Current Pharmaceutical Biotechnology - Volume 17, Issue 1, 2016

Acute myeloid leukemia (AML) is characterized as a heterogeneous disease where the patients are sub grouped according to several classification systems and mutational analyses. Diagnosis of AML is based on identification of the specific myeloid cell initiating the disease, quantification of immature blasts in bone marrow and peripheral blood, as well as detection of mutations and translocations. The heterogeneity of AML is caused by a block in differentiation that may occur in any of the different myeloid cell populations. These undifferentiated cells also harbor an increased proliferation potential that leads to accumulation of immature leukemic cells. The current development of more sensitive and less labor intensive analysis methods has led classification of patients from being a system based on morphology of the leukemic cells to being more sophisticated, detecting translocations and small mutations found in the whole leukemic clone or in a minor subclone. This review aims to describe the most common classification systems of AML, including frequently occurring translocations, mutations and epigenetic alterations, as well as describe traditional and novel methods for diagnosis and analysis of these patients.

Acute myeloid leukemia (AML) is characterized by extensive clinical and biological heterogeneity. Despite vast advances in understanding the molecular pathology in AML during the last two decades few new AML therapeutics have been approved by the European Medicines Agency. Since 2005 only the epigenetic modulators decitabine and azacytidine, as well as histamine (plus interleukin- 2) have been approved against AML. None of these have outstanding efficiency, and decitabine and azacytdine have only been incorporated in frontline therapy of AML with limited enthusiasm. The majority of AML patients are frail and elderly, and lack of mild but effective agents for this patient cohort constitutes a major unmet need as overall survival remains poor. Along with the recent advancements in the molecular characterization of AML, numerous targeted therapies have been tested in clinical trials. In this review, we discuss the biological rationale for a selection of these novel therapeutic approaches, including epigenetic modifiers, agents targeting signalling pathways and inhibitors of nuclear-cytoplasmic shuttling. Further we discuss some of the possible shortcomings in current trial design that could explain the apparent incoherence between our improved biological knowledge and the lack of progress in therapy development of AML.

Chemotherapy for AML is hampered by severe side-effects and failure to eliminate all the blasts that eventually leads to relapse. The use of nanosized particulate drug carriers such as liposomes and polymeric nanoparticles has the potential to improve AML therapy by delivering more of the drug to the disease site, thereby reducing toxicity. For example, encapsulation in liposomes reduces the cardiotoxicity of anthracyclines, giving an improved therapeutic index. Moreover, when the surface properties are engineered appropriately, nanocarriers remain in the circulation and extravasate in tissues with sinusoidal capillaries, one of which is bone marrow, leading to a more favourable distribution of the associated drug. Drug carrier technology contributes to the development of newer drugs, such as nucleic acids that can be protected from degradation and delivered into cells, thus opening the way for gene-silencing strategies. Furthermore, carrier systems provide a means of dispersing poorly water-soluble molecule for in vivo administration and thus increase the “druggability” of new lead compounds, such as heat-shock protein inhibitors. Particulate carriers can transport more than one active agent, allowing synergistic action and theranostic strategies. Notably, phase I and II clinical trials are being performed with CPX-351, a liposomal formulation containing cytarabine and daunorubicin at an optimal ratio. Finally, by attaching suitable ligands to the nanocarrier surface, specific targeting to AML cells can be achieved. In this review, we give examples of successful targeting to folate and transferrin receptors against AML.

Despite the tremendous progress made in the comprehension of acute myeloid leukemia (AML) over the last 30 years most patients die from their disease. Our understanding of AML has relied on an intensive in-vitro research approach, based on AML cell lines as well as primary AML patient cells. However, experimental insight into the early events of AML leukemogenesis before they become clinically observable is not possible in humans. Thus, preclinical animal models have served the purpose to extend our knowledge of the disease as well as to develop innovative therapeutic strategies. Today, xenograft models using patient-derived neoplastic/leukemia cells represent the strategy of choice for preclinical studies of AML. These models exhibit several key advantages over AML cell lines. In fact, patientderived cells, in contrast to AML cell lines, encompass the entire complexity of AML disease and can therefore provide more trustworthy results on the efficacy outcome of novel therapies. One other important aspect in the development of xenograft models of AML is the possibility to use imaging techniques to monitor in-vivo the progression of the disease. Imaging techniques also authorize the evaluation of the efficacy of an experimental treatment on tumor growth. This review will focus on the description of xenograft models of AML and will provide researchers and clinicians an overview of how these models have been used for the development of new therapeutic options and new imaging approaches to study AML in-vivo.

