MUC4 mucin- a therapeutic target for pancreatic ductal adenocarcinoma

Introduction: Pancreatic cancer (PC) is characterized by mucin overexpression. MUC4 is the most differentially overexpressed membrane-bound mucin that plays a functional role in disease progression and therapy resistance.

Area covered: We describe the clinicopathological significance of MUC4, summarize mechanisms contributing to its deregulated expression, review preclinical studies aimed at inhibiting MUC4, and discuss how MUC4 overexpression provides opportunities for developing targeted therapies. Finally, we discuss the challenges for developing MUC4-based therapeutics, and identify areas where efforts should be directed to effectively exploit MUC4 as a therapeutic target for PC.

Expert opinion: Studies demonstrating that abrogation of MUC4 expression reduces proliferation and metastasis of PC cells and enhances sensitivity to therapeutic agents affirm its utility as a therapeutic target. Emerging evidence also supports the suitability of MUC4 as a potential immunotherapy target. However, these studies have been limited to in vitro, ex vivo or in vivo approaches using xenograft tumors in immunodeficient murine models. For translational relevance, MUC4-targeted therapies should be evaluated in murine models with intact immune system and accurate tumor microenvironment. Additionally, future studies evaluating MUC4 as a target for immunotherapy must entail characterization of immune response in PC patients and investigate its association with immunosuppression and survival.     

CIAPIN1 as a therapeutic target in cancer

Importance of the field: Cytokine-induced apoptosis inhibitor 1 (CIAPIN1) is a newly identified cytokine-induced apoptosis inhibitor, which has roles in cell division and angiogenesis. Owing to its prognostic value for human tumors and involvement in cancer progression and tumor cell resistance to anticancer agents, CIAPIN1 has been proposed as an attractive target for new anticancer interventions.

Areas covered in this review: We define CIAPIN1's potential function as a new therapeutic target for anticancer interventions and this review covers all related literature on CIAPIN1 in cancer from the past 5 years

What the reader will gain: Several preclinical studies have demonstrated that CIAPIN1 is associated with chemotherapy resistance, increased tumor recurrence and shorter patient survival in different human tumor models, making anti-CIAPIN1 therapy an attractive cancer treatment strategy. Recent studies also suggest that CIAPIN1 is expressed at low levels in some types of malignant tumors and that its overexpression may inhibit their proliferation or tumorigenesis.

Take home message: Considering that the exact expression and function of CIAPIN1 are still not well characterized and understood, better knowledge of CIAPIN1 in normal versus tumor tissues will be instrumental for the design of optimal strategies to selectively disrupt CIAPIN1 in cancer.     

Targeting miR-21 in glioma: a small RNA with big potential

Importance of the field: Glioma therapies have produced relatively small improvements over the past decade, highlighting an important need to identify novel ways to target this disease. Targeted therapies against single activated protein kinases have proven effective in some cancers including gastrointestinal stromal cancer and colon cancer, but not yet in gliomas where multiple pathways and targets may be involved. MicroRNAs are emerging as key regulators of multiple pathways involved in cancer development and progression and may become the next targeted therapies in glioma.

Areas covered in this review: This review covers the basics of microRNA biology and specifically focuses on the roles of miR-21 in glioma and its potential as target for glioma therapy.

What the reader will gain: This review will provide the reader with an in depth understanding of how miR-21 functions in glioma. We also review the current state of studies designed to specifically target miR-21 as a potential future therapeutic.

Take home message: Identifying novel targets for the treatment of glioma is critical for advancing the current state of the field. MicroRNAs provide a novel target; and in glioma, targeting miR-21 may have broad consequences for the tumor that make it an attractive potential therapeutic.     

Targeting the thyrotropin receptor in thyroid disease

Introduction: The thyrotropin receptor (TSHR) is essential for thyroid growth and for the production of thyroid hormones. It is unique among the glycoprotein hormone receptors, in that some of the TSHRs undergo cleavage and shedding of the alpha subunit.

