Targeting cancer stem cells

Recent evidence has demonstrated the existence of a small subset of the tumour mass that is wholly responsible for the sustained growth and propagation of the tumour. This cancer stem cell (CSC) compartment is also likely to be responsible both for disease relapse and the resistance to therapy that often accompanies relapse. The evidence for CSCs in various malignancies is presented. The failure of existing therapeutics to eradicate CSCs suggests that they are relatively resistant to present cancer treatments. This resistance may reflect the preservation of normal stem cell protective mechanisms, such as an increased expression of drug efflux pumps or alterations in apoptotic, cell cycle and DNA repair mechanisms. Targeting these mechanisms, and taking advantage of potential differences in the biology of normal stem cells and CSCs, such as differences in surface phenotype, self renewal/quiescence and stem cell–niche interactions are discussed and preliminary preclinical or clinical data are presented. Finally, the authors give their opinion of the direction in which one must travel to successfully target the CSC and improve treatment outcomes in malignant disease.     

Targeting embryonic signaling pathways in cancer therapy

Introduction: The embryonic signaling pathways (ESP), Hedgehog, Notch and Wnt, are critical for the regulation of normal stem cells and cellular development processes. They are also activated in the majority of cancers. ESP are operational in putative cancer stem cells (CSC), which drive initial tumorigenesis and sustain cancer progression and recurrence in non-CSC bulk subpopulations. ESP represent novel therapeutic targets. A variety of inhibitors and targeting strategies are being developed.

Areas covered: This review discusses the rationale for targeting ESP for cancer treatment, as well as specific inhibitors under development; mainly focusing on those approaching clinical use and the challenges that lie ahead. The data sources utilized are several database search engines (PubMed, Google, Clinicaltrials.gov), and the authors' involvement in the field.

Expert opinion: CSC research is rapidly evolving. Expectations regarding their therapeutic targeting are rising quickly. Further definition of what constitutes a true CSC, proper validation of CSC markers, a better understanding of cross-talk among ESP and other pathways, and interactions with tumor non-CSC and the tumor microenvironment are needed. The appropriate patient population, the right clinical setting and combination strategies to test these therapies, as well as the proper pharmacodynamic markers to measure, need to be further established.     

Potential of transglutaminase 2 as a therapeutic target

Importance of the field: Increased expression and activity of transglutaminase 2 – a calcium-dependent enzyme which catalyzes protein cross-linking, polyamination or deamidation at selective glutamine residues – are involved in the etiopathogenesis of several pathological conditions, such as neurodegenerative disorders, autoimmune diseases and inflammatory diseases. Inhibition of enzyme activity has potential for therapeutic management of these diseases.

Areas covered in this review: The major results achieved in the last twelve years of research in the field of inhibition of tranglutaminase activity using cell cultures as well as in vivo models of high-social-impact or widespread diseases, such as CNS neurodegenerative disorders, celiac sprue, cancer and fibrotic diseases.

What the reader will gain: Beneficial effects of enzyme activity inhibition have been observed in neurodegeneration and fibrosis in vivo models by delivery of the competitive inhibitor cystamine and more recently designed inhibitors, such as thiomidaziolium or norleucine derivatives, which irreversibly bind the active site cysteine residue. Transglutaminase 2 targeting with specific antibodies has also been shown to be a promising tool for celiac disease treatment.

Take home message: New insights from transglutaminase inhibition studies dealing with side effects of in vivo administration of pan-transglutaminase inhibitors will help in design of novel therapeutic approaches to various diseases.     

Approaches for targeting self-renewal pathways in cancer stem cells: implications for hematological treatments

Introduction: Self-renewal is considered a defining property of stem cells. Self-renewal is essential in embryogenesis and normal tissue repair and homeostasis. However, in cancer, self-renewal pathways, e.g. WNT, NOTCH, Hedgehog and BMP, frequently become de-regulated in stem cells, or more mature progenitor cells acquire self-renewal properties, resulting in abnormal tissue growth and tumorigenesis.

Areas covered: This review considers the conserved embryonic self-renewal pathways, including WNT, NOTCH, Hedgehog and BMP. The article describes recent advances in our understanding of these pathways in leukemia and, more specifically, leukemia stem cells (LSC), how these pathways cross-talk and interact with the LSC microenvironment, and discusses the clinical implications and potential therapeutic strategies, both in preclinical and in clinical trials for hematological malignancies.

