Insulin-Like Growth Factors,Insulin, and Growth Hormone Signaling in Breast Cancer: Implications for Targeted Therapy

ObjectiveIn recent decades, multiple therapeutics targeting the estrogen and human epidermal growth factor-2 (HER2) receptors have been approved for the treatment of breast cancer.MethodsThis review discusses a number of growth factor pathways that have been implicated in resistance to both anti-estrogen and HER2-targeted therapies. The association between growth factors and breast cancer is well established. Over decades, numerous laboratories have studied the link between insulin-like growth factor (IGF), insulin, and growth hormone (GH) to the development and progression of breast cancer.ResultsAlthough preclinical data demonstrates that blockade of these receptors inhibits breast cancer growth, progression, and drug resistance, therapies targeting the IGF, insulin, and GH receptors (GHRs) have not been successful in producing significant increases in progression- free, disease-free, or overall survival for patients with breast cancer. The failure to demonstrate a benefit of growth factor blockade in clinical trials can be attributed to redundancy in IGF, insulin, and GHR signaling pathways. All 3 receptors are able to activate oncogenic phosphoinositide- 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways.ConclusionConsequently, multitargeted blockade of growth factor receptors and their common downstream kinases will be necessary for the successful treatment of breast cancer. (Endocr Pract. 2014;20:1214-1221)     

Promise and challenges on the horizon of MET-targeted cancer therapeutics

MET(MNNG HOS transforming gene) is one of the receptor tyrosine kinases whose activities are frequently altered in human cancers, and it is a promising therapeutic target. MET is normally activated by its lone ligand, hepatocyte growth factor(HGF), eliciting its diverse biological activities that are crucial for development and physiology. Alteration of the HGF-MET axis results in inappropriate activation of a cascade of intracellular signaling pathways that contributes to hallmark cancer events including deregulated cell proliferation and survival, angiogenesis, invasion, andmetastasis. Aberrant MET activation results from autocrine or paracrine mechanisms due to overexpression of HGF and/or MET or from a ligand-independent mechanism caused by activating mutations or amplification of MET. The literature provides compelling evidence for the role of MET signaling in cancer development and progression. The finding that cancer cells often use MET activation to escape therapies targeting other pathways strengthens the argument for MET-targeted therapeutics. Diverse strategies have been explored to deactivate MET signaling, and compounds and biologics targeting the MET pathway are in clinical development. Despite promising results from various clinical trials, we are still waiting for true MET-targeted therapeutics in the clinic. This review will explore recent progress and hurdles in the pursuit of METtargeted cancer drugs and discuss the challenges in such development.     

Neuroprotective strategies for NMDAR-mediated excitotoxicity in Huntington’s Disease

BACKGROUND

Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disease causing severe neurodegeneration of the striatum as well as marked cognitive and motor disabilities. Excitotoxicity, caused by overstimulation of NMDA receptors (NMDARs) has been shown to have a key role in the neuropathogenesis of HD, suggesting that targeting NMDAR-dependent signaling may be an effective clinical approach for HD. However, broad NMDAR antagonists are generally poor therapeutics in clinical practice. It has been suggested that GluN2A-containing, synaptically located NMDARs activate cell survival signaling pathways, while GluN2B-containing, primarily extrasynaptic NMDARs trigger cell death signaling. A better approach to development of effective therapeutics for HD may be to target, specifically, the cell-death specific pathways associated with extrasynaptic GluN2B NMDAR activation, while maintaining or potentiating the cellsurvival activity of GluN2A-NMDARs.

OBJECTIVE

This review outlines the role of NMDAR-mediated excitotoxicity in HD and overviews current efforts to develop better therapeutics for HD where NMDAR excitotoxicity is the target.

METHODS

A systematic review process was conducted using the PubMed search engine focusing on research conducted in the past 5-10 years. 235 articles were consulted for the review, with key search terms including “Huntington’s Disease,” “excitotoxicity,” “NMDAR” and “therapeutics.”

RESULTS

A wide range of NMDAR excitotoxicity-based targets for HD were identified and reviewed, including targeting NMDARs directly by blocking GluN2B, extrasynaptic NMDARs and/or potentiating GluN2A, synaptic NMDARs, targeting glutamate release or uptake, or targeting specific downstream cell-death signaling of NMDARs.

CONCLUSION

The current review identifies NMDAR-mediated excitotoxicity as a key player in HD pathogenesis and points to various excitotoxicity-focused targets as potential future preventative therapeutics for HD.

