Nanocarrier-mediated drugs targeting cancer stem cells: an emerging delivery approach

Introduction: Cancer stem cells (CSCs) play an important role in the development of drug resistance, metastasis and recurrence. Current conventional therapies do not commonly target CSCs. Nanocarrier-based delivery systems targeting cancer cells have entered a new era of treatment, where specific targeting to CSCs may offer superior outcomes to efficient cancer therapies.

Areas covered: This review discusses the involvement of CSCs in tumor progression and relevant mechanisms associated with CSCs resistance to conventional chemo- and radio-therapies. It highlights CSCs-targeted strategies that are either under evaluation or could be explored in the near future, with a focus on various nanocarrier-based delivery systems of drugs and nucleic acids to CSCs. Novel nanocarriers targeting CSCs are presented in a cancer-specific way to provide a current perspective on anti-CSCs therapeutics.

Expert opinion: The field of CSCs-targeted therapeutics is still emerging with a few small molecules and macromolecules currently proving efficacy in clinical trials. However considering the complexities of CSCs and existing delivery difficulties in conventional anticancer therapies, CSC-specific delivery systems would face tremendous technical and clinical challenges. Nanocarrier-based approaches have demonstrated significant potential in specific drug delivery and targeting; their success in CSCs-targeted drug delivery would not only significantly enhance anticancer treatment but also address current difficulties associated with cancer resistance, metastasis and recurrence.     

Approaches for targeting cancer stem cells drug resistance

ABSTRACT

Introduction: Several reports have suggested that a population of undifferentiated cells known as cancer stem cells (CSCs), is responsible for cancer formation and maintenance. In the last decade, the presence of CSCs in solid cancers have been reported.

Areas covered: This review summarizes the main approaches for targeting CSCs drug resistance. It is indeed known that CSCs may contribute to resistance to conventional chemotherapy, radiotherapy and targeted agents. Among the mechanisms by which CSCs escape anticancer therapies, removal of therapeutic agents by drug efflux pumps, enhanced DNA damage repair, activation of mitogenic/anti-apoptotic pathways; the main features of CSCs, stemness and EMT, are involved, as well as the capability to evade immune response.

Expert opinion: Different approaches are suitable to target CSCs mediated drug resistance. Some of them are currently under clinical evaluation in different cancer types. A better understanding of CSC biology, as well as more accurate study design, may maximize the therapeutic effects of these agents. In this respect, it is important to establish: (i) which molecules should be targeted; (ii) what drug combinations may be suitable; (iii) which patient settings will CSC targeting offer the highest clinical benefit; and (iv) how to integrate therapeutic approaches targeting CSCs with standard cancer therapy.     

The cancer stem cell paradigm: a new understanding of tumor development and treatment

Importance of the field: Cancer is the second leading cause of death in the United States, and therefore remains a central focus of modern medical research. Accumulating evidence supports a ‘cancer stem cell’ (CSC) model – where cancer growth and/or recurrence is driven by a small subset of tumor cells that exhibit properties similar to stem cells. This model may provide a conceptual framework for developing more effective cancer therapies that target cells propelling cancer growth.

Areas covered in this review: We review evidence supporting the CSC model and associated implications for understanding cancer biology and developing novel therapeutic strategies. Current controversies and unanswered questions of the CSC model are also discussed.

What the reader will gain: This review aims to describe how the CSC model is key to developing novel treatments and discusses associated shortcomings and unanswered questions.

Take home message: A fresh look at cancer biology and treatment is needed for many incurable cancers to improve clinical prognosis for patients. The CSC model posits a hierarchy in cancer where only a subset of cells drive malignancy, and if features of this model are correct, has implications for development of novel and hopefully more successful approaches to cancer therapy.     

p53–Mdm2 inhibitors: patent review (2009 – 2010)

Introduction: p53 plays a central role in protecting the integrity of the genome. Its activity is ubiquitously lost in cancers, either by inactivation of its protein (p53 pathway) or by mutation in the p53 gene, thereby indicating its importance in understanding cancer and as a therapeutic target. Activated p53 is known to induce cell cycle arrest thereby leading to apoptosis and has been the subject of intensive research in the area of medicinal chemistry. Efforts are in progress to synthesize a variety of scaffolds that could inhibit the p53–Mdm2 interaction by binding to Mdm2 in the region where p53 is likely to bind. These molecules have the potential to be developed as anticancer drug candidates and have been largely explored by both academia and industry. Interestingly, some of these molecules are in the early stage of clinical trials.

