TRAIL receptor signaling and therapeutics

Importance of the field: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells by engaging specific death receptors, TRAIL-R1 and TRAIL-R2, while having low toxicity towards normal cells. There is interest in cancer therapy inducing cell death by activation of the death-receptor-mediated apoptotic pathway while avoiding decoy-receptor-mediated neutralization of the signal. This has led to the development of a number of receptor-specific TRAIL-variants and agonistic antibodies. Some of these soluble recombinant TRAIL and agonist antibodies targeting TRAIL-R1 and/or TRAIL-R2 are progressing in clinical trials. In addition, TRAIL-resistant tumors can be sensitized to TRAIL by a combination of TRAIL or agonistic antibodies with chemotherapeutic agents, targeted small molecules or irradiation.

Areas covered in this review: Recent advances in developing TRAIL or its agonist receptor antibodies in cancer therapy. We also discuss combination therapies in overcoming TRAIL resistance in cancer cells.

What the reader will gain: Knowledge of current clinical trials, the promise and obstacles in the future development of therapies affecting TRAIL signaling pathways.

Take home message: Cancer therapeutics targeting the TRAIL/TRAIL receptor signaling pathway hold great promise for molecularly targeted pro-apoptotic anti-cancer therapy.     

Emerging MEK inhibitors

Importance of the field: The Ras/Raf/MEK/ERK pathway is often activated by genetic alterations in upstream signaling molecules. Integral components of this pathway such as Ras and B-Raf are also activated by mutation. The Ras/Raf/MEK/ERK pathway has profound effects on proliferative, apoptotic and differentiation pathways. This pathway can often be effectively silenced by MEK inhibitors.

Areas covered by this review: This review will discuss targeting of MEK which could lead to novel methods to control abnormal proliferation which arises in cancer and other proliferative diseases. This review will cover the scientific literature from 1980 to present and is a follow on from a review which focused on Emerging Raf Inhibitors published in this same review series.

What the reader will gain: By reading this review the reader will understand the important roles that genetics play in the response of patients to MEK inhibitors, the potential of combining MEK inhibitors with other types of therapy, the prevention of cellular aging and the development of cancer stem cells.

Take home message: Targeting MEK has been shown to be effective in suppressing many important pathways involved in cell growth and the prevention of apoptosis. MEK inhibitors have many potential therapeutic uses in the suppression of cancer, proliferative diseases and aging.     

Targeting Mcl-1 for the therapy of cancer

Introduction: Human cancers are genetically and epigenetically heterogeneous and have the capacity to commandeer a variety of cellular processes to aid in their survival, growth and resistance to therapy. One strategy is to overexpress proteins that suppress apoptosis, such as the Bcl-2 family protein Mcl-1. The Mcl-1 protein plays a pivotal role in protecting cells from apoptosis and is overexpressed in a variety of human cancers.

Areas covered: Targeting Mcl-1 for extinction in these cancers, using genetic and pharmacological approaches, represents a potentially effectual means of developing new efficacious cancer therapeutics. Here we review the multiple strategies that have been employed in targeting this fundamental protein, as well as the significant potential these targeting agents provide in not only suppressing cancer growth, but also in reversing resistance to conventional cancer treatments.

Expert opinion: We discuss the potential issues that arise in targeting Mcl-1 and other Bcl-2 anti-apoptotic proteins, as well problems with acquired resistance. The application of combinatorial approaches that involve inhibiting Mcl-1 and manipulation of additional signaling pathways to enhance therapeutic outcomes is also highlighted. The ability to specifically inhibit key genetic/epigenetic elements and biochemical pathways that maintain the tumor state represent a viable approach for developing rationally based, effective cancer therapies.     