The identification of protein biomarkers for acute myeloid leukemia (AML) that could find applications in AML diagnosis and prognosis, treatment and the selection for bone marrow transplant requires substantial comparative analyses of the proteomes from AML patients. In the past years, several studies have suggested some biomarkers for AML diagnosis or AML classification using methods for sample preparation with low proteome coverage and low resolution mass spectrometers. However, most of the studies did not follow up, confirm or validate their candidates with more patient samples. Current proteomics methods, new high resolution and fast mass spectrometers allow the identification and quantification of several thousands of proteins obtained from few tens of μg of AML cell lysate. Enrichment methods for posttranslational modifications (PTM), such as phosphorylation, can isolate several thousands of site-specific phosphorylated peptides from AML patient samples, which subsequently can be quantified with high confidence in new mass spectrometers. While recent reports aiming to propose proteomic or phosphoproteomic biomarkers on the studied AML patient samples have taken advantage of the technological progress, the access to large cohorts of AML patients to sample from and the availability of appropriate control samples still remain challenging.

Nature is an important source for anti-cancer therapeutics, and nearly half of the currently marketed cancer drugs are derived from natural products. Most of the therapeutic natural products are derived from terrestrial sources, such as paclitaxel, vincristine, epothilones, doxorubicin, etoposide and camptothecin. However, the oceans have received growing interest as a source for new useful bioactive compounds, and there are currently several drugs derived from marine natural products for the treatment of cancer on the market. The current recommended chemotherapy of acute myeloid leukemia (AML) is founded on cytarabine, a molecule derived from a natural product isolated from a marine sponge. However, in order to increase the efficiency of the chemotherapy used in the treatment of AML, it is necessary to develop more targeted drugs with less pronounced side effects. In this review, we argue that marine natural products have many of the desired properties of such a drug, and that prefractionated extract libraries of marine plants, animals and microorganisms should be a part of the screening efforts for new AML chemotherapeutics.

Cyanobacteria are an inspiring source of bioactive secondary metabolites. These bioactive agents are a diverse group of compounds which are varying in their bioactive targets, the mechanisms of action, and chemical structures. Cyanobacteria from various environments, especially marine benthic cyanobacteria, are found to be rich sources for the search for novel bioactive compounds. Several compounds with anticancer activities have been discovered from cyanobacteria and some of these have succeeded to enter the clinical trials. Varying anticancer agents are needed to overcome increasing challenges in cancer treatments. Different search methods are used to reveal anticancer compounds from natural products, but cell based methods are the most common. Cyanobacterial bioactive compounds as agents against acute myeloid leukemia are not well studied. Here we examined our new results combined with previous studies of anti-leukemic compounds from cyanobacteria with emphasis to reveal common features in strains producing such activity. We report that cyanobacteria harbor specific anti-leukemic compounds since several studied strains induced apoptosis against AML cells but were inactive against non-malignant cells like hepatocytes. We noted that particularly benthic strains from the Baltic Sea, such as Anabaena sp., were especially potential AML apoptosis inducers. Taken together, this review and re-analysis of data demonstrates the power of maintaining large culture collections for the search for novel bioactivities, and also how anti-AML activity in cyanobacteria can be revealed by relatively simple and low-cost assays.

Even though malnutrition is associated with an adverse prognosis after allogeneic stem cell transplantation, few studies have addressed the question what is the optimal nutritional support for these patients. There is a general agreement that the body weight, body mass index and nutritional intake can be used to guide the post-transplant nutritional support; enteral nutrition may then be tried but most patients will require parenteral nutrition. There is no scientific basis for further standardization of post-transplant nutritional support. The nutritional status with regard to amino acid as well as fatty acid metabolism and vitamin levels are important for immunoregulation. Several amino acids and their metabolites function as signaling molecules through their binding to specific receptors, and they are thereby become important both in dendritic cell differentiation and T cell activation and the metabolic switch that often occurs during the activation of immunocompetent cells. We review previous studies of nutritional support in allotransplant recipients and discuss possible molecular mechanisms involved in metabolic immunoregulation and the development of post-transplant immunemediated complications.

Modern analytical techniques provide an unprecedented insight to biomedical samples, allowing an in depth characterization of cells or body fluids, to the level of genes, transcripts, peptides, proteins, metabolites, or metallic ions. The fine grained picture provided by such approaches holds the promise for a better understanding of complex pathologies, and consequently the personalization of diagnosis, prognosis and treatment procedures. In practice however, technical limitations restrict the resolution of the acquired data, and thus of downstream biomedical inference. As a result, the study of complex diseases like leukemia and other types of cancer is impaired by the high heterogeneity of pathologies as well as patient profiles. In this review, we propose an introduction to the general approach of characterizing samples and inferring biomedical results. We highlight the main limitations of the technique with regards to complex and heterogeneous pathologies, and provide ways to overcome these by improving the ability of experiments in discriminating samples.