Areas covered: Areas covered in this review include patents relating to p53–Mdm2 inhibitors during the time period 2009 – 2010. The focus of the review was on small-molecule inhibitors.

Expert opinion: Inducing apoptosis in cancerous cells by the activation of p53 is an area that is being actively explored. There are strong indications that it could become a therapeutic method for the treatment of cancer. As a result, extensive research is being performed by both academia and industry. It is observed that small molecules that are present in early clinical trials are expected to be developed as potential drugs for cancer therapy.     

Targeting the Wnt/β-catenin signaling pathway in human cancers

Introduction: The Wnt/β-catenin signaling pathway plays a pivotal role in the regulation of cell growth, cell development and the differentiation of normal stem cells. Constitutive activation of the Wnt/β-catenin signaling pathway is found in many human cancers, and is thus an attractive target for anti-cancer therapy. Specific inhibitors of this pathway have been keenly researched and developed.

Areas covered: This review discusses the potential of inhibiting the Wnt/β-catenin signaling pathway, as a therapeutic approach for cancer, along with an overview of the development of specific inhibitors.

Expert opinion: Cancer stem cells (CSCs) play a significant role in the development and recurrence of several cancers, and Wnt/β-catenin signaling is important for the proliferation of CSCs. Inhibition of Wnt/β-catenin signaling is therefore a promising treatment approach. Progress has been made in the development of screening methods to identify Wnt/β-catenin signaling inhibitors. Biomarker-based screening is an effective and promising method for the identification of compounds of interest.     

Cancer stem cell patents

Background: Cancer stem cells (CSCs) are a small subpopulation of the tumour mass that are capable of sustaining its growth, are resistant to many cancer specific therapies, and can reinitiate disease relapse. CSCs are resistant to current cancer treatments due to specialised transporters, cell cycle changes, DNA repair and antiapoptotic mechanisms. Objective: This paper reviews CSC biology and diagnostic and therapeutic patents as well as those associated with the isolation of CSCs. Methods: Literature and patent searches using the NCBI PubMed, European Patent Office, Scopus, and PATENTSCOPE^® websites were conducted to examine and link CSC biology and therapy development with current patent literature. Conclusion: Development in basic CSC biology research is increasing the patents filed in this area; however, therapeutic patents directly targeting CSCs are more limited, as research in this area remains in its infancy.     

Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy

Introduction: Pancreatic adenocarcinoma remains one of the most clinically challenging cancers despite an in-depth characterization of the molecular underpinnings and biology of this disease. Recent whole-genome-wide studies have elucidated the diverse and complex genetic alterations which generate a unique oncogenic signature for an individual pancreatic cancer patient and which may explain diverse disease behavior in a clinical setting.

Areas covered: In this review article, we discuss the key oncogenic pathways of pancreatic cancer including RAS-MAPK, PI3KCA and TGF-β signaling, as well as the impact of these pathways on the disease behavior and their potential targetability. The role of tumor suppressors particularly BRCA1 and BRCA2 genes and their role in pancreatic cancer treatment are elaborated upon. We further review recent genomic studies and their impact on future pancreatic cancer treatment.

Expert opinion: Targeted therapies inhibiting pro-survival pathways have limited impact on pancreatic cancer outcomes. Activation of pro-apoptotic pathways along with suppression of cancer-stem-related pathways may reverse treatment resistance in pancreatic cancer. While targeted therapy or a ‘precision medicine’ approach in pancreatic adenocarcinoma remains an elusive challenge for the majority of patients, there is a real sense of optimism that the strides made in understanding the molecular underpinnings of this disease will translate into improved outcomes.     