Approaches to Ras signaling modulation and treatment of Ras-dependent disorders: a patent review (2007 – present)

Introduction: Ras proteins are small GTPases molecular switches that cycle through two alternative conformational states, a GDP-bound inactive state and a GTP-bound active state. In the active state, Ras proteins interact with and modulate the activity of several downstream effectors regulating key cellular processes including proliferation, differentiation, survival, senescence, migration and metabolism. Activating mutations of RAS genes and of genes encoding Ras signaling members have a great incidence in proliferative disorders, such as cancer, immune and inflammatory diseases and developmental syndromes. Therefore, Ras and Ras signaling represent important clinical targets for the design and development of pharmaceutically active agents, including anticancer agents.

Areas covered: The authors summarize methods available to down-regulate the Ras pathway and review recent patents covering Ras signaling modulators, as well as methods designed to kill specifically cancer cells bearing activated RAS oncogene.

Expert opinion: Targeted therapy approach based on direct targeting of molecules specifically altered in Ras-dependent diseases is pursued with molecules that down-regulate expression or inhibit the biological function of mutant Ras or Ras signaling members. The low success rate in a clinical setting of molecules targeting activated members of the Ras pathway may require development of novel approaches, including combined and synthetic lethal therapies.     

The PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer

Introduction: Immunotherapy is emerging as a powerful approach in cancer treatment. Preclinical data predicted the antineoplastic effects seen in clinical trials of programmed death-1 (PD-1) pathway inhibitors, as well as their observed toxicities. The results of early clinical trials are extraordinarily promising in several cancer types and have shaped the direction of ongoing and future studies.

Areas covered: This review describes the biological rationale for targeting the PD-1 pathway with monoclonal antibodies for the treatment of cancer as a context for examining the results of early clinical trials. It also surveys the landscape of ongoing clinical trials and discusses their anticipated strengths and limitations.

Expert opinion: PD-1 pathway inhibition represents a new frontier in cancer immunotherapy, which shows clear evidence of activity in various tumor types including NSCLC and melanoma. Ongoing and upcoming trials will examine optimal combinations of these agents, which should further define their role across tumor types. Current limitations include the absence of a reliable companion diagnostic to predict likely responders, as well as lack of data in early-stage cancer when treatment has the potential to increase cure rates.     

Selective genetic analysis of myoma pseudocapsule and potential biological impact on uterine fibroid medical therapy

Introduction: Tumor-associated angiogenesis is one of the essential hallmarks underlying cancer development and metastasis. Anti-angiogenic agents accordingly aim to restrain cancer progression by blocking the formation of new vessels, improving the delivery of chemotherapeutic agents to the tumor site and reducing the shedding of metastatic cells into the circulation. This review article addresses some key issues in the use of angiogenesis inhibitors in cancer.

Areas covered: The authors review the complex interactions between cell signaling pathways involved in tumor angiogenesis, and focus in particular on the molecular mechanisms that may induce resistance to angiogenesis inhibitors. They will also discuss some novel therapeutic strategies evolving within anti-angiogenic therapy such as the targeting of VEGFR-3, endothelial integrins and hepatocyte growth factor-MET signaling.

Expert opinion: Although anti-angiogenic therapy is targeted at the non-malignant part of the tumor, the intricate network of growth promoting signaling pathways and in particular the redundancy when single pathways are targeted in endothelial cells represents a major therapeutic obstacle. A key challenge will be to develop more efficient inhibitors, combined with an individualized approach based on each tumor's own endothelial signaling profile. Furthermore, reliable biomarkers which pinpoint those patients that will benefit from anti-angiogenic therapy need to be identified.     

Targeting the insulin-like growth factor signaling pathway: figitumumab and other novel anticancer strategies

Introduction: There are clear preclinical data that support the involvement of the insulin-like growth factor (IGF) signaling pathway in oncogenesis and cancer progression. Such evidence has led to the design and conduct of drug development programs targeting the IGF-I receptor (IGF-IR) over the past 10 years.