Areas covered: This review discusses the structure and function of the TSHR, followed by an evaluation of its role in thyroid disease. Possible limitations of the TSHR as a therapeutic target are also discussed.

Expert opinion: The TSHR is involved in a number of hereditary and acquired disorders of the thyroid making it of potential importance as a therapeutic target in thyroid disease. Expression of the TSHR in several non-thyroidal tissues and the development of systemic manifestations of thyroid disease suggest that the TSHR is also of interest as a therapeutic target outside the thyroid.     

TGF-β signalling and immunity in prostate tumourigenesis

Importance of the field: The TGF-β's are pleiotropic cytokines that regulate multiple cellular functions. Their role in the prostate is important for normal prostate development and also in prostate tumourigenesis.

Areas covered in this review: The interactions TGF-β-mediated signalling has with maintaining prostate health, as well as its role in prostate tumourigenesis and prostate tumour immune evasion, with emphasis on how a breakdown in these interactions may influence disease progression.

What the reader will gain: That TGF-β influences normal prostate growth and differentiation by regulating the balance between epithelial cell proliferation and apoptosis, and involving the androgen receptor pathway. That TGF-β protects and maintains prostate stem cells and a review of the contrasting role TGF-β has in prostate tumourigenesis and tumour development, where TGF-β acts as a tumour suppressor and then switches roles to become a tumour promoter, and creates a local immunosuppressive niche leading to systemic tumour tolerance.

Take home message: TGF-β signalling in prostate cancer is a valid target for the treatment of this disease; however any therapeutic regimen will require an understanding of all aspects of the TGF-β-signalling nexus, otherwise by the very pleiotrophic nature of TGF-β, limited clinical benefits may result.     

Targeting mitochondrial dysfunction in neurodegenerative disease: Part I

Importance of the field: The socioeconomic burden of an aging population has accelerated the urgency of novel therapeutic strategies for neurodegenerative disease. One possible approach is to target mitochondrial dysfunction, which has been implicated in the pathogenesis of numerous neurodegenerative disorders.

Areas covered in this review: This review examines the role of mitochondrial defects in aging and neurodegenerative disease, ranging from common diseases such as Alzheimer's and Parkinson's disease to rare familial disorders such as the spinocerebellar ataxias. The review is provided in two parts; in this first part, we discuss the mitochondrial defects that have been most extensively researched: oxidative stress; bioenergetic dysfunction and calcium deregulation.

What the reader will gain: This review provides a comprehensive examination of mitochondrial defects observed in numerous neurodegenerative disorders, discussing therapies that have reached clinical trials and considering potential novel therapeutic strategies to target mitochondrial dysfunction.

Take home message: This is an important area of clinical research, with several novel therapeutics already in clinical trials and many more in preclinical stages. In part II of this review we will focus on possible novel approaches, looking at mitochondrial defects which have more recently been linked to neurodegeneration.     

Hepatocyte growth factor is an attractive target for the treatment of pulmonary fibrosis

Introduction: Pulmonary fibrosis (PF) is a progressive fatal disorder and is characterized by alveolar epithelial injury, myofibroblast proliferation, and extracellular matrix remodeling, resulting in irreversible distortion of lung's architecture. Available therapies are associated with side effects and show restricted efficacy. Therefore, there is an urgent need to find a therapeutic solution to PF. Therapeutic strategies interfering myofibroblast expansion, apoptosis of epithelial and endothelial cells might be beneficial for treatment of PF. Hepatocyte growth factor (HGF), a pleiotropic growth factor, plays an important role in lung development, inflammation, repair, and regeneration. In animal model of PF, administration of recombinant HGF protein or ectopic HGF expression ameliorates fibrosis.

Areas covered: The focus of this review is to highlight HGF as a promising therapeutic approach for the treatment of PF. The review discusses the currently available treatment option for PF as well as highlights the possible beneficial effect of HGF as a drug target.