Galanin receptor subtypes 1 and 2 as therapeutic targets in head and neck squamous cell carcinoma

Importance of the field: Despite advances in the therapeutic approaches for head and neck squamous cell carcinoma (HNSCC) at some sites, no substantial improvement in treatment efficacy and survival has occurred over the past several decades. Recent application of molecular biology has focused on the importance of galanin and its receptors as potential therapeutic targets for HNSCC.

Areas covered in this review: Our aim is to examine galanin receptor 1 (GALR1) and galanin receptor 2 (GALR2) as HNSCC therapeutic targets and explore opportunities and strategies for making use of GALR1 and GALR2 signaling.

What the reader will gain: This review provides recent data about galanin receptor signaling and function in various cell types, especially HNSCC. Signaling through GALR1 induces cell cycle arrest and suppresses proliferation in HNSCC. Similar to GALR1, GALR2 not only induces cell cycle arrest but also apoptosis, which was not observed with GALR1.

Take home messages: GALR1 and GALR2 act as tumor suppressors in HNSCC, in a p53-independent manner. The current data suggest that GALR1 and GALR2 are potentially significant therapeutic targets and prognostic factors in HNSCC.     

Advances in stem cells,induced pluripotent stem cells,and engineered cells: delivery vehicles for anti-glioma therapy

Introduction: A limitation of small molecule inhibitors, nanoparticles (NPs) and therapeutic adenoviruses is their incomplete distribution within the entirety of solid tumors such as malignant gliomas. Currently, cell-based carriers are making their way into the clinical setting as they offer the potential to selectively deliver many types of therapies to cancer cells.

Areas covered: Here, we review the properties of stem cells, induced pluripotent stem cells and engineered cells that possess the tumor-tropic behavior necessary to serve as cell carriers. We also report on the different types of therapeutic agents that have been delivered to tumors by these cell carriers, including: i) therapeutic genes; ii) oncolytic viruses; iii) NPs; and iv) antibodies. The current challenges and future promises of cell-based drug delivery are also discussed.

Expert opinion: While the emergence of stem cell-mediated therapy has resulted in promising preclinical results and a human clinical trial utilizing this approach is currently underway, there is still a need to optimize these delivery platforms. By improving the loading of therapeutic agents into stem cells and enhancing their migratory ability and persistence, significant improvements in targeted cancer therapy may be achieved.     

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.     

Cancer stem cell-targeted therapeutics and delivery strategies

Introduction: Cancer initiating or stem cells (CSCs) are a small population of cells in the tumor mass, which have been reported to be present in different types of cancers. CSCs usually reside within the tumor and are responsible for reoccurrence of cancer. The imprecise, inaccessible nature and increased efflux of conventional therapeutic drugs make these cells resistant to drugs. We discuss the specific markers for identification of these cells, role of CSCs in chemotherapy resistance and use of different therapeutic means to target them, including elucidation of specific cell markers, exploitation of different signaling pathways and use of nanotechnology.

Area covered: This review covers cancer stem cell signaling which are used by these cells to maintain their quiescence, stemness and resistant phenotype, distinct cell surface markers, contribution of these cells in drug resistance, inevitability to cure cancer and use of nanotechnology to overcome this hurdle.

Expert opinion: Cancer stem cells are the main culprit of our failure to cure cancer. In order to cure cancer along with other cells types in cancer, cancer stem cells need to be targeted in the tumor bed. Nanotechnology solutions can facilitate clinical translation of the therapeutics along with other emerging technologies to cure cancer.     

Patented inhibitors of p53–Mdm2 interaction (2006 – 2008)

Importance of the field: Induction of apoptosis by reactivation of p53 in cancer cells is an emerging therapeutic concept for the treatment of cancer. The discovery and design of novel small molecules that block the p53–Mdm2 protein interaction, thereby activating p53, has provided interesting drug candidates that have currently entered clinical trials or are at the preclinical development stage.

Areas covered in this review: A selection of the interesting patents focusing on small molecule inhibitors of the p53–Mdm2 interaction, recorded from 2006 until 2009, is presented together with a review of the related structural chemistry space.

