Therapeutic targeting of B7-H1 in breast cancer

INTRODUCTION: Breast cancer is the most common form of malignancy occurring in women worldwide. B7-H1 is a co-inhibitory molecule expressed by several types of tumors, including breast cancer. The aberrant expression of B7-H1 in breast cancer cells has been determined, its role in recruiting regulatory T cells into the tumor microenvironment has been elucidated and a strong link to B7-H1 induction in highly proliferative breast cancer has been provided. It has also been demonstrated that doxorubicin, a drug commonly used for breast cancer treatment, downregulates the cell surface expression of B7-H1 and upregulates its nuclear expression, which therefore suggests an anti-apoptotic role of B7-H1 in breast cancer. AREAS COVERED: This review illustrates the various factors involved in the induction of B7-H1 and its role in immune evasion and chemoresistance. It also provides potential therapeutic strategies for targeting B7-H1 in breast cancer. EXPERT OPINION: B7-H1 should be considered as a potential therapeutic target for breast cancer. Indeed, there is increasing evidence for the potential efficacy of B7-H1 blockade in the prevention of immune evasion by cancer cells. Additionally, B7-H1 targeting can be used in conjunction with other therapeutic modalities for improved efficacy and reduced toxicity. We expect that B7-H1 blockade in combination with other therapeutics will be a prime therapeutic strategy in the future.     

The PD-1/PD-L1 pathway: biological background and clinical relevance of an emerging treatment target in immunotherapy

Introduction: The co-inhibitory receptor programmed death 1 (PD-1) and its ligands are key regulators in a wide spectrum of immune responses and play a critical role in autoimmunity and self-tolerance as well as in cancer immunology. Emerging evidence suggests that cancer cells might use the PD-1/PD-ligand (PD-L) pathway to escape anti-tumor immunity. Based on this evidence, early phase human clinical trials targeting the PD-1/PD-L pathway are currently underway for multiple human cancers.

Areas covered: The role of the PD-1/PD-L pathway in autoimmune disease, viral infections as well as in malignant neoplasms is discussed and an overview of the existing therapeutics as well as the results of clinical trials targeting this pathway in cancer is given.

Expert opinion: The PD-1/PD-L pathway represents an important mechanism of immune evasion for malignant neoplasms. Early clinical trials indicate effectiveness of PD-1/PD-L pathway blockade in several solid cancers. However, greater insight into the exact mechanisms by which tumors are able to evade anti-tumor immunity is needed to increase clinical effectiveness, for example by combination blockade of diverse co-inhibitory receptors.     

Consideration of GREB1 as a potential therapeutic target for hormone-responsive or endocrine-resistant cancers

Introduction: Steroid hormones increase the incidence and promote the progression of many types of cancer. Exogenous estrogens increase the risk of developing breast, ovarian and endometrial cancer and many breast cancers initially respond to estrogen deprivation. Although steroid hormone signaling has been extensively studied, the mechanisms of hormone-stimulated cancer growth have not yet been fully elucidated, limiting opportunities for novel approaches to therapeutic intervention.

Areas covered: This review examines growing evidence for the important role played by the steroid hormone-induced gene called GREB1, or growth regulation by estrogen in breast cancer 1. GREB1 is a critical mediator of both the estrogen-stimulated proliferation of breast cancer cells and the androgen-stimulated proliferation of prostate cancer cells.

Expert opinion: Although its exact function in the cascade of hormone action remains unclear, the ability of GREB1 to modulate tumor progression in models of breast, ovarian and prostate cancer renders this gene an excellent candidate for further consideration as a potential therapeutic target. Research examining the mechanism of GREB1 action will help to elucidate its role in proliferation and its potential contribution to endocrine resistance and will determine whether GREB1 interference may have therapeutic efficacy.     

Targeting miR-375 in gastric cancer

Introduction: Gastric cancer remains a major cancer burden in the world, with a poor 5-year survival rate. It is necessary to develop new effective therapeutic strategies to improve the long-term clinical outcome. MicroRNA (miRNA), a class of small non-coding RNA, has been identified as a key regulator of gene expression, and is implicated in the pathogenesis of gastric cancer.

