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Nicolini A.,University of Pisa | Ferrari P.,University of Pisa | Kotlarova L.,Edukafarm | Rossi G.,National Research Council Italy | Biava P.M.,Scientific Institute of Research and Care Multimedica
Current Pharmaceutical Biotechnology

Acquired hormone resistance is an old hurdle and still represents to be a constant challenge in oncology for the medical community. Most recently, mainly following the results of BOLERO-2 study, the activation of the PI3K-AKT-mTOR pathway is considered clinically relevant for tumor escape from hormone dependence in breast cancer. In the BOLERO-2 trial, a combination of everolimus, mTOR inhibitor, and exemestane significantly prolonged the median progression free survival (PFS) compared to exemestane alone in advanced breast cancer patients with acquired endocrine resistance. Therefore, the inhibitors of the PI3K-AKT-mTOR pathway are a new class of drugs in great expansion joined with great expectation. This review article focuses on this special issue and briefly reports on the results of clinical trials using PI3K-AKT-mTOR inhibitors. However, the emergence of resistance to this new class of drugs, evidenced by the basic research and the relatively less benefit shown in the clinical trials, has been emerging as a new undesirable complication. Therefore, the principal elucidated mechanisms of the resistance to the inhibitors of the PI3K-AKT-mTOR pathway and the related potential therapeutic strategies are described. A more general immunological approach to delay acquired hormone resistance has also been considered and commented upon. © 2015 Bentham Science Publishers. Source

Biava P.M.,Scientific Institute of Research and Care Multimedica | Norbiato G.,University of Milan
Current Pharmaceutical Biotechnology

As the modern society is troubled by multi-factorial diseases, research has been conductedon complex realities including chronic inflammation, cancer, obesity, HIV infection, metabolic syndrome and its detrimental cardiovascular complications as well as depression and other brain disorders. Deterioration of crucial homeostatic mechanisms in such diseases invariably results in activation of inflammatorymediators, chronic inflammation, loss in immunological function, increased susceptibility to diseases, alteration of metabolism, decrease of energy production and neuro-cognitive decline. Regulation of genes expression by epigenetic code is the dominant mechanism for the transduction ofenvironmental inputs, such as stress and inflammation to lasting physiological changes. Acute and chronic stress determines DNA methylation and histone modifications in brain regions which may contribute to neuro-degenerative disorders.Nuclear glucocorticoids receptor interacts with the epigenoma resulting in a cortisol resistance status associated with a deterioration of the metabolic and immune functions. Gonadal steroids receptors have a similar capacity to produce epigenomic reorganization of chromatine structure. Epigenomic-induced reduction in immune cells telomeres length has been observed in many degenerative diseases, including all types of cancer. The final result of these epigenetic alterations is a serious damage to the neuro-endocrine-immune-metabolic adaptive systems. In this study, we propose a treatment with stem cells differentiation stage factors taken from zebrafish embryos which are able to regulate the genes expression of normal and pathological stem cells in a different specific way. © 2015 Bentham Science Publishers. Source

Biava P.M.,Scientific Institute of Research and Care Multimedica | Canaider S.,University of Bologna | Canaider S.,Italian National Institute of Biosystems and Biostructures | Facchin F.,University of Bologna | And 9 more authors.
Current Pharmaceutical Biotechnology

In spite of the growing body of evidence on the biology of the Zebrafish embryo and stem cells, including the use of Stem Cell Differentiation Stage Factors (SCDSFs) taken from Zebrafish embryo to impact cancer cell dynamics, comparatively little is known about the possibility to use these factors to modulate the homeostasis of normal human stem cells or to modulate the behavior of cells involved in different pathological conditions. In the present review we recall in a synthetic way the most important researches about the use of SCDSFs in reprogramming cancer cells and in modulating the high speed of multiplication of keratinocytes which is characteristic of some pathological diseases like psoriasis. Moreover we add here the results about the capability of SCDSFs in modulating the homeostasis of human adiposederived stem cells (hASCs) isolated from a fat tissue obtained with a novel-non enzymatic method and device. In addition we report the data not yet published about a first protein analysis of the SCDSFs and about their role in a pathological condition like neurodegeneration. © 2015 Bentham Science Publishers. Source

Nicolini A.,University of Pisa | Carpi A.,University of Pisa | Ferrari P.,University of Pisa | Biava P.M.,Scientific Institute of Research and Care Multimedica | Rossi G.,National Research Council Italy
Current Drug Targets

Historically, antiestrogen is the first targeted therapy used in breast cancer treatment. In fact, its rationale lies in the molecular pathways elucidated by basic research. In estrogen receptor (ER)-alpha positive metastatic breast cancer patients, hormone-therapy remains the first option of treatment. While tamoxifen concomitant with suppression of ovarian function with luteinizing hormone releasing hormone (LHRH) agonists is the standard first line treatment in premenopausal, third generation aromatase inhibitors (AIs) are the first line standard hormone therapy in postmenopausal. However, the development of acquired resistance during antiestrogen therapy continues to be a central clinical problem. This review provides an update on the antiestrogen action and report on immunological treatment of the advanced disease by some cytokines. Interleukin-2, interleukin-12 and interferons used alone or in combination demonstrated an anti-tumor action directly and/or through synergism with antiestrogens. A rationale for the addition of interferon-beta and interleukin-2 to antiestrogens is described. Furthermore, we summarize and interpret the clinical and laboratory data of a recent long-term hormone-immunotherapy study in metastatic endocrine dependent breast cancer patients. Prospective randomized trials are necessary to confirm some recent promising results based on an immunological approach in addition to antiestrogens to overcome or delay acquired hormone resistance. © 2016 Bentham Science Publishers. Source

Sell S.,New York State Department of Health | Nicolini A.,University of Pisa | Ferrari P.,University of Pisa | Biava P.M.,Scientific Institute of Research and Care Multimedica
Current Drug Targets

Current medical literature acknowledges that embryonic micro-environment is able to suppress tumor development. Administering carcinogenic substances during organogenesis in fact leads to embryonic malformations, but not to offspring tumor growth. Once organogenesis has ended, administration of carcinogenic substances causes a rise in offspring tumor development. These data indicate that cancer can be considered a deviation in normal development, which can be regulated by factors of the embryonic microenvironment. Furthermore, it has been demonstrated that teratoma differentiates into normal tissues once it is implanted in the embryo. Recently, it has been shown that implanting a melanoma in Zebrafish embryo did not result in a tumor development; however, it did in the adult specimen. This demonstrates that cancer cells can differentiate into normal tissues when implanted in the embryo. In addition, it was demonstrated that other tumors can revert into a normal phenotype and/or differentiate into normal tissue when implanted in the embryo. These studies led some authors to define cancer as a problem of developmental biology and to predict the present concept of "cancer stem cells theory". In this review, we record the most important researches about the reprogramming and differentiation treatments of cancer cells to better clarify how the substances taken from developing embryo or other biological substances can induce differentiation of malignant cells. Lastly, a model of cancer has been proposed here, conceived by one of us, which is consistent with the reality, as demonstrated by a great number of researches. This model integrates the theory of the "maturation arrest" of cancer cells as conceived by B. Pierce with the theory which describes cancer as a process of deterministic chaos determined by genetic and/or epigenetic alterations in differentiated cells, which leads a normal cell to become cancerous. All the researches here described demonstrated that cancer can be considered a problem of developmental biology and that one of the most important hallmarks of cancer is the loss of differentiation as already described by us in other articles. © 2016 Bentham Science Publishers. Source

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