     

Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers

The fibroblast growth factor receptors (FGFRs) regulate important biological processes including cell proliferation and differentiation during development and tissue repair. Over the past decades, numerous pathological conditions and developmental syndromes have emerged as a consequence of deregulation in the FGFRs signaling network. This review aims to provide an overview of FGFR family, their complex signaling pathways in tumorigenesis, and the current development and application of therapeutics targeting the FGFRs signaling for treatment of refractory human cancers.     

Functional mechanism of Ginsenosides on tumor growth and metastasis

Ginsengs, has long been used as one medicinal herb in China for more than two thousand years. Many studies have shown that ginsengs have preventive and therapeutic roles for cancer, and play a good complementary role in cancer treatment. Ginsenosides, as most important constituents of ginseng, have been extensively investigated and emphasized in cancer chemoprevention and therapeutics. However, the functional mechanism of Ginsenosides on cancer is not well known. This review will focus on introducing the functional mechanisms of ginsenosides and their metabolites, which regulate signaling pathways related with tumor growth and metastasis. Ginsenosides inhibit tumor growth via upregulating tumor apoptosis, inducing tumor cell differentiation and targeting cancer stem cells. In addition, Ginsenosides regulate tumor microenvironment via suppressing tumor angiogenesis-related proteins and pathways. Structural modification of ginsenosides and their administration alone or combinations with other Chinese medicines or chemical medicines have recently been developed to be a new therapeutic strategy for cancer.     

Role of the 5-HT7 Receptor in the Central Nervous System: from Current Status to Future Perspectives

Pharmacological and genetic tools targeting the 5-hydroxytryptamine (5-HT)7 receptor in preclinical animal models have implicated this receptor in diverse (patho)physiological processes of the central nervous system (CNS). Some data obtained with 5-HT7 receptor knockout mice, selective antagonists, and, to a lesser extent, agonists, however, are quite contradictory. In this review, we not only discuss in detail the role of the 5-HT7 receptor in the CNS but also propose some hypothetical models, which could explain the observed inconsistencies. These models are based on two novel concepts within the field of G protein-coupled receptors (GPCR), namely biphasic signaling and G protein-independent signaling, which both have been shown to be mediated by GPCR dimerization. This led us to suggest that the 5-HT7 receptor could reside in different dimeric contexts and initiate different signaling pathways, depending on the neuronal circuitry and/or brain region. In conclusion, we highlight GPCR dimerization and G protein-independent signaling as two promising future directions in 5-HT7 receptor research, which ultimately might lead to the development of more efficient dimer- and/or pathway-specific therapeutics.     

Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer

The introduction of therapeutics targeting specific tumor-promoting oncogenic or non-oncogenic signaling pathways has revolutionized cancer treatment. Mechanistic (previously mammalian) target of rapamycin (mTOR), a highly conserved Ser/Thr kinase, is a central hub of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR network, one of the most frequently deregulated signaling pathways in cancer, that makes it an attractive target for therapy. Numerous mTOR inhibitors have progressed to clinical trials and two of them have been officially approved as anticancer therapeutics. However, mTOR-targeting drugs have met with a very limited success in cancer patients. Frequently, the primary impediment to a successful targeted therapy in cancer is drug-resistance, either from the very beginning of the therapy (innate resistance) or after an initial response and upon repeated drug treatment (evasive or acquired resistance). Drug-resistance leads to treatment failure and relapse/progression of the disease. Resistance to mTOR inhibitors depends, among other reasons, on activation/deactivation of several signaling pathways, included those regulated by glycogen synthase kinase-3 (GSK3), a protein that targets a vast number of substrates in its repertoire, thereby orchestrating many processes that include cell proliferation and survival, metabolism, differentiation, and stemness. A detailed knowledge of the rewiring of signaling pathways triggered by exposure to mTOR inhibitors is critical to our understanding of the consequences such perturbations cause in tumors, including the emergence of drug-resistant cells.Here, we provide the reader with an updated overview of intricate circuitries that connect mTOR and GSK3 and we relate them to the efficacy (or lack of efficacy) of mTOR inhibitors in cancer cells.     

Anti-tumoral effect of scorpion peptides: Emerging new cellular targets and signaling pathways