Areas covered: This review summarizes the role of miRNAs in gastric carcinogenesis, with an emphasis on the expression and function of miR-375 in gastric cancer and beyond. It also discusses the opportunities and challenges of miR-375 as a potential therapeutic target for gastric cancer. The genes targeted by miR-375, including JAK2 and 3′-phosphoinositide dependent protein kinase-1 (PDK1), are also candidates for gastric cancer therapy.

Expert opinion: Although radical surgery and rational chemotherapy are still the main treatment for gastric cancer, targeting miRNAs, in combination with other conventional therapies, may serve as a promising therapy strategy to improve the clinical outcome.     

Acetylcholine Esterase and All Elements of the Cholinergic and Monoaminergic Transmitter Signalling Pathways

Introduction: CD47 is a ubiquitously expressed cell surface receptor that serves as a counter-receptor for SIRPα in recognition of self by the innate immune system. Independently, CD47 also functions as an important signaling receptor for regulating cell responses to stress.

Areas covered: We review the expression, molecular interactions, and pathophysiological functions of CD47 in the cardiovascular and immune systems. CD47 was first identified as a potential tumor marker, and we examine recent evidence that its dysregulation contributes to cancer progression and evasion of anti-tumor immunity. We further discuss therapeutic strategies for enhancing or inhibiting CD47 signaling and applications of such agents in preclinical models of ischemia and ischemia/reperfusion injuries, organ transplantation, pulmonary hypertension, radioprotection, and cancer.

Expert opinion: Ongoing studies are revealing a central role of CD47 for conveying signals from the extracellular microenvironment that limit cell and tissue survival upon exposure to various types of stress. Based on this key function, therapeutics targeting CD47 or its ligands thrombospondin-1 and SIRPα could have broad applications spanning reconstructive surgery, engineering of tissues and biocompatible surfaces, vascular diseases, diabetes, organ transplantation, radiation injuries, inflammatory diseases, and cancer.     

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.     

Therapeutic potential of the chemokine–receptor duo fractalkine/CX3CR1: an update

Introduction: The chemokine fractalkine/CX3CL1 and its highly selective receptor CX3CR1 mediate critical physiological events during inflammatory responses. The fractalkine/CX3CR1 axis has been shown to play a key role in the pathogenesis and the progression of a large number of diseases in which imbalance of the immune response is frequently seen. Since our last review published in early 2010, the fractalkine/CX3CR1 axis has gained vast attention as a potential therapeutic target in the scientific community, which can be clearly seen in the large number of studies that have been published on this issue since then.

Areas covered: A Medline/PubMed search was performed to detect all recently published studies on the role of the fractalkine/CX3CR1 axis as a therapeutic target in a wide range of clinical diseases.

Expert opinion: Recently published studies further underline the high potential of the fractalkine/CX3CR1 axis as a major target for future treatment of pain, inflammation and cancer. However, no clinical trials on novel therapeutics targeting fractalkine or CX3CR1 have been initiated so far, so that the fractalkine/CX3CR1 axis does still not find application in daily clinical practice.     

Development and evaluation of magnetic microemulsion: tool for targeted delivery of camptothecin to BALB/c mice-bearing breast cancer

Abstract

Purpose: Development and evaluation of camptothecin-loaded-microemulsion (ME) and -magnetic microemulsion (MME) for passive/active-targeted delivery to BALB/c mice-bearing breast cancer.

Methods: Based on the pseudo-ternary phase diagrams camptothecin-loaded-MEs and -MMEs were developed using benzyl alcohol:Captex 300 (3:1), TPGS:Tween 80 (2:1) and water. Furthermore, characterized for their droplet size distribution, magnetic susceptibility and effect of droplet size in plasma and evaluated for in vitro and in vivo targeting potential, drug release, haemolytic potential, cytotoxicity, genotoxicity, in vivo biodistribution and lactone ring stability.

