Wnt signaling as a potential therapeutic target for frontotemporal dementia

Progranulin mutations result in frontotemporal dementia, but the underlying pathophysiology has remained largely unexplained. New data by Geschwind and colleagues in this issue of Neuron uncovered that the Wnt/FZD2 signaling pathway is an early and critical contributor to disease pathology.     

The mitogen-activated protein kinase signaling module as a therapeutic target in hematologic malignancies

Important insights into the cellular and molecular biology of cancer in general and of hematologic malignancies in particular have been gained in the past two decades. The genes, and their protein products, involved in the transformation of cells from normal to neoplastic, as well as in the progression of neoplastic cells to a more aggressive, therapy-resistant phenotype, are being elucidated in great detail. However, most hematologic malignancies, particularly adult acute leukemias, remain associated with high mortality rates and new therapeutic approaches are urgently needed. The challenge is therefore to carefully and efficiently translate the information gained into effective therapeutic strategies. The clinical success achieved by tyrosine kinase inhibitors, such as ST1571 in chronic myelogenous leukemia, has stimulated interest for kinase-based signaling pathways as therapeutic targets in hematologic malignancies. The mitogen-activated protein kinase (MAPK) pathway is a common point of convergence of many different mitogenic and anti-apoptotic signal transduction pathways in hematopoietic, as well as epithelial, cancer cells and can now be clinically targeted by highly selective small molecule inhibitors. The mounting preclinical evidence of anti-leukemic activity of MAPK inhibitors, alone or in combination with pro-apoptotic small molecules or with conventional chemotherapeutic agents provides rationale that MAPK inhibition-based treatment strategies could soon enrich our therapeutic armamentarium against human leukemias.     

Dihydrofolate reductase as a therapeutic target

The folate antagonists are an important class of therapeutic compounds, as evidenced by their use as antiinfective, antineoplastic, and antiinflammatory drugs. Thus far, all of the clinically useful drugs of this class have been inhibitors of dihydrofolate reductase (DHFR), a key enzyme in the synthesis of thymidylate, and therefore, of DNA. The basis of the antiinfective selectivity of these compounds is clear; the antifolates trimethoprim and pyrimethamine are potent inhibitors of bacterial and protozoal DHFRs, respectively, but are only weak inhibitors of mammalian DHFRs. These species-selective agents apparently exploit the differences in the active site regions of the parasite and host enzymes. Methotrexate is the DHFR inhibitor used most often in a clinical setting as an anticancer drug and as an antiinflammatory and immunosuppressive agent. Considerable progress has been made recently in understanding the biochemical basis for the selectivity of this drug and the biochemical mechanism (or mechanisms) responsible for the development of resistance to treatment with the drug. This understanding has led to a new generation of DHFR inhibitors that are now in clinical trials.     

CD38 as a therapeutic target

The CD38 molecule is well represented on cell surfaces in many cases of a variety of lymphoid tumors, notably multiple myeloma, AIDS-associated lymphomas, and post-transplant lymphoproliferations. As such, this molecule is a promising target for antibody therapy. After early disappointments, improved anti-CD38 antibodies of strong cytolytic potential have been described by 3 groups. First, a human IgG monoclonal anti-CD38 antibody raised in mice transgenic for human Ig has been found to induce potent complement and cellular cytotoxicities against both myeloma cell lines and fresh harvests from myeloma marrow and leukemic blood. This antibody also exhibits the singular property of inhibiting the CD38 cyclase activity. Second, a series of CD38-specific human antibodies, with high affinities and high ADCC activities against cell lines and primary cultures of myeloma, has been selected from a unique phage-display library. Finally, to enhance specificity for myeloma cells, bispecific domain antibodies targeting both CD38 and CD138 have been developed. As they lack any Fc module, these constructs rely on cytotoxicity for delivering a toxin to tumor cells. The list of candidate CD38-bearing neoplasms as targets for these antibody constructs can now be expanded to include acute promyelocytic leukemia, and possibly other myeloid leukemias, in which surface CD38 can be induced by retinoid treatment. One caveat here is that evidence has been produced to suggest that CD38 promotes pulmonary manifestations of the hazardous retinoic acid syndrome.     

Evaluating DAPK as a therapeutic target

Death associated protein kinase 1 (DAPK) is an important serine/theoreine kinase involved in various cellular processes such as apoptosis, autophagy and inflammation. DAPK expression and activity are misregulated in multiple diseases including cancer, neuronal death, stoke, et al. Methylation of the DAPK gene is common in many types of cancer and can lead to loss of DAPK expression. In this review, we summarize the pathological status and functional roles of DAPK in disease and compare the published reagents that can manipulate the expression or activity of DAPK. The pleiotropic functions of DAPK make it an intriguing target and the barriers and opportunities for targeting DAPK for future clinical application are discussed.     