Areas covered: This review details the structure and function of different members of the IGF system and related pathways, describes the rationale for targeting IGF-IR in cancer and updates the current advances in drug development. The preclinical development of figitumumab, the furthest developed mAb against IGF-IR, is examined as well as the reported data from Phase I - III clinical trials. Future prospects for this target and pathway are also discussed.

Expert opinion: While there have been both successes and failures in the development of novel targeted therapeutics targeting the IGF pathway, the evaluation of such agents should continue, with greater emphasis placed on combinatorial strategies and the development of predictive biomarkers that enhance antitumor responses through appropriate patient selection.     

The discovery and development of cyclooxygenase-2 inhibitors as potential anticancer therapies

Introduction: In the past, clinical studies had demonstrated that aspirin and NSAIDs reduce the risk of colorectal cancer. After the discovery of selective prostaglandin-endoperoxide synthase 2 (PTGS2) inhibitors, the further beneficial effects of celecoxib and some other related structures (coxibs) have been demonstrated in both in vivo and in vitro studies.

Areas covered: The authors illustrate the role of prostaglandins following the overexpression of PTGS2 (COX-2) in signaling pathways. The authors elucidate the role of coxibs in cell proliferation, apoptosis, angiogenesis and multi-drug resistance and discuss the molecular mechanisms involved. The authors also present the strong evidence related to the usefulness of coxibs in several cancer cell lines.

Expert opinion: There have been a number of PTGS2 (COX-2) selective inhibitors suggested as potential anticancer therapies. In recent years, the development of nanotechnology has also had an impact on chemotherapy. Indeed, nanoparticles of cytotoxic drug carriers have demonstrated potential through their accumulation in cancer cells, and targeting these nanoparticles has been under evaluation. This area could be opened up for coxib development as they are potentially important targets in cancer cells. Further research using celecoxib as a co-drug with PTGS2-overexpressed and PTGS2-independent cancer is still needed.     

Investigational parathyroid hormone receptor analogs for the treatment of osteoporosis

Introduction: Intermittent parathyroid hormone (PTH) administration, acting through multiple signaling pathways, exerts an osteoanabolic effect on the skeleton that surpasses the effect of other antiosteoporotic agents. However, its efficacy is limited by the coupling effect and relatively common adverse events. Thus, the development of more sophisticated PTH receptor analogs seems imperative.

Areas covered: In this review, the authors summarize the role of PTH signaling pathway in bone remodeling. The authors also summarize investigational analogs targeting this pathway, which may be potential treatments for osteoporosis.

Expert opinion: β-arrestins are multifunctional cytoplasmic molecules that are decisive for regulating intracellular PTH signaling. Recently, in preclinical studies, arrestin analogs have achieved the anabolic bone effect of PTH without an accompanying increase in bone resorption. However, it is not yet known whether these analogs have adverse effects and there are no clinical data for their efficacy to date. On the other hand, several molecules derived either from PTH and PTH-related protein (PTHrP) molecules have been developed. Alternative routes of PTH 1 – 34 delivery (oral, transdermal), the PTH analog ostabolin and the N-terminal PTHrP analogs PTHrP 1 – 36 and abaloparatide, have recently been or are currently being tested in clinical trials and are more likely to become available for use in the near future.     

Tumor endothelial markers as a target in cancer

Introduction: Several anti-angiogenic agents have been developed and some of them have been clinically applied in the tumor therapy. Anti-angiogenic therapy faces some hurdles: inherent or acquired resistance, increased invasiveness, and lack of biomarkers. Characterization of tumor endothelial markers may help to target endothelium and to identify potential predictive factors of response to anti-angiogenic therapies. Numerous surrogates, angiogenic and endothelium markers have emerged from recent pre-clinical studies, including physiological and soluble molecules in plasma and from platelets, circulating cells, tumor tissue factors and imaging markers. However, no wholly validated biomarkers currently exist to predict the success or the failure of the anti-angiogenic therapy of cancer. Therefore, the research of suitable and validate biomarkers is currently ongoing.