Results: Drug-loaded MEs showed uniform droplet distribution, extended drug release (76.07?±?4.30% at 24?h), acceptable level of haemolytic activity (<20%), significant cytotoxicity (129?±?3.9?ng/mL) against MCF-7 cancer cells and low DNA damage in lymphocytes. Targeting potential of MMEs was documented in 4T1 breast cancer-induced BALB/c mice. MMEs were concentrated more at the target tissue on introduction of external magnetic field. In vivo biodistribution study documented the active targeting of 5067.56?±?354.72?ng/gm and passive targeting of 1677.58?±?134.20?ng/gm camptothecin to breast cancer from MME and ME, respectively. Lactone stability study shows around 80% of the lactone stable at 24?h.

Conclusions: Developed ME and MME may act as a promising nanocarrier for efficient targeting of breast cancer tissues.     

SMARCAD1 knockdown uncovers its role in breast cancer cell migration,invasion, and metastasis

Objective: Breast cancer is the most common cancer seen in women worldwide and breast cancer patients are at high risk of recurrence in the form of metastatic disease. Identification of genes associated with invasion and metastasis is crucial in order to develop novel anti-metastasis targeted therapy. It has been demonstrated that the DEAD-BOX helicase DP103 was implicated in breast cancer invasion and metastasis. SMARCAD1 is also a DEAD/H box-containing helicase, suggested to play a role in genetic instability. However, its involvement in cancer migration, invasion, and metastasis has never been explored.

Research design and methods: Using two different designs of shRNA targeting SMARCAD1, we investigated the impact of SMARCAD1 knockdown on the migration, invasion, and metastasis potential of the breast cancer cells MDA-MB-231 and T47D.

Results: We observed that SMARCAD1 knockdown in the invasive breast cancer cells MDA-MB-231, unlike in the non-invasive breast cancer cells T47D, was associated with an increased cell-cell adhesion and a significant decrease in cell migration, invasion, and metastasis due at least in part to a strong inhibition of STAT3 phosphorylation.

Conclusions: These results indicate that SMARCAD1 is involved in breast cancer metastasis and can be a promising target for metastatic breast cancer therapy.     

Targeting miR-205 in breast cancer

As small non-coding regulatory RNAs, microRNAs are capable of silencing gene expression by translational repression or mRNA degradation. Accumulating evidence indicates that deregulation of microRNAs is often associated with human malignancies and suggests a causal role of microRNAs in neoplasia, presumably because microRNAs can function as oncogenes or tumor suppressors. Among them, miR-205 is significantly underexpressed in breast tumors compared with matched normal breast tissue although miR-205 has been shown to be upregulated in some other type of tumors. Furthermore, breast cancer cell lines, including MCF-7 and MDA-MB-231, express a lower level of miR-205 than the non-malignant MCF-10A cells. Ectopic expression of miR-205 significantly inhibits cell proliferation and anchorage-independent growth as well as cell invasion. These findings establish the tumor suppressive role of miR-205, which is probably through direct targeting of oncogenes such as ErbB3 and Zeb1. Therefore, miR-205 may serve as a unique therapeutic target for breast cancer.     

Dual inhibition of STAT1 and STAT3 activation downregulates expression of PD-L1 in human breast cancer cells

Objectives: Breast cancer is the most commonly diagnosed cancer, and it is a leading cause of cancer-related deaths in females worldwide. Triple-negative breast cancer (TNBC) constitutes 15% of breast cancer and shows distinct metastasis profiles with poor prognosis. Strong PD-L1 expression has been observed in some tumors, supporting their escape from immune surveillance. Targeting PD-L1 could be a promising therapeutic approach in breast cancer patients. We investigated potential molecular mechanisms for constitutive expression of PD-L1 by inhibiting upstream STAT1 and STAT3 signals.

Methods: PD-L1 expression in three breast cancer cell lines was measured using quantitative PCR and western blotting. Activation of STAT1 and STAT3 was blocked using pharmacological inhibitors and siRNA. The mechanism underlying the constitutive expression of PD-L1 was investigated using ChIP and co-immunoprecipitation assays.

Results: We found that individual inhibition of STAT1 and STAT3 activation partially downregulated PD-L1, while combined inhibition completely downregulated PD-L1 expression. Moreover, our results suggest that pSTAT1-pSTAT3 dimerize in cytosol and translocate to the nucleus, where they bind to PD-L1 promoter and induce PD-L1 expression.