Expert opinion: The conserved embryonic self-renewal pathways are frequently de-regulated in cancer stem cells (CSC), including LSCs. There is significant cross-talk between self-renewal pathways, and their downstream targets, and the microenvironment. Effective targeting of these pathways is challenging due to cross-talk, and importantly, because these pathways are important for normal stem cells as well as CSC, adverse effects on normal tissues may mean a therapeutic window cannot be identified. Nonetheless, several agents targeting these pathways are currently in clinical trials in hematological malignancies.     

Stem cell-derived endothelial cells for cardiovascular disease: a therapeutic perspective

Stem cell therapy and organ regeneration are therapeutic approaches that will, we suggest, become mainstream for the treatment of human disease. Endothelial cells, which line the luminal surface of every vessel in the body, are essential components in any organ regeneration programme. There are a number of potentially therapeutic endothelial cell types, including embryonic, adult progenitor and induced pluripotent stem cell-derived endothelial cells, as well as host vascular cells. The features (benefits as well as disadvantages) of each cell type that make them potentially useful in therapy are important to consider. The field of stem cell biology is well developed in terms of protocols for generating endothelium. However, where there is a distinct and urgent unmet need for knowledge concerning how the endothelial cells from these different sources function as endothelium and how susceptible they may be to inflammation and atherosclerosis. Furthermore, where stem cells have been used in clinical trials there is little commonality in protocols for deriving the cells (and thereby the specific phenotype of cells used), administering the cells, dosing the cells and/or in assessing efficacy attributed to the cells themselves. This review discusses these and other issues relating to stem cell-derived endothelial cells in cell therapy for cardiovascular disease.     

Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist

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Smoothened antagonists: a promising new class of antitumor agents

Background: Hedgehog signaling is essential for the development of most metazoans. In recent years, evidence has accumulated showing that many human tumors aberrantly re-activate this developmental signaling pathway and that interfering with it may provide a new strategy for the development of novel anti-cancer therapeutics. Smoothened is a G-protein coupled receptor-like protein that is essentially involved in hedgehog signal transduction and small molecule antagonists of Smoothened have started to show antitumor activity in preclinical models and in clinical trials. Objective: We critically review the role of hedgehog signaling in normal development and in human malignancies, the available drug discovery tools and the classes of small molecule inhibitors that are in development. We further aim to address the potential impact that pathway antagonists may have on the treatment options of cancer patients. Methods: Literature, patents and clinical trial results from the past 5 years were analyzed. Conclusions: 1) A large body of evidence suggests a frequent reactivation of hedgehog signaling in human cancer. 2) Smoothened is an attractive, highly druggable target with extensive preclinical and initial clinical validation in basal cell carcinoma. Several promising novel classes of Smoothened antagonists have been discovered and are being developed as anticancer agents. 3) Our knowledge of the biology of hedgehog signaling in cancer is still very incomplete and significant efforts will be required to understand how to use the emerging novel agents in the clinic.     

神经干细胞移植治疗神经系统疾病的研究进展

神经系统疾病作为最大的医学挑战之一,目前尚无针对性的治疗方法。神经干细胞（NSCs）具有分化潜能,可通过组织修复替代、神经营养、免疫调节、抗炎、抗凋亡等达到治疗神经系统疾病的作用,为神经系统疾病的治疗提供了新思路。近年来针对NSCs的研究愈发深入,NSCs移植成为神经系统疾病治疗方法的研究热点,大量临床前及临床研究数据证明NSCs移植治疗用于神经系统疾病是安全可行的。目前已有多个NSCs细胞系进入临床试验阶段,有望用于脑卒中、脑出血、脊髓损伤、帕金森病、阿尔茨海默病等常见神经系统疾病的治疗。总结了NSCs移植治疗中枢神经系统疾病的研究进展,以期为NSCs移植治疗神经系统疾病研究提供理论支持。     

Targeting microRNAs in epithelial-to-mesenchymal transition-induced cancer stem cells: therapeutic approaches in cancer

Introduction: Epithelial-to-mesenchymal transition (EMT) is a pathological phenomenon of cancer that confers tumor cells with increased cell motility, invasive and metastatic abilities with the acquisition of ‘cancer stem-like cell’ (CSC) phenotype. EMT endows tumor cells with intrinsic/acquired resistant phenotype at achievable doses of anticancer drugs and leads to tumor recurrence and progression. Besides the complex network of signaling pathways, microRNAs (miRNAs) are being evolved as a new player in the induction and regulation of EMT.

Areas covered: In this review article, the author has searched the PubMed and Google Scholar electronic databases for original research and review articles to gather current information on the association of EMT-induced CSCs with therapeutic resistance, tumor growth and metastasis, which are believed to be regulated by certain miRNAs.