What the reader will gain: Readers will rapidly gain an overview of the majority of patented scaffolds of small molecule inhibitors of the p53–Mdm2 protein–protein interaction and learn about current limitations and properties of these compounds.

Take home message: The discovery p53–Mdm2 protein–protein interaction inhibitors have delivered new potential options for a targeted cancer therapy with drug-like, non-toxic small molecules. If successful, this approach could gain considerably more attention in the pharmaceutical industry by targeting a variety of validated intracellular protein–protein interactions.     

The clinical development of p53-reactivating drugs in sarcomas – charting future therapeutic approaches and understanding the clinical molecular toxicology of Nutlins

Introduction: The majority of human sarcomas, particularly soft tissue sarcomas, are relatively resistant to traditional cytotoxic therapies. The proof-of-concept study by Ray-Coquard et al., using the Nutlin human double minute (HDM)2-binding antagonist RG7112, has recently opened a new chapter in the molecular targeting of human sarcomas.

Areas covered: In this review, the authors discuss the challenges and prospective remedies for minimizing the significant haematological toxicities of the cis-imidazole Nutlin HDM2-binding antagonists. Furthermore, they also chart the future direction of the development of p53-reactivating (p53-RA) drugs in 12q13–15 amplicon sarcomas and as potential chemopreventative therapies against sarcomagenesis in germ line mutated TP53 carriers. Drawing lessons from the therapeutic use of Imatinib in gastrointestinal tumours, the authors predict the potential pitfalls, which may lie in ahead for the future clinical development of p53-RA agents, as well as discussing potential non-invasive methods to identify the development of drug resistance.

Expert opinion: Medicinal chemistry strategies, based on structure-based drug design, are required to re-engineer cis-imidazoline Nutlin HDM2-binding antagonists into less haematologically toxic drugs. In silico modelling is also required to predict toxicities of other p53-RA drugs at a much earlier stage in drug development. Whether p53-RA drugs will be therapeutically effective as a monotherapy remains to be determined.     

Targeting of cancer stem cells by inhibitors of DNA and histone methylation

Introduction: Curative chemotherapy should target cancer stem cells (CSCs). The key characteristics of CSCs are a block in differentiation and an epigenetic signature similar to embryonic stem cells (ESCs). Differentiation by ESCs and CSCs is suppressed by gene silencing through the polycomb repressive complex 2 (PRC2) and/or DNA methylation. PRC2 contains the EZH2 subunit, which catalyzes the trimethylation of histone 3 lysine 27, a gene silencing marker. It is possible to reverse this ‘double lock’ mechanism using a combination of inhibitors of EZH2 and DNA methylation (5-aza-2’-deoxycytidine), which exhibits remarkable synergistic antineoplastic activity in preclinical studies.

Areas covered: The authors discuss several specific EZH2 inhibitors that have been synthesized with antineoplastic activity. One such inhibitor, EPZ-6438 (E7438), has been shown to be effective against lymphoma in a Phase I study. The indirect EZH2 inhibitor, 3-deazaneplanocin-A (DZNep), also exhibits remarkable anticancer activity due to its inhibition of methionine metabolism.

Expert opinion: Agents that target EZH2 warrant Phase I trials. Due to its positive pharmacodynamics, DZNep merits a high priority for clinical investigation. Agents that show positive results in Phase I studies should be advanced to clinical trials for use in combination with 5-aza-2’-deoxycytidine due to the interesting potential of this epigenetic therapy to target CSCs.     

Targeting CD133 antigen in cancer

Background: Much attention has been focused on CD133 as a marker of cancer cells with stem-cell-like ability. In the cancer stem cells (CSCs) model, only a small proportion of tumour cells are able to self-renew extensively, while the bulk of cells proceed to differentiate into committed heterogeneous clones. On the basis of the involvement of CSCs in tumourigenesis and treatment resistance, it is conceivable that only eradication of CSCs can lead to a cancer cure. Objective: To highlight the most recent evidence about the role of CD133 as a marker of CSCs in human tumours, and the therapeutic perspectives associated with its specific targeting. Methods: A literature search through Medline to locate published full articles using the following key words for selection: ‘CD133 and cancer targeting’, ‘CD133 and chemo resistance’, and ‘CD133 and molecular pathways’. Only studies in English are considered. Results/Conclusions: The role of CD133 as a marker of CSCs has been documented in several human neoplasms; its expression seems to predict unfavourable prognosis. Novel therapeutic strategies aimed at targeting molecular pathways critical for CD133⁺ CSCs survival are being examined.     