Conclusion: These findings provide a rationale for combined targeting of STAT1 and STAT3 for the development of immune-based cancer therapies for down regulation of PD-L1 expression.     

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.     

Non-histone nuclear factor HMGB1 as a therapeutic target in colorectal cancer

Introduction: High-motility group box (HMGB)-1 is the focus of recent cancer research. HMGB1 plays a critical role in cancer development, progression, and metastasis by activation of cancer cells, enhancement of tumor angiogenesis, and suppression of host anti-cancer immunity. HMGB1 is a relevant target for cancer treatment.

Areas covered: This review aims to overview the biological feature and diverses role in cancer of HMGB1. HMGB1 is a non-histone chromosomal protein, a secretory protein binding to the receptor for advanced glycation end products in cancer cells and monocyte-lineage immune cells, and a DNA presenting chaperon for toll-like receptors. HMGB1 enhances proliferation, motility, invasion and survival of cancer cells. In contrast, HMGB1 induces apoptosis in monocyte-lineage immune cells and inhibits tumor-infiltrating macrophages and dendritic cells, lymph node sinus macrophages and liver Kupffer cells to attenuate anti-cancer immune responses and anti-metastatic organ defense. Then the novel techniques for inhibiting HMGB1 are reviewed.

Expert opinion: Various techniques targeting HMGB1 are subjected to trial. HMGB1 targeting is a potential therapeutic techniqueagainst cancer development, progression, and especially metastasis. Technical breakthroughs in application of HMGB1 targeting to human diseases are now urgently required.     

Therapeutic targets associated to E-cadherin dysfunction in gastric cancer

Introduction: Epithelial cadherin (E-cadherin) plays a key role in epithelial cell-cell adhesion, contributing to tissue differentiation and homeostasis. Throughout the past decades, research has shed light on the molecular mechanisms underlying E-cadherin's role in tumor progression, namely in invasion and metastization. Emerging evidence established E-cadherin as a tumor suppressor and suggests that targeting E-cadherin or downstream signaling molecules may constitute effective cancer therapeutics.

Areas covered: This review aims to cover E-cadherin-mediated signaling during cancer development and progression and highlight putative therapeutic targets.

Expert opinion: Reconstitution of E-cadherin expression or targeting of E-cadherin downstream molecules holds promise in cancer therapies. Considering the high frequency of CDH1 promoter hypermethylation as a second hit in malignant lesions from hereditary diffuse gastric cancer patients, histone deacetylase inhibitors are potential therapeutic agents in combination with conventional chemotherapy, specifically in initial tumor stages. Concerning E-cadherin-mediated signaling, we propose that HER receptors (as epidermal growth factor receptor) and Notch downstream targets are clinically relevant and should be considered in gastric cancer therapeutics and control.     

月腺大戟素A通过干扰PKD1介导的MEK/ERK和PI3K/AKT信号通路抑制乳腺癌细胞增殖的研究

目的乳腺癌是世界上最致命的恶性肿瘤之一。月腺大戟素A(EA)是从中药月腺大戟中提取的乙酰间苯三酚类化合物。探讨EA抑制乳腺癌细胞MCF-7增殖的具体机制,以期为乳腺癌的临床治疗提供新的思路。方法在乳腺癌细胞MCF-7中添加不同浓度的EA药物,检测PKD1蛋白表达水平的变化。构建PKD1的过表达质粒体并转染至细胞,用实时荧光定量PCR技术和Western Blot实验检测PKD1的mRNA和蛋白表达水平。CCK-8实验用于检测细胞增殖能力的变化。Western Blot实验用于检测PKD1介导的相关信号通路中关键蛋白的表达水平。结果EA以剂量依赖的方式抑制乳腺癌细胞中PKD1蛋白的表达(P<0.05)。当转染过表达质粒后,PKD1在mRNA和蛋白水平上显著升高(P<0.001)。同时过表达PKD1显著逆转EA对MCF-7的增殖抑制作用(P<0.001)。信号通路分析证实EA通过抑制PKD1介导的MEK/ERK和PI3K/AKT信号通路活性影响乳腺癌细胞的增殖能力(P<0.05)。结论EA通过调控PKD1介导MEK/ERK和PI3K/AKT信号通路,能够抑制乳腺癌细胞的增殖。     

