Systems medicine in colorectal cancer: from a mathematical model toward a new type of clinical trial.

Current colorectal cancer (CRC) treatment guidelines are primarily based on clinical features, such as cancer stage and grade. However, outcomes may be improved using molecular treatment guidelines. Potentially useful biomarkers include driver mutations and somatically inherited alterations, signaling proteins (their expression levels and (post) translational modifications), mRNAs, micro-RNAs and long noncoding RNAs.

Systems Medicine in Oncology: Signaling Network Modeling and New-Generation Decision-Support Systems.

Two different perspectives are the main focus of this book chapter: (1) A perspective that looks to the future, with the goal of devising rational associations of targeted inhibitors against distinct altered signaling-network pathways. This goal implies a sufficiently in-depth molecular diagnosis of the personal cancer of a given patient. A sufficiently robust and extended dynamic modeling will suggest rational combinations of the abovementioned oncoprotein inhibitors.

APO866 Increases Antitumor Activity of Cyclosporin-A by Inducing Mitochondrial and Endoplasmic Reticulum Stress in Leukemia Cells.

Purpose: The nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, APO866, has been previously shown to have antileukemic activity in preclinical models, but its cytotoxicity in primary leukemia cells is frequently limited. The success of current antileukemic treatments is reduced by the occurrence of multidrug resistance, which, in turn, is mediated by membrane transport proteins, such as P-glycoprotein-1 (Pgp). Here, we evaluated the antileukemic effects of APO866 in combination with Pgp inhibitors and studied the mechanisms underlying the interaction between these two types of agents.

Advances in dynamic modeling of colorectal cancer signaling-network regions, a path toward targeted therapies.

The interconnected network of pathways downstream of the TGFβ, WNT and EGF-families of receptor ligands play an important role in colorectal cancer pathogenesis.We studied and implemented dynamic simulations of multiple downstream pathways and described the section of the signaling network considered as a Molecular Interaction Map (MIM). Our simulations used Ordinary Differential Equations (ODEs), which involved 447 reactants and their interactions.

Sequential dose-dense 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel in patients with early breast cancer with four or more positive lymph nodes.

Aim: The aim of present study was to investigate the feasibility of a densified sequence of FEC75 (5-fluorouracil 600 mg/m2, epirubicin 75 mg/m2, cyclophosphamide 600 mg/m2) and docetaxel 100 mg/m2 (D100) in patients with primary operable high-risk breast cancer.

Methods: Fifty-one consecutive patients with resectable breast cancer and 4 or more positive axillary lymph nodes were enrolled. After a common regimen of 4 cycles of FEC75 given every 14 days, patients received 4 cycles of D100 every 14 days.

Role of genotype-based approach in the clinical management of adult acute myeloid leukemia with normal cytogenetics.

Acute myeloid leukemia (AML) is the most common form of acute leukemia affecting adults. Although it is a complex disease driven by numerous genetic and epigenetic abnormalities, nearly 50% of patients exhibit a normal karyotype (CN-AML) with an intermediate cytogenetic risk. However, a widespread genomic analysis has recently shown the recurrence of genomic aberrations in this category (mutations of FLT3, CEBPA, NPM1, RUNX1, TET2, IDH1/2, DNMT3A, ASXL1, MLL and WT1) thus revealing its marked genomic heterogeneity.

Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice.

Pharmacological treatments targeting CXC chemokines and the associated neutrophil activation and recruitment into atherosclerotic plaques hold promise for treating cardiovascular disorders. Therefore, we investigated whether FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with anti-inflammatory properties that we recently found to reduce neutrophil recruitment into the ischaemic myocardium, would exert beneficial effects in a mouse atherosclerosis model. Atherosclerotic plaque formation was induced by carotid cast implantation in ApoE-/- mice that were fed with a Western-type diet.

Autophagy in blood cancers: biological role and therapeutic implications.

Autophagy is a cell recycling process the molecular apparatus of which has been identified over the past decade. Autophagy allows cells to survive starvation and inhospitable conditions and plays a key role in numerous physiological functions, including hematopoiesis and immune responses. In hematologic malignancies, autophagy can either act as a chemo-resistance mechanism or have tumor suppressive functions, depending on the context.

Evaluating treatment response of chronic myeloid leukemia: emerging science and technology.

Chronic myeloid leukemia (CML) is a hematological disease accounting for about 15-20% of all adult leukemias. The clinical and biologic advances achieved in such a malignancy, represent one of the best successes obtained by translational medicine. Indeed, identification of the fusion oncogene BCR-ABL has allowed using of small molecule inhibitors of its tyrosine kinase activity which, in turn, have literally revolutionized the treatment of CML.

New insights into biology of chronic myeloid leukemia: implications in therapy.

Over the past decades the prognosis of patients with Chronic Myeloid Leukemia (CML) has radically changed due to groundbreaking scientific and translational studies that have revealed the biologic basis of such a hematologic malignancy. These studies have led to the rapid development of many BCR-ABL specific tyrosine kinase inhibitors (TKIs), such as Imatinib, Nilotinib and Dasatinib, which have improved 10-years survival to more than 80%. Although these therapies represent a landmark step in the race for the cure of CML, they did not change the progression in advanced phase of disease.

Intracellular NAD⁺ depletion enhances bortezomib-induced anti-myeloma activity.

We recently demonstrated that Nicotinamide phosphoribosyltransferase (Nampt) inhibition depletes intracellular NAD⁺ content leading, to autophagic multiple myeloma (MM) cell death. Bortezomib has remarkably improved MM patient outcome, but dose-limiting toxicities and development of resistance limit its long-term utility. Here we observed higher Nampt messenger RNA levels in bortezomib-resistant patient MM cells, which correlated with decreased overall survival.

