Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis

Cancer stem cells (CSCs) are a small subpopulation of cancer cells that have increased resistance to conventional therapies and are capable of establishing metastasis. However, only a few biomarkers of CSCs have been identified. Here, we report that ganglioside GD2 (a glycosphingolipid) identifies a small fraction of cells in human breast cancer cell lines and patient samples that are capable of forming mammospheres and initiating tumors with as few as 10 GD2+ cells. In addition, the majority of GD2+ cells are also CD44hiCD24lo, the previously established CSC-associated cell surface phenotype. Gene expression analysis revealed that GD3 synthase (GD3S) is highly expressed in GD2+ as well as in CD44hiCD24lo cells and that interference with GD3S expression, either by shRNA or using a pharmacological inhibitor, reduced the CSC population and CSC-associated properties. GD3S knockdown completely abrogated tumor formation in vivo. Also, induction of epithelial-mesenchymal transition (EMT) in transformed human mammary epithelial cells (HMLER cells) dramatically increased GD2 as well as GD3S expression in these cells, suggesting a role of EMT in the origin of GD2+ breast CSCs. In summary, we identified GD2 as a new CSC-specific cell surface marker and GD3S as a potential therapeutic target for CSCs, with the possibility of improving survival and cure rates in patients with breast cancer.     

The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance

Chemotherapy in cancer patients is still not satisfactory because of drug resistance. The main mechanism of drug resistance results from the ability of cancer cells to actively expel therapeutic agents via transport proteins of the ABC family. ABCB1 and ABCG2 are the two main proteins responsible for drug resistance in cancers. Recent investigations indicate that aldehyde dehydrogenase (ALDH) can also be involved in drug resistance. Expression of the ABC transporters and ALDH enzymes is observed in normal stem cells, cancer stem cells and drug resistant cancers. Current chemotherapy regimens remove the bulk of the tumour but are usually not effective against cancer stem cells (CSCs) expressing ALDH. As a result, the number of ALDH positive drug resistant CSCs increases after chemotherapy. This indicates that therapies targeting drug resistant CSCs should be developed. A number of therapies targeting CSCs are currently under investigation. These therapies include differentiation therapy using different retinoic acids (RA) as simple agents or in combination with DNA methyltransferase inhibitors (DNMTi) and/or histone deacetylase inhibitors (HDACi). Therapies that target cancer stem cell signaling pathways are also under investigation. A number of natural compounds are effective against cancer stem cells and lead to decreasing numbers of ALDH positive cells and downregulation of the ABC proteins. Combinations of differentiation therapies or therapies targeting CSC signaling pathways with classical cytostatics seem promising. This review discusses the role of ALDH and ABC proteins in the development of drug resistance in cancer and current therapies designed to target CSCs.     

Targeting Cancer-initiating Cells With Oncolytic Viruses

Recent studies in a variety of leukemias and solid tumors indicate that there is significant heterogeneity with respect to tumor-forming ability within a given population of tumor cells, suggesting that only a subpopulation of cells is responsible for tumorigenesis. These cells have been commonly referred to as cancer stem cells (CSCs) or cancer-initiating cells (CICs). CICs have been shown to be relatively resistant to conventional anticancer therapies and are thus thought to be responsible for disease relapse. As such, they represent a potentially critical therapeutic target. Oncolytic viruses are in clinical trials for cancer and kill cells through mechanisms different from conventional therapeutics. Because these viruses are not susceptible to the same pathways of drug or radiation resistance, it is important to learn whether CICs are susceptible to oncolytic virus infection. Here we review the available data regarding the ability of several different oncolytic virus types to target CICs for destruction.     