Expert opinion: This review outlines not only the perspective on selective targeting of EMT-induced CSCs through altered expression of novel miRNAs and/or the use of conventional drugs that affect the levels of critical miRNAs but also the strategies on overcoming the drug resistance by interfering with EMT and modulating its associated pathways in CSCs that can be considered as potential therapeutic approaches toward eradicating the tumor recurrence and metastasis.     

Smoothened抑制剂的耐药机制及克服耐药性的策略研究

Hedgehog （HH）信号通路在胚胎的发育、干细胞调节及组织稳态过程中发挥着重要作用,HH通路的异常则与多种肿瘤的发生和发展密切相关。Smoothened （SMO）蛋白是HH通路的主要跨膜蛋白,抑制SMO蛋白可以有效地抑制HH通路,从而有效抑制肿瘤的发生和发展。目前已有3个SMO抑制剂被美国食品药品监督管理局（Food and Drug Administration,FDA）批准上市。然而,这些药物的临床使用往往伴随着耐药的产生。综述SMO抑制剂的主要耐药机制以及克服其耐药性的常用策略。     

Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened

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Targeting mitochondrial function to protect against vision loss

Introduction: Mitochondria, essential to multicellular life, convert food into ATP to satisfy cellular energy demands. Since different tissues have different energy requirements, mitochondrial density is high in tissues with high metabolic needs, such as the visual system, which is therefore highly susceptible to limited energy supply as a result of mitochondrial dysfunction.

Areas covered: Vision impairment is a common feature of most mitochondrial diseases. At the same time, there is mounting evidence that mitochondrial impairment contributes to the pathogenesis of major eye diseases such as glaucoma and might also be involved in the reported vision impairment in neurodegenerative disorders such as Alzheimer’s disease.

Expert opinion: Rather than relying on symptomatic treatment, acknowledging the mitochondrial origin of visual disorders in mitochondrial, neurodegenerative and ocular diseases could lead to novel therapeutics that aim to modulate mitochondrial function in order to protect against vision loss. This approach has already shown some promising clinical results in inherited retinal disorders, which supports the idea that targeting mitochondria could also be a treatment option for other optic neuropathies.     

The Hedgehog signalling pathway as a therapeutic target in early breast cancer development

The Hedgehog (Hh) signalling pathway is a highly conserved developmental pathway, which plays critical roles in patterning of the embryo through epithelial to mesenchymal signalling and the maintenance of stem cells in the adult organism. There is increasing evidence that this pathway is dysregulated in many malignancies, including breast cancer. While there has been a significant decrease in mortality from breast cancer, a number of treatment challenges remain, particularly in those tumours which develop resistance to endocrine-based therapy, or which lack expression of hormone or c-erbB2/HER2 receptors. Therapeutic manipulation of the Hh pathway as a potential cancer therapy is attracting great interest, with preclinical studies and clinical trials underway in a range of malignancies. This review highlights important recent developments that affect the potential of the Hh pathway as a novel therapeutic target in early breast cancer.     

Targeting the Wnt signaling pathway in colorectal cancer

Introduction: The treatment of patients with advanced colorectal cancer still remains challenging, and identification of new target molecules and therapeutic avenues remains a priority. The great majority of colorectal cancers have mutations in one of two genes involved in the Wnt signaling pathway: the adenomatous polyposis coli (APC) and β-catenin (CTNNB1) genes. Up to now, however, no therapeutics for targeting this pathway have been established.

Areas covered: This review article begins with a brief summary of Wnt signaling from the viewpoints of genetics, cancer stem cell biology, and drug development. We then overview current attempts to develop drugs directed at various components of the Wnt signaling pathway.

Expert opinion: APC is a tumor suppressor, and therefore only downstream signal transducers of the APC protein can be considered as targets for pharmaceutical intervention. TRAF2 and NCK-interacting protein kinase (TNIK) was identified as the most downstream regulator of Wnt signaling by two independent research groups, and several classes of small-molecule inhibitors targeting this protein kinase have been developed. TNIK is a multifunctional protein with actions that extend beyond Wnt signaling regulation. Such TNIK inhibitors are expected to have a large variety of clinical applications.     

Non-cell-autonomous signaling by Shh in tumors: challenges and opportunities for therapeutic targets

Importance of the field: The Hedgehog (Hh) pathway is required during many developmental events; in adults the Hedgehog pathway is involved in the maintenance of several stem cell niches. It is therefore not surprising that aberrantly regulated Hh pathway activity can cause birth defects in the developing organism, as well as neoplastic disease later in life.