Expert opinion: HGF with its anti-fibrotic effect provides a promising new therapeutic approach by protecting lung from fibrotic remodeling and also promoting normal regeneration of lung. The development of HGF mimetics may provide a potential attractive therapy for treatment of this devastating and complex disease.     

Delayed release phosphatidylcholine as new therapeutic drug for ulcerative colitis – a review of three clinical trials

Importance of the field: As the pathogenesis of ulcerative colitis (UC) is unknown, a causative therapy is lacking. Therefore, some UC patients suffer from disease activity despite symptomatic anti-inflammatory treatment strategies. We claim that reduction of phosphatidylcholine (PC) in colonic mucus impairs the mucosal barrier and, thus, causes attacks of the commensal bacterial flora to induce colitis. Thus, mucus PC substitution could provide a causal therapy for UC.

Areas covered in this review: A delayed released oral PC preparation (rPC) was found to substitute for the lack of PC in rectal mucus. In non-steroid-treated active UC, 53% of rPC-treated patients reached remission compared with 10% of placebo patients (p < 0.001). In a second trial with chronic-active, steroid-dependent UC patients, steroid withdrawal with a concomitant achievement of remission (CAI ≤ 3) or clinical response (≥ 50% CAI improvement) was reached in 15 rPC-treated patients (50%) but only in 3 (10%) placebo patients (p = 0.002).

What the reader will gain: The concept that missing PC in colonic mucus is the main pathogenetic factor for development of UC. PC can be substituted by rPC, which cures the disease in the majority of patients.

Take home message: rPC is, to our knowledge, the first causative therapeutic option for patients with UC.     

Adiponectin and its receptor signaling: an anti-cancer therapeutic target and its implications for anti-tumor immunity

Introduction: Adiponectin (APN), produced by adipocytes, has direct anti-diabetic, anti-atherogenic and anti-inflammatory properties. Circulating APN levels are lower in obesity, a disease state that is often associated with several malignancies.

Area covered: Increasingly, clinical data suggests that serum APN may have an important protective role in carcinogenesis. Certain cancer cell types express APN receptors and their downstream signaling pathways may influence cancer biology, possibly by regulating cell proliferation and inducing apoptosis. However, APN’s role in the immune system, in particular to the anti-tumor response, remains elusive. Therefore, this review critically addresses all controversies associated with the effect of APN on the immune system.

Expert opinion: Currently, the promise of interfering with APN and its receptor axis as a novel anti-cancer therapeutic target is rather encouraging. Greater understanding of the immunological side effects following this interference is crucial for the development of effective therapeutic strategies against obesity-associated malignancies. APN receptor signaling on immune cells can blunt anti-tumor immunity and induce tumor-specific tolerance. This may also have far-reaching consequences on the application of APN as an anti-cancer agent.     

Targeting disease through novel pathways of apoptosis and autophagy

Introduction: Apoptosis and autophagy impact cell death in multiple systems of the body. Development of new therapeutic strategies that target these processes must address their complex role during developmental cell growth as well as during the modulation of toxic cellular environments.

Areas covered: Novel signaling pathways involving Wnt1-inducible signaling pathway protein 1 (WISP1), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), β-catenin and mammalian target of rapamycin (mTOR) govern apoptotic and autophagic pathways during oxidant stress that affect the course of a broad spectrum of disease entities including Alzheimer's disease, Parkinson's disease, myocardial injury, skeletal system trauma, immune system dysfunction and cancer progression. Implications of potential biological and clinical outcome for these signaling pathways are presented.

Expert opinion: The CCN family member WISP1 and its intimate relationship with canonical and non-canonical wingless signaling pathways of PI3K, Akt1, β-catenin and mTOR offer an exciting approach for governing the pathways of apoptosis and autophagy especially in clinical disorders that are currently without effective treatments. Future studies that can elucidate the intricate role of these cytoprotective pathways during apoptosis and autophagy can further the successful translation and development of these cellular targets into robust and safe clinical therapeutic strategies.     