Areas covered: This review provides an overview of the status of our knowledge concerning tumor endothelial markers, therapeutics targeting, possible resistance mechanisms and predictive value of these biomarkers and discuss future strategies to use and identify them in the anti-angiogenic therapy.

Expert opinion: Anti-angiogenesis is a milestone to improve the treatment of several types of cancer and predictive biomarkers for a response to anti-endothelium therapy are one of the most important challenges for anti-angiogenesis research.     

Targeting VDAC-bound hexokinase II: a promising approach for concomitant anti-cancer therapy

Introduction: Enhancement of glucose metabolism and repression of oxidative phosphorylation followed by the Warburg effect is the common hallmark of cancer cells. Hexokinase II (HKII) plays a dual role – first, HKII up-regulation results in increased glycolysis rates. Second, association of VDAC and HKII contributes to inhibition of apoptosis through repression of the formation of mitochondrial permeability transition pores.

Areas covered: In this review, the role of HKII in evasion of apoptosis, aspects of HKII expression regulation, novel approaches targeting HKII and VDAC–HKII complexes and their application areas are discussed.

Expert opinion: The dual role of HKII in cancer cells makes it an attractive target for anti-cancer therapy. Several agents, either synthetic or plant-derived, that target hexokinase and induce VDAC–HK complex dissociation have been identified to date. Targeting hexokinase, HK–VDAC complexes as well as other glycolytic proteins not only improves the efficacy of commonly used drugs. The most prominent benefit of this approach is the ability to overcome drug resistance, for example, to cisplatin or sorafenib. In some cases, it could create an insurmountable challenge for selection of appropriate therapy. Future studies and trials should address the issue of how to transfer these approaches into clinical practice.     

Update on emerging drug therapies for systemic lupus erythematosus

Importance of the field: Despite the improvement in survival of systemic lupus erythematosus (SLE), a cure for this chronic and disabling disease is still a myth. Refractory manifestations and treatment-related complications are still major causes for mortality and morbidity. More effective but less toxic therapies through modification of existing regimens, combination strategies or more specific targeting at the immunopathogenetic pathways are necessary.

Areas covered in this review: The availability of biotechnology has led to the emergence of targeted therapies for SLE. In the past 5 years, there have been a number of clinical trials in the pipeline that involve existing drugs or novel biological agents. This article updates different novel therapeutic approaches in SLE that have emerged since 2006.

What the readers will gain: Readers will read the latest information and critical appraisals regarding recent clinical trials in lupus. Expert opinions on future directions of SLE treatment trials are also provided.

Take home message: SLE is a clinically and immunologically heterogeneous disease. Targeted therapies are currently available but to the disappointment of the lupus community, data from many recent clinical trials are unfavorable. While flaws and limitations in the study design and outcome measures may contribute to the futility of these trials, selection of SLE subsets by serum and cellular biomarkers may identify those who will benefit from these targeted therapies.     

Investigational drugs for head and neck cancer

Introduction: In the treatment of advanced/metastatic head and neck cancer (HNC), resistance to chemotherapy and to anti-EGFR agents remains a major issue, and new molecular drugs are eagerly awaited. Over the last decade, knowledge of the genetic landscape of HNC has rapidly grown. However, no tailored therapeutic intervention targeting HNC molecular abnormalities is currently available outside from clinical trials.

Areas covered: In this review, the authors analyze new drugs in the HNC setting which have been investigated in recently published trials or are currently being investigated. The article excludes strategies directed towards the EGFR pathway and antivascular agents.