Areas covered in this review: As a consequence of the involvement in pathogenesis, the Hh pathway components are subject to an intense scrutiny as potential targets for therapeutic agents. We aim to provide an overview of the biology of the Hh proteins and the cellular response, in conjunction with potential therapeutic interventions.

What the reader will gain: Specifically, we focus on the recently discovered non-cell-autonomous Shh signaling used by tumors and the implications of this for the design of treatment strategies. This should provide the reader with up-to-date knowledge on the role of the Hh pathway in tumor progression and the options to treat these malignancies.

Take home message: An important concept that we advocate in this review is the need to recognize the need to target both the stromal and the tumor compartment in malignancies that rely on paracrine Shh signaling.     

The Hedgehog pathway and its inhibitors: Emerging therapeutic approaches for basal cell carcinoma

Basal cell carcinoma (BCC) is the most common non-melanoma skin cancer (NMSC). Although surgery is the first-line treatment, BCC can lead in some cases, to a metastatic or advanced form, requiring targeted combination therapies. The Hedgehog (Hh) signalling pathway is the major pathway associated with the formation of basal carcinoma tumorigenesis, thus, targeting this is a promising therapeutic approach. Some Hh inhibitors have been approved by the US Food and Drug Administration (FDA), such as vismodegib and sonidegib. However, both of these showed limited effectiveness against resistant tumors. Therefore, an essential understanding of the mechanisms involved in the Hh signaling pathway is necessary to improve tumor inhibition.     

外周血干细胞移植治疗自身免疫性疾病对照研究及疗效随访

目的　研究、评价大剂量环磷酰胺 (CTX)免疫清除治疗后用及不用造血干细胞救助治疗自身免疫性疾病的安全性及疗效。方法　 ( 1)治疗组自身免疫性疾病 (AD) 11例 ,其中严重性系统性红斑狼疮 9例 ,多发性硬化与晚期类风湿关节炎各 1例 ,采用大剂量CTX免疫清除治疗 (CTX 5 0mg·kg- 1 ·d- 1 × 3d) +造血干细胞 (HSC)救助 ;( 2 )对照组 9例严重性系统性红斑狼疮用血浆置换 +同步化CTX化疗 (CTX 12mg·kg- 1 ·d- 1 × 3d) ,不用造血干细胞救助。结果　 ( 1)治疗组 11例AD所有病人都成功进行了自体外周血干细胞移植 (APBSCT)的全过程 ,造血功能及免疫功能迅速恢复 ,未出现严重的毒性反应及并发症。 9例SLE病人完全缓解 ,相关抗体全部阴转 ,长期随访 (最长 2 4个月 )无 1例复发 ,仅 1例多发性硬化在治疗后 9个月复发 ;( 2 )对照组 9例SLE病人 ,有 3例病人分别在治疗后的第 1、3、8个月疾病复发 ,其中的 2例又进行了APBSCT。结论　 ( 1)血浆置换 +同步化免疫抑制剂CTX化疗 ,不用造血干细胞救助 ,近期疗效较好 ,复发率高 ( 3 3 % ) ;( 2 )大剂量CTX免疫清除治疗后用造血干细胞救助治疗 ,造血功能恢复较快 ,是安全有效的 ,而且持续完全缓解时间长 ,但还需进一步扩大病例 ,长期随访。     

Targeting IL-8 signalling to inhibit breast cancer stem cell activity

Although survival from breast cancer has improved significantly over the past 20 years, disease recurrence remains a significant clinical problem. The concept of stem-like cells in cancer has been gaining currency over the last decade or so, since evidence for stem cell activity in human leukaemia and solid tumours, including breast cancer, was first published. Evidence indicates that this sub-population of cells, known as cancer stem-like cells (CSCs), is responsible for driving tumour formation and disease progression. In breast cancer, there is good evidence that CSCs are intrinsically resistant to conventional chemo-, radio- and endocrine therapies. By evading the effects of these treatments, CSCs are held culpable for disease recurrence. Hence, in order to improve treatment there is a need to develop CSC-targeted therapies. Interleukin-8 (IL-8), an inflammatory cytokine, is upregulated in breast cancer and associated with poor prognostic factors. Accumulating evidence demonstrates that IL-8, through its receptors CXCR1/2, is an important regulator of breast CSC activity. Inhibiting CXCR1/2 signalling has proved efficacious in pre-clinical models of breast cancer providing a good rationale for targeting CXCR1/2 clinically. Here, we discuss the role of IL-8 in breast CSC regulation and development of novel therapies to target CXCR1/2 signalling in breast cancer.