Therapeutic targeting of miRNAs in neuroblastoma

Importance of the field: Neuroblastomas arise from precursor cells of the sympathetic nervous system and are noted for highly heterogeneous clinical behavior. These tumors currently account for ～ 15% of all childhood cancer related deaths in spite of intensive multimodal chemotherapy and are a major problem in pediatric oncology. The identification of novel therapeutic targets is urgently required to reduce patient morbidity.

Areas covered in this review: The purpose of this article is to review and synthesize all of the rapidly expanding evidence for the contribution of microRNAs (miRNAs) in neuroblastoma aggressive disease pathogenesis, along with the prospect of using small RNAs as therapeutics.

What the reader will gain: The reader will obtain insight on the miRNAs that are dysregulated in neuroblastoma along with potential therapeutic strategies and the most promising targets.

Take home message: A number of miRNAs which are associated with aggressive disease pathogenesis in neuroblastoma patients have been demonstrated to contribute in major ways to cell proliferation rates, apoptosis, differentiation, invasiveness and tumor growth in vitro and in vivo. Directly or indirectly interfering with the function of these miRNAs may prove to be an important and novel form of therapy.     

Targeting TRAIL in the treatment of cancer: new developments

Introduction: While apoptosis is critical for maintaining homeostasis in normal cells, defective apoptosis contributes to the survival of cancer cells. TNF-related apoptosis-inducing ligand (TRAIL)-targeted therapy has attracted significant effort for treating cancer, but the clinical results have revealed limitations. The authors review the current status of development of TRAIL-targeted therapy with an outlook towards the future.

Areas covered: Recombinant human proteins, small molecules and agonistic monoclonal antibodies targeting death receptors that trigger TRAIL-mediated apoptosis are covered in this article. The authors review both intrinsic and extrinsic apoptotic pathways, highlighting how the apoptosis serves as a promising therapeutic target. They also review different categories of TRAIL pathway targeting agents and provide a brief overview of clinical trials using these agents. The authors discuss the limitations of conventional approaches for targeting the TRAIL pathway as well as future directions.

Expert opinion: The development of better combination partners for pro-apoptotic TRAIL pathway modulators including novel agents inhibiting anti-apoptotic molecules or targeting alternative resistance pathways may improve the chances for anti-tumor responses in the clinic. Developing predictive biomarkers via circulating tumor cells/DNA, apoptosis signal products, and genetic signatures/protein biomarkers from tumor tissue are also suggested as future directions.     

Adrenomedullin as a therapeutic target in angiogenesis

Importance of the field: Hypoxia, a frequent characteristic in the microenvironment of solid tumors, leads to adrenomedullin (AM) upregulation through the hypoxia inducible factor-1 pathway, explaining its high expression in a variety of malignant tissues. AM is believed to play an important role in tumor progression and angiogenesis in many cancers. Therefore, it could become a new therapeutic target.

Areas covered in this review: We performed a review of the literature based on published data to highlight AM's critical roles in tumor cell growth and cancer invasiveness, and its involvement in tumor angiogenesis through promotion of recruitment of hematopoietic progenitors, vascular morphogenesis, and blood vessel stabilization and maturation. Inhibition of AM has antitumoral effects linked to antiangiogenic effects but in some cases also to direct antiproliferative activity on cancer cells. Several studies demonstrated that systemic inhibition of AM receptors was well tolerated in murine models.

What the reader will gain: The goal of this review is to inform readers about the role of AM in tumor angiogenesis and cancer progression and, therefore, about its possible place as a new therapeutic target.

Take home message: Taken together, these data support targeting the AM pathway as a new potential therapy in cancer, complementary to other existing treatments.     

Pharmacotherapy for end-stage coronary artery disease

Importance of the field: Coronary artery disease remains the leading cause of mortality in the industrialized world. Despite advances in surgical and catheter-based interventions, a select number of patients remain with no options for invasive therapy. The goal of this review is to discuss the current status of pharmacotherapeutic interventions to treat end-stage coronary artery disease.