Recent advances in the HER2 targeted therapy of gastric cancer

Recent advances in molecular targeted therapies, including targeting human epidermal growth factor receptor 2(HER2), had a major forward step in the therapy for gastric cancer patients. Application of HER2-targeted therapies, in particular trastuzumab in combination with chemotherapy in metastatic HER2-positive gastric cancers, resulted in improvements in response rates, time to progression and overall survival. Nevertheless, as with breast cancer, many patients with gastric cancer develop resistance to trastuzumab. Several promising therapies are currently being developed in combination with chemotherapy to increase the efficacy and overcome the cancerresistance. Here we review the current overview of clinical application of agents targeting HER2 in gastric cancer. We also discuss the ongoing trials supporting the use of HER2-targeted agents combined with cytotoxic agents or other monoclonal antibodies.     

乳腺癌HER-2靶向治疗的现状与发展前景

目的人表皮生长因子受体2(HER2)是表皮生长因子受体(EGFR或Er Bb)家族中扮演中心角色的一个成员。本文对HER2靶向治疗的现状与发展方向作一综述。方法查阅Pubmed、中国知网、万方、维普等数据库与乳腺癌HER2靶向治疗方面相关的文章,共纳入52篇文献。结果 HER2信号能够调节细胞增殖、存活和分化,与乳腺癌、胃癌、肺癌与卵巢癌等多种肿瘤的发生发展密切相关。目前使用的HER2靶向治疗有助于改善临床化疗药物疗效、提高患者无疾病生存期和5年存活率,但肿瘤的耐药性也越来越严重,已经引起人们的关注。结论 HER2靶向治疗对提高HER2阳性乳腺癌患者治疗效果起到重要作用,其耐药性需要进一步研究解决。     

Nursing perspectives on fulvestrant for the treatment of postmenopausal women with metastatic breast cancer

Fulvestrant is an estrogen receptor antagonist indicated for the treatment of hormone receptor-positive metastatic breast cancer (MBC) in postmenopausal women with disease progression following antiestrogen therapy. Fulvestrant has a different mechanism of action than other hormonal therapies, including aromatase inhibitors and tamoxifen. In clinical trials of postmenopausal women with MBC, fulvestrant was effective and well tolerated compared to anastrozole after failure of tamoxifen. The monthly injection regimen of fulvestrant provides nurses with an additional opportunity to improve patient adherence to hormonal therapy, reinforce patient education, and monitor side effects. Several ongoing trials will elucidate the role of fulvestrant in the treatment of MBC. Issues that are being addressed in those trials include alternative doses and schedules, efficacy and safety in other patient populations, and the development of novel treatment combinations. This article provides oncology nurses with the knowledge needed to educate patients on the use of fulvestrant, to effectively administer this medication, and to prevent and manage potential side effects.     

The therapeutic promise of the cancer stem cell concept

Cancer stem cells (CSCs) are a subpopulation of tumor cells that selectively possess tumor initiation and self-renewal capacity and the ability to give rise to bulk populations of nontumorigenic cancer cell progeny through differentiation. As we discuss here, they have been prospectively identified in several human malignancies, and their relative abundance in clinical cancer specimens has been correlated with malignant disease progression in human patients. Furthermore, recent findings suggest that clinical cancer progression driven by CSCs may contribute to the failure of existing therapies to consistently eradicate malignant tumors. Therefore, CSC-directed therapeutic approaches might represent translationally relevant strategies to improve clinical cancer therapy, in particular for those malignancies that are currently refractory to conventional anticancer agents directed predominantly at tumor bulk populations.     

NSABP breast cancer clinical trials: recent results and future directions

Over the past 40 years, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has conducted several large, randomized clinical trials evaluating various aspects of surgical and adjuvant therapy in patients with operable breast cancer. Results from these trials have contributed significantly in reducing the extent of surgical procedures and in improving the outcome of patients with early-stage breast cancer. Furthermore, they have helped to establish standards of care for the surgical management of invasive and non-invasive disease and for the use of adjuvant hormonal therapy and adjuvant chemotherapy for patients with negative as well as for those with positive axillary nodes. More recent trials are evaluating several new classes of promising drugs such as the aromatase inhibitors in postmenopausal women with invasive or intraductal breast cancer, the taxanes for patients with positive nodes and in the neoadjuvant setting and other targeted molecular therapies such as trastuzumab and bisphosphonates. Results from these ongoing and recently completed trials could improve outcomes and quality of life for patients with early-stage breast cancer.     