CD133 as a target for colon cancer

Introduction: Recent evidence based on cancer stem cell (CSC) models, is boosting the progress of translational research and providing relevant clinical implications in many tumour types, including colorectal cancer. The current failure of standard therapies is attributed to a small fraction of the primary cell population with stem-like characteristics, such as self-renewal and differentiation. Identification of CSCs is based on two different criteria of selection: stemness-selective conditions and direct isolation based on putative stem cell markers expression. CD133, a transmembrane glycoprotein, was associated with tumor-initiating cells derived from several histological variants of tumors, including colon.

Areas covered: In this review the current understandings about CD133 as putative marker of tumour-initiating cells in colorectal cancer (CRC) is described. The focus of the discussion is on the need for additional markers to better identify the cell population able to recapitulate the parental tumor in immunocompromised mice.

Expert opinion: Identification and characterization of CSCs represents a relevant issue to define innovative therapeutic approaches, overcoming the emergence of cancer cell clones capable of evading standard therapy.     

Targeting CSCs within the tumor microenvironment for cancer therapy: a potential role of mesenchymal stem cells

Introduction: Mesenchymal stem cells (MSCs) are one subgroup of adult stem cells and possess a proliferative potential and ability to differentiate into various ceells.

Areas covered: Emerging evidence suggests that MSCs can reprogram toward cancer stem cells (CSCs), due to alterations of intrinsic and extrinsic microenvironments, leading to tumorigenesis. The CSC concept has fundamental clinical implications because of its involvement in cell migration/invasion, metastasis, and treatment resistance. Therefore, targeting CSCs provides a novel therapeutic strategy for cancer treatment. However, the origin of CSCs and its molecular connections are not fully understood. Emerging evidence suggests the existence of an inter-relationship between CSCs and epithelial-to-mesenchymal transition (EMT) phenotypic cells, in the context of inflammation and hypoxia, as well as the potential role of miRNAs.

Expert opinion: We suggest that targeting CSC signatures along with EMT, inflammation, and hypoxia will provide a more effective therapeutic approach for the elimination of CSCs. To that end, curcumin especially its synthetic novel analog CDF have been shown to attenuate CSC characteristics along with the deregulation of multiple pathways and miRNAs, leading to the inhibition of human tumor growth in vivo, suggesting the potential role of CDF as an anti-tumor agent for the prevention/treatment of tumor progression.     

Nanoparticles for imaging and treatment of metastatic breast cancer

Introduction: Metastatic breast cancer is one of the most devastating cancers that have no cure. Many therapeutic and diagnostic strategies have been extensively studied in the past decade. Among these strategies, cancer nanotechnology has emerged as a promising strategy in preclinical studies by enabling early identification of primary tumors and metastases, and by effective killing of cancer cells.

Areas covered: This review covers the recent progress made in targeting and imaging of metastatic breast cancer with nanoparticles, and treatment using nanoparticle-enabled chemo-, gene, photothermal- and radio-therapies. This review also discusses recent developments of nanoparticle-enabled stem cell therapy and immunotherapy.

Expert opinion: Nanotechnology is expected to play important roles in modern therapy for cancers, including metastatic breast cancer. Nanoparticles are able to target and visualize metastasis in various organs, and deliver therapeutic agents. Through targeting cancer stem cells, nanoparticles are able to treat resistant tumors with minimal toxicity to healthy tissues/organs. Nanoparticles are also able to activate immune cells to eliminate tumors. Owing to their multifunctional, controllable and trackable features, nanotechnology-based imaging and therapy could be a highly potent approach for future cancer research and treatment.