The PTEN–AKT3 signaling cascade as a therapeutic target in melanoma

Melanocytes undergo extensive genetic changes during transformation into aggressive melanomas. These changes deregulate genes whose aberrant activity promotes the development of this disease. The phosphoinositide‐3‐kinase (PI3K) and mitogen‐activated protein (MAP) kinase pathways are two key signaling cascades that have been found to play prominent roles in melanoma development. These pathways relay extra‐cellular signals via an ordered series of consecutive phosphorylation events from cell surface throughout the cytoplasm and nucleus regulating diverse cellular processes including proliferation, survival, invasion and angiogenesis. It is generally accepted that therapeutic agents would need to target these two pathways to be an effective therapy for the long‐term treatment of advanced‐stage melanoma patients. This review provides an overview of the PI3 kinase pathway focusing specifically on two members of the pathway, called PTEN and Akt3, which play important roles in melanoma development. Mechanisms leading to deregulation of these two proteins and therapeutic implications of targeting this signaling cascade to treat melanoma are detailed in this review.     

Notch signaling and Notch signaling modifiers

Originally discovered nearly a century ago, the Notch signaling pathway is critical for virtually all developmental programs and modulates an astounding variety of pathogenic processes. The DSL (Delta, Serrate, LAG-2 family) proteins have long been considered canonical activators of the core Notch pathway. More recently, a wide and expanding network of non-canonical extracellular factors has also been shown to modulate Notch signaling, conferring newly appreciated complexity to this evolutionarily conserved signal transduction system. Here, I review current concepts in Notch signaling, with a focus on work from the last decade elucidating novel extracellular proteins that up- or down-regulate signal potency.     

Mammalian target of rapamycin as a therapeutic target in leukemia

Reflecting its critical role in integrating cell growth and division with the cellular nutritional environment, the mammalian target of rapamycin *(mTOR) is a highly conserved downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway. mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1. As a consequence of inhibiting its downstream messengers, mTOR inhibitors prevent cyclin-dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause GI phase arrest. Constitutive activation of the PI3K/Akt kinases occur in human leukemias. FLT3, VEGF, and BCR-ABL mediate their activities via mTOR. New rapamycin analogs including CCI-779, RAD001, and AP23573, are entering clinical studies for patients with hematologic malignancies.     

MicroRNAs as a therapeutic target for cardiovascular diseases

MicroRNAs (miRNAs) are tiny, endogenous, conserved, non-coding RNAs that negatively modulate gene expression by either promoting the degradation of mRNA or down-regulating the protein production by translational repression. They maintain optimal dose of cellular proteins and thus play a crucial role in the regulation of biological functions. Recent discovery of miRNAs in the heart and their differential expressions in pathological conditions provide glimpses of undiscovered regulatory mechanisms underlying cardiovascular diseases. Nearly 50 miRNAs are overexpressed in mouse heart. The implication of several miRNAs in cardiovascular diseases has been well documented such as miRNA-1 in arrhythmia, miRNA-29 in cardiac fibrosis, miRNA-126 in angiogenesis and miRNA-133 in cardiac hypertrophy. Aberrant expression of Dicer (an enzyme required for maturation of all miRNAs) during heart failure indicates its direct involvement in the regulation of cardiac diseases. MiRNAs and Dicer provide a particular layer of network of precise gene regulation in heart and vascular tissues in a spatiotemporal manner suggesting their implications as a powerful intervention tool for therapy. The combined strategy of manipulating miRNAs in stem cells for their target directed differentiation and optimizing the mode of delivery of miRNAs to the desired cells would determine the future potential of miRNAs to treat a disease. This review embodies the recent progress made in microRNomics of cardiovascular diseases and the future of miRNAs as a potential therapeutic target - the putative challenges and the approaches to deal with it.     

Metabolic reprograming of cancer as a therapeutic target

Our understanding of metabolic reprogramming in cancer has tremendously improved along with the technical progression of metabolomic analysis. Metabolic changes in cancer cells proved much more complicated than the classical Warburg effect. Previous studies have approached metabolic changes as therapeutic and/or chemopreventive targets. Recently, several clinical trials have reported anti-cancer agents associated with metabolism. However, whether cancer cells are dependent on metabolic reprogramming or favor suitable conditions remains nebulous. Both scenarios are possibly intertwined. Identification of downstream molecules and the understanding of mechanisms underlying reprogrammed metabolism can improve the effectiveness of cancer therapy. Here, we review several examples of the metabolic reprogramming of cancer cells and the therapies targeting the metabolism-related molecules as well as discuss practical approaches to improve the next generation of cancer therapies focused on the metabolic reprogramming of cancer.     