Expert opinion: Agents acting on the PI3K axis have a strong biological rationale and show the preliminary signs of activity, in particular when combined with other agents. There is limited clinical data of the other discussed pathways; the CMET/HGF pathway as a possible modulator of anti-EGFR drug sensitivity and agents directed towards MEK, WEE-1, NOTCH represent new interesting approaches to HNC. It is of the utmost importance to try and incorporate the molecular dissection of the tumor profiles in clinical trials with such agents. Moreover, the mutational status of other cross-talking pathways should be assessed, since potential resistance mechanisms can be recognized and possibly overcome by a careful selection of patients and combination regimens. Immunotherapy represents a growing field in HNC and its wider application will impact on future therapeutic strategies, including the association with chemotherapy, targeted agents and radiation.     

Stimulation of Brain Nicotinic Acetylcholine Receptors (nAChR) and Inhibition of Brain Acetylcholinesterase (AChE) Activity

Introduction: The Fas/FasL system plays a significant role in tumorigenesis. Research has shown that its impairment in cancer cells may lead to apoptosis resistance and contribute to tumor progression. Thus, the development of effective therapies targeting the Fas/FasL system may play an important role in the fight against cancer.

Areas covered: In this review the recent literature on targeting the Fas/FasL system for therapeutic exploitation at different levels is reviewed. Promising pre-clinical approaches and various exceptions are highlighted. The potential of combined therapies is also explored, whereby tumor sensitivity to Fas-mediated apoptosis is restored, before an effective targeted therapy is employed.

Expert opinion: The success of the Fas/FasL system targeting for therapeutics will require a better understanding of the alterations conferring resistance, in order to use the most appropriate sensitizing chemotherapeutic or radiotherapeutic agents in combination with effective targeted therapies.     

New phosphatidylinositol 3-kinase inhibitors for cancer

Introduction: Cancer treatment is moving away from conventional cytotoxic drugs and towards agents that target specific proteins important to cancer development or survival. The PI3K signaling axis is an important pathway involved in myriad human malignancies. Inhibition of this axis is a promising therapeutic approach for several cancers.

Areas covered: This article reviews current literature and recent conference proceedings to analyze the rationale for targeting PI3K and its downstream effectors in cancer. Preclinical and clinical results of several PI3K and PI3K–mammalian target of rapamycin (mTOR) inhibitors in early clinical trials, as single agents and in combination with other drugs, are discussed. Thus far, clinical results have been mixed.

Expert opinion: The clinical utility of PI3K and PI3K–mTOR inhibitors will depend on appropriate selection of patients. Mutations in the PI3K pathway may predict sensitivity to PI3K inhibition but they are not reliable biomarkers at this point. Efforts to define predictive biomarkers will probably be the key to finding therapeutic uses for this novel class of anticancer agents.     

Targeting silibinin in the antiproliferative pathway

Importance of the field: Due to the failure and severe toxicity of cancer chemotherapy, silibinin, a natural flavonoid from the seeds of milk thistle, has recently received more attention for its potential anticancer and nontoxic roles in animals and humans. Silibinin has clearly demonstrated inhibition of multiple cancer cell signaling pathways, including growth inhibition, inhibition of angiogenesis, chemosensitization, and inhibition of invasion and metastasis. Cumulative evidence implicates that silibinin is a potential agent for cancer chemoprevention and chemotherapy.

Areas covered in this review: Our aim is to discuss the recent progress of silibinin in regulating multiple anticancer proliferative signaling pathways; the review covers literature mainly from the past 3 – 5 years.

What the reader will gain: One of the strategies for tumor therapy is eradication of cancer cells through targeting specific cell-proliferative pathways. This review highlights the current knowledge of silibinin in regulating multiple cellular proliferative pathways in cancer cells, including receptor tyrosine kinases, androgen receptor, STATs, NF-κB, cell cycle regulatory and apoptotic signaling pathways.

Take home message: The molecular mechanisms of silibinin-mediated antiproliferative effects are mainly via receptor tyrosine kinases, androgen receptor, STATs, NF-κB, cell cycle regulatory and apoptotic signaling pathways in various cancer cells. Targeting inhibition of proliferative pathways through silibinin treatment may provide a new approach for improving chemopreventive and chemotherapeutic effects.