The potential role of estrogen receptors and the SRC family as targets for the treatment of breast cancer

Background: Breast cancer has a number of subtypes, the main ones are estrogen-receptor (ER)-positive, luminal type A and B. Treatment selection, with respect to hormonal therapy, is based upon ER expression. Whilst for ER-positive cancers, endocrine therapy is highly successful in the adjuvant setting, a significant proportion of cancers exhibit hormone resistance, often associated with altered growth factor receptor or ER signalling. Modulation of steroid receptor function by receptor co-activators or repressors is a potential mechanism of resistance. The p160 or SRC proto-oncogene family of co-activators are important in breast cancer response to endocrine therapy and can act as a paradigm of co-activator function. Objective/methods: This review focuses on the role of ER and ER co-activators in breast cancer and current approaches to targeting SRC co-factors for treatment of hormone-receptor-positive breast cancer. Results/conclusions: There is a drive to selectively apply aromatase inhibitors on the basis of either risk or biological evidence of resistance to tamoxifen treatment. Both strategies may yield improved treatment to benefit ratios.     

Oncogenic role and therapeutic target of transient receptor potential melastatin 7 channel in malignancy

Introduction: The transient receptor potential (TRP) family is a superfamily of cation channels which regulates many features of malignant cancers, such as lack of differentiation, increased migratory and invasive phenotype and chemoresistance. The TRP cation channel, TRPM7 (subfamily M, member 7), is a ubiquitous, Ca²⁺ and Mg²⁺-permeant ion channel that is unique in that it is an ion channel and a serine/threonine kinase. TRPM7 has been associated with cell proliferation, survival and development and thus correlated with growth and progression of several types of tumor cells, including breast cancer, gastric cancer, head and neck cancer, nasopharyngeal carcinoma, pancreatic cancer, prostate cancer, retinoblastoma and leukemia. Increased TRPM7 expression in human breast and pancreatic cancer tissues also correlates with clinicopathological parameters, such as tumor grade, the Ki-67 proliferation index and patient survival.

Areas covered: In this review, we focus on recent advancements in knowledge of aberrant TRPM7 channel function and its contribution to tumor progression and angiogenesis. This includes crosstalk between multiple signaling pathways. The role of TRPM7 in tumor development, particularly in regard to its channel function mediating both Ca²⁺ and Mg²⁺ influx as well as its kinase activity is also addressed. In addition, we will discuss its role in the stem cell and cancer stem cell, as well as its potential as tumor drug target.

Expert opinion: Better understanding of the structure, function and regulation of TRPM7 channel, as well as its complex crosstalk with other oncogenic signals in tumor cells will be essential to ensure rational use of treatment and development of new combinatory therapeutic possibilities.     

Atezolizumab for the treatment of non-small cell lung cancer

Introduction: The immune system can restrain or promote cancer development and growth. Antibodies targeting immune checkpoints have revolutionized cancer treatment. Among the best responses have been in non-small cell lung cancer (NSCLC) which is largely caused by chronic exposure to carcinogens; associated with high neoantigen creation and sensitization to immune recognition. Atezolizumab was the first approved antibody that targets the PD-1 ligand (PD-L1).

Areas covered: This drug profile article covers the basics of the cancer-immunity cycle and reviews some aspects of innate and adaptive immunology. We discuss the discovery of PD-L1 and PD-L2 while highlight the potential differences in targeting PD-L1 versus PD-1. In addition, we briefly summarized the available pre-clinical and clinical data of atezolizumab use in NSCLC. A special section covers the challenges of PD-L1 immunohistochemistry assay.

Expert commentary: PD-1:PD-L1 blockade has taken the lead in the immunotherapeutics field and represents the backbone of developing combination immunotherapies. Atezolizumab represents a step forward in the treatment of advanced NSCLC, nonetheless PD1:PD-L1 blockade in early-stage lung cancer is still a matter of debate.