Targeting metastatic and advanced breast cancer

OBJECTIVES: To review the chemotherapy and targeted biologic options for treatment of advanced and metastatic breast cancer. DATA SOURCES: Clinical and research articles and textbook chapters. CONCLUSION: Recent clinical research has led to the use of novel targeted therapies in the management of locally advanced and metastatic breast cancer. Although metastatic breast cancer remains incurable, increases in disease-free and overall survival has been achieved. IMPLICATIONS FOR NURSING PRACTICE: Recent advances in the biological targeted therapies against Her2/neu, VEGF, and EGFR are now either approved therapies or are in the final stages of clinical testing. Oncology nurses can help decrease toxicities and maintain better QOL by fully understanding the mechanism of action of the drugs, expected side effects, and anticipated response to the novel regimen.     

Hormono-biological therapy in metastatic breast cancer: preclinical evidence, clinical studies and future directions

Breast cancer growth is regulated by coordinated actions of the estrogen receptor (ER) and various growth factor receptor signalling pathways. This complex interactive signalling potentially explains some of the reasons behind endocrine therapy action and resistance. Recent research into the molecular biology of ER signalling has revealed new molecular targets which, if present in cancer cells, might be additionally targeted using various signal transduction inhibitors to overcome or prevent resistance to endocrine therapy. The dynamic inverse relationship between the expression of ER and growth factor receptors brings more excitement to the potential of restoring ER expression in apparently ER-negative cells by inhibition of growth factor signalling. The multiple pathways involved in activating ERs also provide a rationale for combining endocrine and non-endocrine therapies that block different signalling pathways. Ongoing clinical trials promise to further improve the present care for breast cancer patients.     

Pinostrobin inhibits proliferation and induces apoptosis in cancer stem-like cells through a reactive oxygen species-dependent mechanism

Current treatments and targeted therapies for malignancies are limited due to their severe toxicity and the development of resistance against such treatments, which leads to relapse. Past evidence has indicated that a number of plant-derived dietary agents possess biological activity against highly tumorigenic and resistant cell populations associated with cancer relapse. These subpopulations, termed cancer stem-like cells (CSCs), have been targeted with plant-derived dietary flavonoids. The present study was undertaken to assess the anti-proliferative potential of pinostrobin, a dietary flavonoid, against CSCs. Sphere-forming cells were developed from HeLa cell lines using specific culture conditions. The existence of a CSC population was confirmed by the morphological examination and analysis of surface markers using confocal microscopy and flow cytometry. The effect of pinostrobin on the cell viability of the CSC population, evaluated through MTT reduction assays and the expression levels of surface markers (CD44⁺ and CD24⁺), was studied through various biological assays. HeLa-derived CSCs showed higher CD44⁺ and lower CD24⁺ expression. Pinostrobin inhibited the self-renewal capacity and sphere formation efficiency of CSCs in a dose-dependent manner. Increased ROS production, and decreased mitochondrial membrane potential and CD44⁺ expression indicated that pinostrobin promoted ROS-mediated apoptosis in CSCs. These results thus demonstrate the therapeutic potential and effectiveness of pinostrobin in the chemoprevention and relapse of cancer by targeting the CSC population. Thus, pinostrobin, in combination with currently available chemo and radiation therapies, could possibly be used as a safe strategy to alleviate adverse treatment effects, together with enhancing the efficacy.

The anti-proliferative potential of pinostrobin, a dietary flavonoid, is evaluated against cancer stem-like cells.     

Metastatic breast cancer: an updating.

