins in prevention and therapy of cancer

Statyny, będące inhibitorami 3-hydroksy-3-metylo-glutarylo-koenzymu A (HMG-CoA), jednego z najważniejszych enzymów szlaku syntezy cholesterolu, należą do grupy leków powszechnie stosowanych w leczeniu hipercholesterolemii. Obecnie duże zainteresowanie wzbudza ich potencjalne działanie zapobiegające powstawaniu nowotworu i zastosowanie w terapii chorób nowotworowych. Wyniki badań in vitro i in vivo potwierdzają cytostatyczne i cytotoksyczne działanie statyn w stosunku do różnych linii komórek nowotworowych. Ponadto statyny hamują waskularyzację w obrębie guza i zapobiegają przerzutom. Obserwacje kliniczne nie potwierdzają w pełni wyników badań przedklinicznych. Dotychczas w próbach randomizowanych nie potwierdzono wyników badań kliniczno-kontrolnych, w których wykazano znaczący spadek ryzyka choroby nowotworowej u pacjentów przyjmujących statyny. Również kliniczne próby wykorzystania statyn w terapii nie przyniosły oczekiwanego rezultatu. Niniejsza praca jest podsumowaniem dotychczasowej wiedzy na temat możliwości zastosowania statyn w prewencji i terapii nowotworów, a także prezentacją kierunków obecnie prowadzonych badań.Statins, inhibitors of one of the most important enzymes of cholesterol synthesis pathway - 3-hydroxy-3- -methyl-glutharyl-coenzyme-A (HMG-CoA), are commonly used as cholesterol level reducing drugs. Nowadays, more and more scientists take an interest of statins as potential both preventive and therapeutical anticancer agents. In vitro and in vivo experiments showed cytotoxic and cytostatic effect of statins in numerous cancer cell lines. Moreover, statins inhibit vascularisation in tumor and prevent metastasis. Optimistic pre-clinical tests results are not completely confirmed by clinical observations. Very promising results of clinical control trials showing a significant reduction of cancer risk in patients receiving statins were not confirmed in randomized clinical trials so far. Clinical trials concerning statins in anticancer therapy were not as successful as supposed. In this article we are trying to summarize current knowledge about potential statins usage in cancer prevention and treatment

Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor

Objectives: Systemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-β) plays a major role in tissue fibrosis, including downregulation of caveolin-1 (Cav-1); however, its role in defective angiogenesis is less clear. Pigment epithelium-derived factor (PEDF), a major antiangiogenic factor, is abundantly secreted by SSc fibroblasts. Here, we investigated the effect of TGF-β and Cav-1 on PEDF expression and the role of PEDF in the ability of SSc fibroblasts to modulate angiogenesis. Methods: PEDF and Cav-1 expression in fibroblasts and endothelial cells were evaluated by means of immunohistochemistry on human and mouse skin biopsies. PEDF and Cav-1 were silenced in cultured SSc and control fibroblasts using lentiviral short-hairpin RNAs. Organotypic fibroblast–endothelial cell co-cultures and matrigel assays were employed to assess angiogenesis. Results: PEDF is highly expressed in myofibroblasts and reticular fibroblasts with low Cav-1 expression in SSc skin biopsies, and it is induced by TGF-β in vitro. SSc fibroblasts suppress angiogenesis in an organotypic model. This model is reproduced by silencing Cav-1 in normal dermal fibroblasts. Conversely, silencing PEDF in SSc fibroblasts rescues their antiangiogenic phenotype. Consistently, transgenic mice with TGF-β receptor hyperactivation show lower Cav-1 and higher PEDF expression levels in skin biopsies accompanied by reduced blood vessel density. Conclusions: Our data reveal a new pathway by which TGF-β suppresses angiogenesis in SSc, through decreased fibroblast Cav-1 expression and subsequent PEDF secretion. This pathway may present a promising target for new therapeutic interventions in SSc

