4,254 research outputs found
New Approaches to Target T-ALL.
No full textAcute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although it is now curable in 80-90% of cases, patients with T-ALL experience a higher frequency of induction failure and early relapse. Despite aggressive treatment approaches, including transplantation and new salvage regimens, most children with relapsed T-ALL will not be cured. As such, we are in need of new targeted therapies for the disease. Recent advances in the molecular characterization of T-ALL have uncovered a number of new therapeutic targets. This review will summarize recent advancements in the study of inhibiting the NOTCH1, PI3K-AKT and Cyclin D3:CDK4/6 pathways as therapeutic strategies for T-ALL. We will focus on preclinical studies supporting the testing of small-molecule inhibitors targeting these proteins and the rationale of combination therapies. Moreover, epigenetic approaches to modulate T-ALL are rapidly emerging. Here we will discuss the data supporting the role of BET bromodomain inhibitors in human T-ALL
Targeting NOTCH1 in hematopoietic malignancy.
No full textNOTCH1 is a well-validated target in hematopoietic malignancy, with NOTCH1 activating mutations identified in more than 50% of T-cell acute lymphoblastic leukemias. Moreover, a recent report has identified NOTCH1 activating mutations in 12% of chronic lymphocytic leukemias. While the frequency of NOTCH1 mutations and the well-documented role of this protein in the pathogenesis and maintenance of T-ALL support targeting NOTCH1 as a therapeutic strategy, the critical role of this protein in normal cell-fate specification and differentiation lead to complexities in its successful targeting. In this review, we will discuss potential approaches to targeting NOTCH1 in hematopoietic malignancies, including inhibition of the enzymes involved in its activation, antibodies directed against either the receptor or its ligands, and direct interference with the NOTCH1 transcriptional complex. Moreover, we will discuss the challenges to each of these approaches as well as potential solutions to overcoming these difficulties
Genetic and Proteomic Approaches to Identify Cancer Drug Targets
No full textWhile target-based small-molecule discovery has taken centre-stage in the pharmaceutical industry, there are many cancer-promoting proteins not easily addressed with a traditional target-based screening approach. In order to address this problem, as well as to identify modulators of biological states in the absence of knowing the protein target of the state switch, alternative phenotypic screening approaches, such as gene expression-based and high-content imaging, have been developed. With this renewed interest in phenotypic screening, however, comes the challenge of identifying the binding protein target(s) of small-molecule hits. Emerging technologies have the potential to improve the process of target identification. In this review, we discuss the application of genomic (gene expression-based), genetic (short hairpin RNA and open reading frame screening), and proteomic approaches to protein target identification.Version of Recor
Targeting Notch Trafficking and Processing in Cancers
No full textThe Notch family comprises a group of four ligand-dependent receptors that control evolutionarily conserved developmental and homeostatic processes and transmit signals to the microenvironment. NOTCH undergoes remodeling, maturation, and trafficking in a series of post-translational events, including glycosylation, ubiquitination, and endocytosis. The regulatory modifications occurring in the endoplasmic reticulum/Golgi precede the intramembrane γ-secretase proteolysis and the transfer of active NOTCH to the nucleus. Hence, NOTCH proteins coexist in different subcellular compartments and undergo continuous relocation. Various factors, including ion concentration, enzymatic activity, and co-regulatory elements control Notch trafficking. Interfering with these regulatory mechanisms represents an innovative therapeutic way to bar oncogenic Notch signaling. In this review, we briefly summarize the role of Notch signaling in cancer and describe the protein modifications required for NOTCH to relocate across different subcellular compartments. We focus on the functional relationship between these modifications and the corresponding therapeutic options, and our findings could support the development of trafficking modulators as a potential alternative to the well-known γ-secretase inhibitors
Strategies to Overcome Resistance Mechanisms in T-Cell Acute Lymphoblastic Leukemia
No full textChemoresistance is a major cause of recurrence and death from T-cell acute lymphoblastic leukemia (T-ALL), both in adult and pediatric patients. In the majority of cases, drug-resistant disease is treated by selecting a combination of other drugs, without understanding the molecular mechanisms by which malignant cells escape chemotherapeutic treatments, even though a more detailed genomic characterization and the identification of actionable disease targets may enable informed decision of new agents to improve patient outcomes. In this work, we describe pathways of resistance to common chemotherapeutic agents including glucocorticoids and review the resistance mechanisms to targeted therapy such as IL7R, PI3K-AKT-mTOR, NOTCH1, BRD4/MYC, Cyclin D3: CDK4/CDK6, BCL2 inhibitors, and selective inhibitors of nuclear export (SINE). Finally, to overcome the limitations of the current trial-and-error method, we summarize the experiences of anti-cancer drug sensitivity resistance profiling (DSRP) approaches as a rapid and relevant strategy to infer drug activity and provide functional information to assist clinical decision one patient at a time
THERAPEUTIC TARGETING OF NOTCH SIGNALING PATHWAY IN HEMATOLOGICAL MALIGNANCIES
No full textThe Notch pathway plays a key role in several processes including stem-cell self-renewal, proliferation, and cell differentiation. Several studies identified recurrent mutations in hematological malignancies making Notch one of the most desirable target in leukemia and lymphoma. The Notch signaling mediates resistance to therapy and controls cancer stem cells supporting the development of on-target therapeutic strategies to improve patients’ outcome. In this brief review, we outline the therapeutic potential of targeting Notch pathway in T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia and mantle cell lymphoma
Le «buone letture». 2. Giovanni Casati
No full textIl saggio è costituito da due parti, la prima delle quali, dedicata alla fondazione della Federazione italiana delle biblioteche circolanti cattoliche, è stata pubblicata nel precedente numero dei «Nuovi Annali», XXVII (2013), pp. 137-163. In questa seconda parte viene delineata la figura intellettuale di Giovanni Casati, che diresse la «Rivista di letture» dal 1912 al 1944, trasformando il periodico della Federazione in una rivista impegnata nella divulgazione della cultura cattolica. A questo impegno militante Casati fece corrispondere un intenso programma editoriale, che trovò espressione nella pubblicazione di saggi letterari, di manuali e opere repertoriali.The study consists of two parts; the first is dedicated to the history of the Federazione italiana delle biblioteche circolanti cattoliche since its foundation (1904) up to 1912 and was published in the previous volume of the «Nuovi Annali », XXVII (2013), pp. 137-163. In this second part, the author outlines the intellectual figure of Giovanni Casati, who directed the «Rivista di letture» from 1912 to 1944, transforming the magazine of the Federation in a journal engaged in the spreading of Catholic culture. To this militant engagement Casati matched an intense publishing program, which found its expression in the publication of literary essays, manuals and reference works
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