This article reports on recent advances on metastatic breast cancer. Detection, prognostic factors, predictors of response to therapy and therapy, with particular regard to targeted therapies, were examined. DETECTION: Unlike current guidelines that yet do not routinely recommend intensive clinical-instrumental post-operative follow-up of breast cancer patients, relatively large data collected in the last decades have shown that an intensive post-operative follow-up with 'dynamic evaluation' of a suitable tumour marker panel precedes a few months as average the clinical and/or instrumental sign of a pending relapse in most relapsed patients and largely limits the use of the common instrumental examinations. PROGNOSIS AND THERAPY PREDICTORS: Disease-free interval (DFI)24 months and disease confined to bony skeleton are prognostic factors more often correlated with relatively poor or prolonged survival, respectively. Estrogen receptor (ER) expression in primary tumour and at the relapse correlates strongly with response to salvage hormone therapy and data from large trials showed that 38-59% of ER and/or PR+ post-menopausal patients had clinical benefit from first line tamoxifen or aromatase inhibitors. An inverse correlation of ER with epidermal growth factor receptor (EGFR) has been found. The co-expression of HER-2/neu and/or elevated serum HER-2/neu protein level were associated with a low rate and shorter duration of response of ER+ patients to first line hormone therapy. Accordingly, ER-EGFR- compared with ER-EGFR+ tumours are usually more responsive to endocrine therapy. High class III beta-tubulin expression or fall in insulin-like growth factor binding protein-3 (IGFBP-3) from baseline levels have been found to significantly predict resistance to chemotherapeutic agents. THERAPY: Liposomes as carrier of doxorubicin (Caelix, Evacet, Myocet) is one approach to decrease the anthracycline-related cardiac toxicity. Weekly paclitaxel or docetaxel and oral formulation of vinorelbine and 5-fluorouracil (5-FU) (capecitabine) provide new effective and well tolerated options that reach greater dose intensity and cumulative dose than with the conventional schedules. As to the so called 'tailored' or targeted therapies, the more potent and highly selective third generation of aromatase inhibitors (letrozole, anastrozole, exemestane) targeting ER+ tumours by estrogen deprivation, challenge tamoxifen as current standard first line therapy in postmenopausals. One pilot study showed that stimulation of cellular immunity by the addition of beta-interferon-interleukin-2 sequence in patients on clinical benefit on first line tamoxifen significantly prolonged median overall survival (OS) and duration of response compared to that observed in similar patients only treated with tamoxifen. Trastuzumab, a humanised monoclonal antibody to extracellular domain of HER-2, plus conventional chemotherapy has become a standard of care for women with overexpressing HER-2 tumours. Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor (VEGF) that in refractory metastatic breast cancer doubled the response rate of capecitabine although it did not affect survival. Finally, the so called 'oligometastatic' and a few stage IV diseases are conditions amenable to be rendered with no evidence of disease (NED) after local surgery and/or radiation. In both, as well as in complete responders to chemotherapy, minimal residual disease (m.r.d.) likely continues to be present. Recent data suggest that 'biological' therapy (immunomodulators and/or retinoids with or without hormone therapy), might be suitable to be successfully tested in these patients as maintenance treatment given soon after local intervention or chemotherapy.     

Dual or multiple drug loaded nanoparticles to target breast cancer stem cells

Breast cancer stem(-like) cells (BCSCs) have been found to be responsible for therapeutic resistance and disease relapse. BCSCs are difficult to eradicate due to their high resistance to conventional treatments and high plasticity. Functionalised nanoparticles have been investigated as smart vehicles to transport across various barriers and increase the interaction of therapeutic agents with cancer cells, as well as BCSCs. In this review, we discuss the different characteristics of BCSCs, and challenges to tackle BCSCs at cellular and molecular levels. The mechanisms of action and physicochemical properties of the current BCSC targeting agents are also covered. We will focus on the rational design and recent advances of “Nano + Nano” or single tumour targeting nanoparticle systems loaded with dual or multiple agents to kill all cancer cells including BCSCs. These cocktail therapies include the combination of a chemotherapy agent with a BCSC-specific inhibitor, a phytochemical agent or RNA based therapy. Given the heterogeneity of breast tumour tissue, targeting both BCSCs and bulk breast cancer cells simultaneously with multiple agents holds great promise in eliminating breast cancer. The future research needs to focus on overcoming various barriers in the ‘clinical translation’ of BCSC-targeting nanomedicines to cure breast cancer, which requires a significant multidisciplinary effort.