Scorpion toxins have been the subject of many studies exploring their pharmacological potential. The high affinity and the overall selectivity to various types of ionic channels endowed scorpion toxins with a potential therapeutic effect against many channelopathies. These are diseases in which ionic channels play an important role in their development. Cancer is considered as a channelopathy since overexpression of some ionic channels was highlighted in many tumor cells and was linked to the pathology progression.Interestingly, an increasing number of studies have shown that scorpion venoms and toxins can decrease cancer growth in vitro and in vivo. Furthermore through their ability to penetrate the cell plasma membrane, certain scorpion toxins are able to enhance the efficiency of some clinical chemotherapies. These observations back-up the applicability of scorpion toxins as potential cancer therapeutics.In this review, we focused on the anti-cancer activity of scorpion toxins and their effect on the multiple hallmarks of cancer. We also shed light on effectors and receptors involved in signaling pathways in response to scorpion toxins effect. Until now, the anticancer mechanisms described for scorpion peptides consist on targeting ion channels to (i) inhibit cell proliferation and metastasis; and (ii) induce cell cycle arrest and/or apoptosis through membrane depolarization leading to hemostasis deregulation and caspase activation. Putative targets such as metalloproteinases, integrins and/or growth factor receptors, beside ion channels, have been unveiled to be affected by scorpion peptides.     

PI3K: a potential therapeutic target for cancer

Phosphatidylinositol 3-kinase (PI3K), one member of lipid kinase family, has been demonstrated to play a key role in regulating cell proliferation, adhesion, survival, and motility. Recent studies indicate that PI3K related signaling pathway is one of the most commonly activated pathways in human cancers. Accordingly, pharmacological inhibition of key nodes in this signaling cascade has been a focus in developmental therapeutics. To date, Inhibitors targeting PI3K or nodes in this pathway, AKT and mTOR, are best studied and have reached clinical trials. In this review, we will focus on recent progress on understanding of PI3Ks signaling pathway and the development of PI3K inhibitors.     

MicroRNAs as important players in regulating cancer through PTEN/PI3K/AKT signalling pathways

Cancer being the leading cause of mortality has become a great threat worldwide. Current cancer therapeutics lack specificity and have side effects due to a lack of understanding of the molecular mechanisms and signalling pathways involved in carcinogenesis. In recent years, researchers have been focusing on several signalling pathways to pave the way for novel therapeutics. The PTEN/PI3K/AKT pathway is one of the important pathways involved in cell proliferation and apoptosis, leading to tumour growth. In addition, the PTEN/PI3K/AKT axis has several downstream pathways that could lead to tumour malignancy, metastasis and chemoresistance. On the other hand, microRNAs (miRNAs) are important regulators of various genes leading to disease pathogenesis. Hence studies of the role of miRNAs in regulating the PTEN/PI3K/AKT axis could lead to the development of novel therapeutics for cancer. Thus, in this review, we have focused on various miRNAs involved in the carcinogenesis of various cancer via the PTEN/PI3K/AKT axis.     

Lung Cancer Stem Cells and Implications for Future Therapeutics

Lung cancer is the most dreaded of all cancers because of the higher mortality rates associated with it worldwide. The various subtypes of lung cancer respond differently to a particular treatment regime, which makes the therapeutic interventions all the more complicated. The concept of cancer stem cells (CSCs) is based primarily on the clinical and experimental observations that indicate the existence of a subpopulation of cells with the capacity to self-renew and differentiate as well as show increased resistance to radiation and chemotherapy. They are considered as the factors responsible for the cases of tumor relapse. The CSCs may have significant role in the development of lung tumorigenesis based on the identification of the CSCs which respond during injury. The properties of multi-potency and self-renewal are shared in common by the lung CSCs with the normal pluripotent stem cells which can be isolated using the similar markers. This review deals with the origin and characteristics of the lung cancer stem cells. The role of different markers used to isolate lung CSCs like CD44, ALDH (aldehyde dehydrogenase), CD133 and ABCG2 (ATP binding cassette sub family G member 2) have been discussed in detail. Analysis of the developmental signaling pathways such as Wnt/β-catenin, Notch, hedgehog in the regulation and maintenance of the lung CSCs have been done. Finally, before targeting the lung CSC biomarkers for potential therapeutics, challenges faced in lung cancer stem cell research need to be taken into account. With the accepted notion that the CSCs are to blame for cancer relapse and drug resistance, targeting them can be an important aspect of lung cancer therapy in the future.     

Cancer cell metabolism: Rewiring the mitochondrial hub

To adapt to tumoral environment conditions or even to escape chemotherapy, cells rapidly reprogram their metabolism to handle adversities and survive. Given the rapid rise of studies uncovering novel insights and therapeutic opportunities based on the role of mitochondria in tumor metabolic programing and therapeutics, this review summarizes most significant developments in the field. Taking in mind the key role of mitochondria on carcinogenesis and tumor progression due to their involvement on tumor plasticity, metabolic remodeling, and signaling re-wiring, those organelles are also potential therapeutic targets. Among other topics, we address the recent data intersecting mitochondria as of prognostic value and staging in cancer, by mitochondrial DNA (mtDNA) determination, and current inhibitors developments targeting mtDNA, OXPHOS machinery and metabolic pathways. We contribute for a holistic view of the role of mitochondria metabolism and directed therapeutics to understand tumor metabolism, to circumvent therapy resistance, and to control tumor development.     