Targeting mitochondria as a therapeutic target in cancer

Knowledge of re-programming in cancer cells with metabolic differences from their normal counterparts has resulted in new examination of therapeutic approaches. Several studies of the role of tumor mitochondria in cancer have led to the development of non-genotoxic therapies which target mitochondrial proteins, function. The now well-established functions of mitochondria in apoptosis provide novel targets for tumor cell suicide. Mitochondria serve as a central hub for responses to cellular stress as well as injury. The alterations in cancer cells which result in protection from apoptosis can be targeted to inhibit proliferation. Because of the reprogramming of cancer cell metabolism involving increased glycolysis, it appears that blocking InsP(3)R Ca(2+) release or adaptive pathways in response to hypoxia by targeting HIF-1 or metabolic enzymes encoded by the HIF-1 gene represents a feasible therapeutic approach to cancer. A very early in vitro event found in tumor cells following resveratrol addition is an increase in intracellular Ca(2+), measurable within seconds. Ca(2+) release is also observed with non-toxic flavonoids and a goal to identify the sentinel targets of resveratrol as a model compound involved in calcium activation seems worthwhile. New findings of the relationship between autophagy and apoptosis are discussed. The contribution of reactive oxygen species (ROS) generated by mitochondria is also considered. New data as to how cyclophilins and VDAC are involved in mitochondrial hexokinase protection of factors that induce apoptosis are reviewed. In addition, chemotherapeutic approaches based on Akt-activated mTORC1 are described, and their relationship to the role of aerobic glycolysis in this protection.     

Nucleo-cytoplasmic transport as a therapeutic target of cancer

Shuttling of specific proteins out of the nucleus is essential for the regulation of the cell cycle and proliferation of both normal and malignant tissues. Dysregulation of this fundamental process may affect many other important cellular processes such as tumor growth, inflammatory response, cell cycle, and apoptosis. It is known that XPO1 (Exportin-1/Chromosome Region Maintenance 1/CRM1) is the main mediator of nuclear export in many cell types. Nuclear proteins exported to the cytoplasm by XPO1 include the drug targets topoisomerase IIα (topo IIα) and BCR-ABL and tumor suppressor proteins such as Rb, APC, p53, p21, and p27. XPO1 can mediate cell proliferation through several pathways: (i) the sub-cellular localization of NES-containing oncogenes and tumor suppressor proteins, (ii) the control of the mitotic apparatus and chromosome segregation, and (iii) the maintenance of nuclear and chromosomal structures. The XPO1 protein is elevated in ovarian carcinoma, glioma, osteosarcoma, pancreatic and cervical cancer. There is a growing body of research indicating that XPO1 may have an important role as a prognostic marker in solid tumors. Because of this, nuclear export inhibition through XPO1 is a potential target for therapeutic intervention in many cancers. The best understood XPO1 inhibitors are the small molecule nuclear export inhibitors (NEIs; Leptomycin B and derivatives, ratjadones, PKF050-638, valtrate, ACA, CBS9106, selinexor/KPT-330, and verdinexor/KPT-335). Selinexor and verdinexor are orally bioavailable, highly potent, small molecules that are classified as Selective Inhibitors of Nuclear Export (SINE). KPT-330 is the only NEI currently in Phase I/II human clinical trials in hematological and solid cancers. Of all the potential targets in nuclear cytoplasmic transport, the nuclear export receptor XPO1 remains the best understood and most advanced therapeutic target for the treatment of cancer.     

Modulation of IL-33/ST2 signaling as a potential new therapeutic target for cardiovascular diseases

IL-33 belongs to the IL-1 family of cytokines, which function as inducers of Th2 cytokine production by binding with ST2L and IL-1RAcP. This, in turn, activates various signaling pathways, including the mitogen-activated protein kinase (MAPK), the inhibitor of Kappa-B kinase (IKK) pathway, and the phospholipase D-sphingosine kinase pathway. IL-33 has demonstrated protective effects against various cardiovascular diseases (CVDs) by inducing Th2 cytokines and promoting alternative activating M2 polarization. However, the soluble decoy form of ST2 (sST2) mitigates the biological effects of IL-33, exacerbating CVDs. Furthermore, IL-33 also plays a significant role in the development of asthma, arthritis, atopic dermatitis, and anaphylaxis through the activation of Th2 cells and mast cells. In this review, we aim to demonstrate the protective role of IL-33 against CVDs from 2005 to the present and explore the potential of serum soluble ST2 (sST2) as a diagnostic biomarker for CVDs. Therefore, IL-33 holds promise as a potential therapeutic target for the treatment of CVDs.