Breast cancer stem(-like) cells (BCSCs) have been found to be responsible for therapeutic resistance and disease relapse.     

Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer

INTRODUCTION: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) that combines intracellular delivery of the potent cytotoxic agent, DM1 (a derivative of maytansine) with the antitumor activity of trastuzumab. While there are several ADCs in Phase III development, T-DM1 is the only one in which the targeting antibody has antitumor properties. T-DM1 is also the only ADC that is directed toward the human EGFR 2 (HER2). Effective therapies are limited in HER2-positive advanced or metastatic breast cancer (MBC), particularly following progression on available HER2-targeted therapies. AREAS COVERED: The mechanisms of action, preclinical efficacy and clinical profile of T-DM1 are reported. The latest preclinical and clinical data for T-DM1 are examined. EXPERT OPINION: T-DM1 has significant antitumor potency in vitro and in vivo, which is maintained in tumors resistant to trastuzumab or lapatinib. In Phase I and II trials, T-DM1 provided objective tumor responses and was well tolerated across various lines of therapy in patients with HER2-positive MBC. In addition, it showed similar efficacy to trastuzumab plus docetaxel in first-line MBC. Ongoing trials (including two Phase III studies) are investigating T-DM1 as single-agent therapy or combined with other chemotherapeutic or biologic agents, and the results should help to define the place of T-DM1 within current treatment algorithms for HER2-positive disease.     

Cetuximab in non-melanoma skin cancer

Human epidermal growth factor receptor 2 (HER2) was acknowledged as an important therapeutic target in breast cancer more than 25 years ago. Subsequently, significant basic science and translational discoveries have resulted in the approval of four HER2-targeted therapies over the past 15 years. This editorial discusses future challenges regarding selection and development of treatments for HER2-positive breast cancer, which can only be met by continuing to support research efforts into the basic mechanisms by which cancer cells escape targeted therapies. Identifying specific molecular mechanisms underlying the sensitivity or resistance to each HER2-targeted agent will ultimately allow individualized therapy for each patient.     

The role of gene therapy in combined modality treatment strategies for cancer

Multimodality therapy has been widely used in cancer treatment for enhancing efficacy, reducing toxicity, and preventing or delaying development of resistance. However, as the difference in biochemical signals between normal and malignant cells is usually trivial, combinations of conventional therapies often cause intolerably high levels of toxicity in most cancer patients. Gene therapy uses genetically encoded functions to attack molecular events involved in the development and maintenance of malignancies, providing a molecular approach to eradicate cancer cells or to protect normal cells from the toxicity of conventional therapies. Furthermore, gene therapy can also be used to augment biochemical signals required for effective chemotherapy and radiotherapy. Recent preclinical studies have shown that synergistic effects can be achieved by combining gene therapy and conventional anticancer therapies. Moreover, several phase I/II clinical studies have demonstrated that anticancer gene therapy is well tolerated and that combining gene therapy with chemotherapy, radiotherapy, or both, resulted in enhanced antitumor activity without increased toxicity. Favorable clinical responses, including a pathologically complete response, have been reported in a subset of patients with advanced disease or with cancers resistant to chemotherapy or radiotherapy. Thus, combining gene therapy and conventional therapies may provide an improvement in the treatment of cancers, especially for those resistant to conventional therapies. This review focuses on the most recent achievements in cancer treatment by combining gene therapy with conventional therapies.     