TGF-β receptors: In and beyond TGF-β signaling

Transforming growth factor β (TGF-β) plays an important role in normal development and homeostasis. Dysregulation of TGF-β responsiveness and its downstream signaling pathways contribute to many diseases, including cancer initiation, progression, and metastasis. TGF-β ligands bind to three isoforms of the TGF-β receptor (TGFBR) with different affinities. TGFBR1 and 2 are both serine/threonine and tyrosine kinases, but TGFBR3 does not have any kinase activity. They are necessary for activating canonical or noncanonical signaling pathways, as well as for regulating the activation of other signaling pathways. Another prominent feature of TGF-β signaling is its context-dependent effects, temporally and spatially. The diverse effects and context dependency are either achieved by fine-tuning the downstream components or by regulating the expressions and activities of the ligands or receptors. Focusing on the receptors in events in and beyond TGF-β signaling, we review the membrane trafficking of TGFBRs, the kinase activity of TGFBR1 and 2, the direct interactions between TGFBR2 and other receptors, and the novel roles of TGFBR3.     

Far beyond anti-angiogenesis: Benefits for anti-basicFGF therapy in cancer

Basic FGF (bFGF) was discovered as a typical inducer of angiogenesis and has already been studied for 3 decades. Recent evidence indicates that bFGF plays different roles and controls signaling pathways that participate in the hallmarks of cancer, underscoring bFGF an appealing target for anti-cancer therapy. However, the early clinical trials designed to block bFGF signaling showed safety without satisfiable benefits for cancer patients. In this review, we firstly discuss bFGF's canonical signaling pathways and later review newly identified bFGF's functions that contribute to the cancer hallmarks besides its typical role in angiogenesis. After, we summarize the role of bFGF as a therapeutic target in response to different cancer therapies including radiotherapy, chemotherapy, targeted therapy, immunotherapy, and highlight the difficulties we must solve regarding the design of drugs targeting specifically bFGF. We also emphasize the need, especially for natural bFGF traps, to deepen their molecular mechanisms of action considering the specific context of cancer with different FGFR status, as well as the urgence of stratifying patients for both anti-bFGF first line and second line anti-cancer therapy. Finally, a perspective on potential feed-forward oncogenic signaling pathways mediated by bFGF is made. We discuss the importance of developing additional robust biomarkers to select patients who will benefit from bFGF-targeted therapy, as well as the rationale of developing combinatory therapies targeting either bFGF and/or its intracellular (co)effectors. This would ultimately provide novel therapeutic strategies to fight cancer.     

Dissecting Nck/Dock signaling pathways in Drosophila visual system

The establishment of neuronal connections during embryonic development requires the precise guidance and targeting of the neuronal growth cone, an expanded cellular structure at the leading tip of a growing axon. The growth cone contains sophisticated signaling systems that allow the rapid communication between guidance receptors and the actin cytoskeleton in generating directed motility. Previous studies demonstrated a specific role for the Nck/Dock SH2/SH3 adapter protein in photoreceptor (R cell) axon guidance and target recognition in the Drosophila visual system, suggesting strongly that Nck/Dock is one of the long-sought missing links between cell surface receptors and the actin cytoskeleton. In this review, I discuss the recent progress on dissecting the Nck/Dock signaling pathways in R-cell growth cones. These studies have identified additional key components of the Nck/Dock signaling pathways for linking the receptor signaling to the remodeling of the actin cytoskeleton in controlling growth-cone motility.     

MicroRNA replacement therapy in cancer

Despite the recent progress in cancer management approaches, the mortality rate of cancer is still growing and there are lots of challenges in the clinics in terms of novel therapeutics. MicroRNAs (miRNA) are regulatory small noncoding RNAs and are already confirmed to have a great role in regulating gene expression level by targeting multiple molecules that affect cell physiology and disease development. Recently, miRNAs have been introduced as promising therapeutic targets for cancer treatment. Regulatory potential of tumor suppressor miRNAs, which enables regulation of entire signaling networks within the cells, makes them an interesting option for developing cancer therapeutics. In this regard, over recent decades, scientists have aimed at developing powerful and safe targeting approaches to restore these suppressive miRNAs in cancerous cells. The present review summarizes the function of miRNAs in tumor development and presents recent findings on how miRNAs have served as therapeutic agents against cancer, with a special focus on tumor suppressor miRNAs (mimics). Moreover, the latest investigations on the therapeutic strategies of miRNA delivery have been presented.