Areas covered in this review: Literature review on the topic of therapeutic angiogenesis from 1980 to 2009.

What the reader will gain: Insight into current therapeutic strategies employed to manage end-stage coronary artery disease.

Take home message: A promising approach focuses on augmenting the endogenous angiogenic response to chronic myocardial ischemia via the use of growth factors.     

Targeting PDGF pathway in pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) encompasses a rare potentially lethal group of diseases characterized by vasoconstriction, in situ thrombosis and vascular remodeling. Most of the existing therapies including endothelin receptor antagonists, prostacyclin and derivatives, or phsophodiesterase-5 inhibitors tackle mainly the endothelial dysfunction, leaving the remodeling suboptimally inhibited. This explains the disease progression that occurs even with combined therapies and the need for other therapies able to adequately inhibit the vascular remodeling.

Areas covered: Platelet-derived growth factor (PDGF) signaling pathway was demonstrated to be involved in the vascular remodeling in PAH, and therefore, it might be a desirable therapeutic target in this setting. This review discusses the pathogenic role of this pathway in PAH and its potential inhibitory approaches, focusing on imatinib as well as on the existing preclinical data on this compound.

Expert opinion: Preclinical studies demonstrated that PDGF inhibition with receptor antagonists such as imatinib reduces vascular remodeling. Therefore, PDGF might represent a plausible therapeutic target in this disease. However, compounds able to block this pathway via different mechanisms might also become potential PAH therapies.     

Targeting AAC-11 in cancer therapy

Importance of the field: Since its discovery in 1997, the antiapoptotic factor AAC-11 has rapidly gained attention due to its potential use in cancer therapy. Indeed, most cancer cells express elevated levels of AAC-11, which is now known to be involved in both tumor cells growth as well as sensitivity to chemotherapeutic drugs.

Areas covered in this review: In this review, we examine the most recent evidence about the role of AAC-11 in cancer biology and the therapeutic perspectives associated with its specific targeting. For that purpose, literature dealing with AAC-11 in the PubMed database was reviewed from 1997 up to date.

What the reader will gain: AAC-11 is an antiapoptotic gene that has the potential to be a target for anti-cancer therapy, and warrants further investigation. As its expression seems to predict unfavorable prognosis, at least in some cancers, it also may become a potent prognostic marker.

Take home message: Blocking AAC-11 function in cancer for therapeutic purposes might be of great interest. The recent report of efficient AAC-11 inhibiting peptides that sensitize tumor cells to chemotherapeutic drugs has raise the exciting notion that AAC-11 might be a druggable target and fueled the search for new therapeutic agents that could block AAC-11 function.     

p53–Mdm2 inhibitors: patent review (2009 – 2010)

Introduction: p53 plays a central role in protecting the integrity of the genome. Its activity is ubiquitously lost in cancers, either by inactivation of its protein (p53 pathway) or by mutation in the p53 gene, thereby indicating its importance in understanding cancer and as a therapeutic target. Activated p53 is known to induce cell cycle arrest thereby leading to apoptosis and has been the subject of intensive research in the area of medicinal chemistry. Efforts are in progress to synthesize a variety of scaffolds that could inhibit the p53–Mdm2 interaction by binding to Mdm2 in the region where p53 is likely to bind. These molecules have the potential to be developed as anticancer drug candidates and have been largely explored by both academia and industry. Interestingly, some of these molecules are in the early stage of clinical trials.

Areas covered: Areas covered in this review include patents relating to p53–Mdm2 inhibitors during the time period 2009 – 2010. The focus of the review was on small-molecule inhibitors.

Expert opinion: Inducing apoptosis in cancerous cells by the activation of p53 is an area that is being actively explored. There are strong indications that it could become a therapeutic method for the treatment of cancer. As a result, extensive research is being performed by both academia and industry. It is observed that small molecules that are present in early clinical trials are expected to be developed as potential drugs for cancer therapy.