Parameter space exploration within dynamic simulations of signaling networks.

We started offering an introduction to very basic aspects of molecular biology, for the reader coming from computer sciences, information technology, mathematics. Similarly we offered a minimum of information about pathways and networks in graph theory, for a reader coming from the bio-medical sector. At the crossover about the two different types of expertise, we offered some definition about Systems Biology.

Intracellular NAD(+) depletion induces autophagic death in multiple myeloma cells.

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by the proliferation of plasma cells in the bone marrow. Despite recent therapeutic advances, MM remains an incurable disease. Therefore, research has focused on defining new aspects in MM biology that can be therapeutically targeted.

The NAD+-dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses.

Cytokine secretion by cancer cells contributes to cancer-induced symptoms and angiogenesis. Studies show that the sirtuin SIRT6 promotes inflammation by enhancing TNF expression. Here, we aimed to determine whether SIRT6 is involved in conferring an inflammatory phenotype to cancer cells and to define the mechanisms linking SIRT6 to inflammation.

New insights into the treatment of multiple myeloma with histone deacetylase inhibitors.

Multiple Myeloma (MM) is a common hematologic malignancy of plasma cells representing an excellent model of epigenomics dysregulation in human disease. Importantly, these findings, in addition to providing a better understanding of the underlying molecular changes leading to this malignance, furnish the basis for an innovative therapeutic approach. Histone deacetylase inhibitors (HDACIs), including Vorinostat and Panobinostat, represent a novel class of drugs targeting enzymes involved in epigenetic regulation of gene expression, which have been evaluated also for the treatment of multiple myeloma.

Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition.

Malignant cells have a higher nicotinamide adenine dinucleotide (NAD(+)) turnover rate than normal cells, making this biosynthetic pathway an attractive target for cancer treatment. Here we investigated the biologic role of a rate-limiting enzyme involved in NAD(+) synthesis, Nampt, in multiple myeloma (MM). Nampt-specific chemical inhibitor FK866 triggered cytotoxicity in MM cell lines and patient MM cells, but not normal donor as well as MM patients PBMCs.

Tracking molecular relapse of chronic myeloid leukemia by measuring Hedgehog signaling status.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the expansion of a leukemic stem cell (LSC) clone, carrying a Philadelphia translocation, able to overcome the non-malignant hematopoietic stem cells. The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib are gold-standard for CML treatment. Each shows an impressive rate of complete cytogenetic response in chronic phase (CP)-CML.

Proteasome inhibitors as immunosuppressants: biological rationale and clinical experience.

Accumulating evidence supports the potential of proteasome inhibitors as immunosuppressants. Proteasome inhibitors interfere with antigen processing and presentation, as well as with the signaling cascades involved in immune cell function and survival. Both myeloma and healthy plasma cells appear to be highly susceptible to proteasome inhibitors due to impaired proteasomal activity in both cell types.

Inhibition of nicotinamide phosphoribosyltransferase reduces neutrophil-mediated injury in myocardial infarction.

Aims: Nicotinamide phosphoribosyltransferase (Nampt) is a key enzyme for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, and recent evidence indicates its role in inflammatory processes. Here, we investigated the potential effects of pharmacological Nampt inhibition with FK866 in a mouse myocardial ischemia/reperfusion model. In vivo and ex vivo mouse myocardial ischemia/reperfusion procedures were performed.

Anti-cancer activity of 5-O-alkyl 1,4-imino-1,4-dideoxyribitols.

New derivatives of 1,4-dideoxy-1,4-imino-D-ribitol have been prepared and evaluated for their cytotoxicity on solid and haematological malignancies. 1,4-Dideoxy-5-O-[(9Z)-octadec-9-en-1-yl]-1,4-imino-D-ribitol (13, IC(50) ∼2 μM) and its C(18)-analogues (IC(50) <10 μM) are cytotoxic toward SKBR3 (breast cancer) cells. 13 also inhibits (IC(50) ∼8 μM) growth of JURKAT cells.

Synergistic interactions between HDAC and sirtuin inhibitors in human leukemia cells.

Aberrant histone deacetylase (HDAC) activity is frequent in human leukemias. However, while classical, NAD(+)-independent HDACs are an established therapeutic target, the relevance of NAD(+)-dependent HDACs (sirtuins) in leukemia treatment remains unclear. Here, we assessed the antileukemic activity of sirtuin inhibitors and of the NAD(+)-lowering drug FK866, alone and in combination with traditional HDAC inhibitors.

Potent synergistic interaction between the Nampt inhibitor APO866 and the apoptosis activator TRAIL in human leukemia cells.

Objective: The nicotinamide phosphoribosyltransferase (Nampt) inhibitor APO866 depletes intracellular nicotinamide adenine dinucleotide (NAD(+)) and shows promising anticancer activity in preclinical studies. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to plasma membrane receptors DR4 and DR5 and induces apoptosis via caspase-8 and -10. Here we have explored the interaction between APO866 and TRAIL in leukemia cell lines and in primary B-cell chronic lymphocytic leukemia cells.

Novel 2-[(benzylamino)methyl]pyrrolidine-3,4-diol derivatives as alpha-mannosidase inhibitors and with antitumor activities against hematological and solid malignancies.

Novel alpha-mannosidase inhibitors of the type (2R,3R,4S)-2-({[(1R)-2-hydroxy-1-arylethyl]amino}methyl)pyrrolidine-3,4-diol have been prepared and assayed for their anticancer activities. Compound 30 with the aryl group=4-trifluoromethylbiphenyl inhibits the proliferation of primary cells and cell lines of different origins, irrespective of Bcl-2 expression levels, inducing a G2/Mcell cycle arrest and by modification of genes involved in cell cycle progression and survival.