The utility of MRI for the screening and staging of breast cancer

INTRODUCTION & BACKGROUND: Contrast-enhanced magnetic resonance imaging (MRI) of the breast has been recently introduced as a potential clinical tool for the detection, diagnosis, staging and management of breast cancer. In this article, we consider the established and evolving roles of MRI with particular reference to screening in high risk women and staging of the primary tumour. Controversies are discussed in the context of the tumour biology and natural history of breast cancer. METHODS: Articles were identified by searches of PubMed and MEDLINE up to October 2007. RESULTS: Contrast-enhanced MRI is an effective tool for screening women at high risk of breast cancer. However, randomized trials have yet to demonstrate a reduction in mortality. MRI can also facilitate local staging, in particular, the evaluation of ipsilateral multicentric or multifocal lesions and synchronous contralateral disease which may be 'missed' by conventional imaging. However, efficacy with respect to clinically relevant and patient oriented end-points has yet to be addressed in the context of clinical trials. CONCLUSIONS: In women at high risk of breast cancer, screening MRI should be used in conjunction with published guidelines. In women with newly diagnosed breast cancer, the utility of MRI is less clearly defined and should be restricted to selected cases within the multidisciplinary setting.     

Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer

Introduction: Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) that combines intracellular delivery of the potent cytotoxic agent, DM1 (a derivative of maytansine) with the antitumor activity of trastuzumab. While there are several ADCs in Phase III development, T-DM1 is the only one in which the targeting antibody has antitumor properties. T-DM1 is also the only ADC that is directed toward the human EGFR 2 (HER2). Effective therapies are limited in HER2-positive advanced or metastatic breast cancer (MBC), particularly following progression on available HER2-targeted therapies.

Areas covered: The mechanisms of action, preclinical efficacy and clinical profile of T-DM1 are reported. The latest preclinical and clinical data for T-DM1 are examined.

Expert opinion: T-DM1 has significant antitumor potency in vitro and in vivo, which is maintained in tumors resistant to trastuzumab or lapatinib. In Phase I and II trials, T-DM1 provided objective tumor responses and was well tolerated across various lines of therapy in patients with HER2-positive MBC. In addition, it showed similar efficacy to trastuzumab plus docetaxel in first-line MBC. Ongoing trials (including two Phase III studies) are investigating T-DM1 as single-agent therapy or combined with other chemotherapeutic or biologic agents, and the results should help to define the place of T-DM1 within current treatment algorithms for HER2-positive disease.     

PARP inhibitors in breast cancer

The therapeutic implications of DNA damage in cancer therapy have long been appreciated and form the basis of many successful cytotoxic chemotherapy and radiotherapy treatment strategies. A novel class of DNA repair defect targeted therapeutics that inhibit poly (ADP-Ribose) polymerase (PARP) are being rapidly developed in breast cancer based on exciting preliminary clinical activity as single agents in BRCA mutation-associated breast cancer and in combination with chemotherapy in triple-negative breast cancer. Though there is widespread enthusiasm to move these drugs forward quickly, much remains to be understood about the optimal use of the novel agents. Here we review the clinical development of PARP inhibitors in breast cancer and highlight clinical trials in progress. We also provide commentary on a series of outstanding questions in the field, the answers to which will be critical for the successful development of PARP inhibitor-based strategies in early- and late-stage breast cancer.     

Bevacizumab treatment of prostate cancer

Introduction: Angiogenesis plays an important role in the development and progression of prostate cancer. Vascular endothelial growth factor (VEGF) is a primary mediator of this process and is a target for novel therapies. Bevacizumab is a recombinant anti-VEGF monoclonal antibody that has demonstrated antitumor activity in a variety of cancers. Areas covered: In this review, we present the results of several clinical trials for bevacizumab in prostate cancer. Overall, these trials have shown improvements in progression-free survival but no changes in overall survival. Ongoing clinical trials are testing bevacizumab in combination with novel cytotoxic drugs and targeted therapies in metastatic and localized settings. Expert opinion: Bevacizumab has biological activity in prostate cancer. However, the mixed clinical trial results support the theory that prostate cancers may be driven only in part by angiogenesis. Questions remain about the future role of bevacizumab in the treatment of prostate cancer.