Integrin αv signaling influences phenotype and maturation of primary human osteoblasts on alumina surface

Due to the growing interest in stem cells application in tissue engineering the better understanding of primary human osteoblasts behavior in vitro, on biomaterial surface, is required. Among other molecules integrins may be taken into account as being involved in these phenomena. Integrins are a family of cell adhesion receptors, which may regulate many cellular functions e.g., adhesion, motility, phenotype and cell maturation. The aim of this study was to determine the effect of the biomaterial surfaces and αv integrin signaling pathway on the behavior, phenotype and maturation of human osteoblasts in vitro. Human bone derived cells (HBDCs) obtained from adult femoral bone fragments were cultured on both alumina disks and tissue culture polystyrene (TCPS) dishes. After 7, 14, and 21 days of culture, localization and mRNA expression level of αv integrin subunits and BGLAP (osteocalcin) on polystyrene were analyzed in addition, we treated the cell cultures with monoclonal antibodies against human αv integrin to block its ligand-binding activity, on both alumina and TCPS substrates. We found that the αv integrin was present in focal contacts and cell cytoplasm at subsequent stages of cell maturation and the level of αv integrin mRNA was the highest in mature osteoblasts. Blocking αv integrin transduction pathway caused changes in cell activity and morphology, decreased cells proliferation on TCPS and reduced expression of alkaline phosphatase (ALP) on both materials. The results suggest that αv integrin is involved as an important receptor facilitating osteogenic differentiation

Clonal Evolution of Multiple Myeloma—Clinical and Diagnostic Implications

Plasma cell dyscrasias are a heterogeneous group of diseases characterized by the expansion of bone marrow plasma cells. Malignant transformation of plasma cells depends on the continuity of events resulting in a sequence of well-defined disease stages, from monoclonal gammopathy of undetermined significance (MGUS) through smoldering myeloma (SMM) to symptomatic multiple myeloma (MM). Evolution of a pre-malignant cell into a malignant cell, as well as further tumor progression, dissemination, and relapse, require development of multiple driver lesions conferring selective advantage of the dominant clone and allowing subsequent evolution under selective pressure of microenvironment and treatment. This process of natural selection facilitates tumor plasticity leading to the formation of genetically complex and heterogenous tumors that are notoriously difficult to treat. Better understanding of the mechanisms underlying tumor evolution in MM and identification of lesions driving the evolution from the premalignant clone is therefore a key to development of effective treatment and long-term disease control. Here, we review recent advances in clonal evolution patterns and genomic landscape dynamics of MM, focusing on their clinical implications

FoxP3 Tregs Response to Sublingual Allergen Specific Immunotherapy in Children Depends on the Manifestation of Allergy

Over the last decades allergic diseases has become a major health problem worldwide. The only specific treatment to date is allergen specific immunotherapy (ASIT). Although it was shown that ASIT generates allergen-tolerant T cells, detailed mechanism underlying its activity is still unclear and there is no reliable method to monitor its effectiveness. The aim of our study was to evaluate ASIT influence on the frequency of forkhead box P3 (FoxP3) Tregs in allergic children with various clinical manifestations. The relative number of FoxP3 Tregs in 32 blood samples from allergic children at baseline and/or after 1 year of ASIT was assessed by flow cytometry. In the entire studied group, the percentage of FoxP3 Tregs did not increase 1 year after ASIT. Nevertheless, the percentage of FoxP3 Tregs after ASIT significantly increased in children with respiratory allergy (conjunctivitis, asthma, and rhinitis) coexisting with nonrespiratory manifestations (food allergy and/or atopic dermatitis), whereas, in patients with respiratory allergy only, the percentage of FoxP3 Tregs decreased. To the best of our knowledge, this is the first report showing various differential FoxP3 Tregs response to ASIT in allergic children. FoxP3 Tregs number could be useful in treatment monitoring. Further studies are warranted to confirm these observations