Targeting survivin in cancer: patent review

Importance of the field: Survivin is a prominent anti-apoptotic molecule expressed widely in the majority of cancers. Overexpression of survivin leads to uncontrolled cancer cell growth and drug resistance. Efficient downregulation of survivin expression and its functions can sensitise the tumour cells to various therapeutic interventions such as chemotherapeutic agents leading to cell apoptosis.

Areas covered in this review: The article thoroughly analyses up-to-date information on the knowledge generated from the survivin patents. Various key areas of research in terms of understanding survivin biology and its targeting are discussed in detail.

What the reader will gain: The article clearly gives an insight on the recent developments undertaken to understand the roles of survivin in cancer and in validating various treatment paradigms that suppress survivin expression in cancer cells.

Take home message: Most recent developments are helpful for effectively downregulating survivin expression by using various therapeutic platforms such as chemotherapeutic drugs, immunotechnology, antisense, dominant negative survivin mutant, RNA interference and peptide-based methods. However, selective and specific targeting of survivin in cancer cells still poses a major challenge. Nanotechnology-based platforms are currently under development to enable site-specific targeting of survivin in tumour cells.     

Overcoming multidrug resistance with nanomedicines

Introduction: Cancer remains the leading cause of death worldwide. Numerous therapeutic strategies that include smart biological treatments toward specific cellular pathways are being developed. Yet, inherent and acquired multidrug resistance (MDR) to chemotherapeutic drugs remains the major obstacle in effective cancer treatments.

Areas covered: Herein, we focused on an implementation of nanoscale drug delivery strategies (nanomedicines) to treat tumors that resist MDR. Specifically, we briefly discuss the MDR phenomenon and provide structural and functional characterization of key proteins that account for MDR. We next describe the strategies to target tumors using nanoparticles and provide a mechanistic overview of how changes in the influx:efflux ratio result in overcoming MDR.

Expert opinion: Various strategies have been applied in preclinical and clinical settings to overcome cancer MDR. Among them are the use of chemosensitizers that aim to sensitize the cancer cells to chemotherapeutic treatment and the use of nanomedicines as delivery vehicles that can increase the influx of drugs into cancer cells. These strategies can enhance the therapeutic response in resistant tumors by bypassing efflux pumps or by increasing the nominal amounts of therapeutic payloads into the cancer cells at a given time point.     

Role of AMPK signaling in mediating the anticancer effects of silibinin in esophageal squamous cell carcinoma

Objective: Emerging evidence suggests that activation of adenosine monophosphate-activated protein kinase (AMPK) may suppress cancer growth. Identification of novel AMPK activators is therefore crucial to exploit AMPK as a potential target for cancer prevention and treatment.

Research design and methods: We determined the expression status and role of AMPK in esophageal squamous cell carcinoma (ESCC) and investigated whether silibinin, a nontoxic natural product, could activate AMPK to inhibit ESCC development.

Results: Our results from 49 pairs of human ESCC and normal tissues showed that AMPK was constitutively inactive in the majority (69.4%) of ESCC. We found that silibinin induced apoptosis, and inhibited ESCC cell proliferation in vitro and tumorigenicity in vivo without any adverse effects. Silibinin also markedly suppressed the invasive potential of ESCC cells in vitro and their ability to form lung metastasis in nude mice. The anticancer effects of silibinin were abrogated by the presence of compound C or shRNA against AMPK. More importantly, silibinin enhanced the sensitivity of ESCC cells and tumors to the chemotherapeutic drugs, 5-fluorouracil and cisplatin.

Conclusions: This preclinical study supports that AMPK is a valid therapeutic target and suggests that silibinin may be a potentially useful therapeutic agent and chemosensitizer for esophageal cancer.     

Liposomal antibiotics for the treatment of infectious diseases

Introduction: Liposomal delivery systems have been utilized in developing effective therapeutics against cancer and targeting microorganisms in and out of host cells and within biofilm community. The most attractive feature of liposome-based drugs are enhancing therapeutic index of the new or existing drugs while minimizing their adverse effects.

Areas covered: This communication provides an overview on several aspects of liposomal antibiotics including the most widely used preparation techniques for encapsulating different agents and the most important characteristic parameters applied for examining shape, size and stability of the spherical vesicles. In addition, the routes of administration, liposome–cell interactions and host parameters affecting the biodistribution of liposomes are highlighted.

Expert opinion: Liposomes are safe and suitable for delivery of variety of molecules and drugs in biomedical research and medicine. They are known to improve the therapeutic index of encapsulated agents and reduce drug toxicity. Recent studies on liposomal formulation of chemotherapeutic and bioactive agents and their targeted delivery show liposomal antibiotics potential in the treatment of microbial infections.     

Strategies for tumor-directed delivery of siRNA

Introduction: Current treatment of malignant tumors relies predominantly on chemotherapy delivering a single antineoplastic drug or a combination of two or more drugs intravenously. Problems with such treatments can include the killing of healthy cells, adverse side effects and chemoresistance. As cancer basically results from different types of mutation leading to the overexpression or suppression of the signaling cascades responsible for cancer cell survival and proliferation, tailor-made approaches capable of interfering precisely with those pathways are the potential revolutionary tools that could pave the way for highly effective cancer therapy.

Areas covered: This review summarizes recent progress in the identification and validation of the target genes for cancer gene therapy using small interfering RNA (siRNA) technology and, more importantly, the delivery strategies that have been designed and implemented for tumor-directed delivery of siRNAs.

Expert opinion: Cancer-targeted delivery of a gene in order to produce a particular protein (such as a tumor-suppressor or a nucleic acid sequence that can silence the expression of a specific gene, such as an oncogene or an antiapoptotic gene) is the most promising concept for cancer treatment in the future. siRNA has the ability to recognize and cleave a specific mRNA, thus inhibiting the expression of a particular protein. The success of targeted gene silencing as a potential cancer therapeutic demands the development of more effective delivery devices and the removal of siRNA off-target effects.     

DNA synthesis inhibitors for the treatment of gastrointestinal cancer

Introduction: Intensive laboratory, preclinical and clinical studies have identified and validated molecular targets in cancers, leading to a shift toward the development of novel, rationally designed and specific therapeutic agents. However, gastrointestinal cancers continue to have a poor prognosis, largely due to drug resistance.

Areas covered: Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies.

Expert opinion: Conventional agents, including DNA synthesis inhibitors such as fluoropyrimidines and platinum analogs, remain the most effective therapeutics and are the standards against which new drugs are compared. Novel DNA synthesis inhibitors for the treatment of gastrointestinal malignancies include a combination of the antimetabolite TAS-102, which consists of trifluorothymidine with a thymidine phosphorylase inhibitor, and a novel micellar formulation of cisplatin NC-6004 that uses a nanotechnology-based drug delivery system. The challenges of translational cancer research using DNA synthesis inhibitors include the identification of drugs that are specific to tumor cells to reduce toxicity and increase antitumor efficacy, biomarkers to predict pharmacological responses to chemotherapeutic drugs, identification of ways to overcome drug resistance and development of novel combination therapies with DNA synthesis inhibitors and other cancer therapies, such as targeted molecular therapeutics. Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies.     

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.     

Selective genetic analysis of myoma pseudocapsule and potential biological impact on uterine fibroid medical therapy

Introduction: Tumor-associated angiogenesis is one of the essential hallmarks underlying cancer development and metastasis. Anti-angiogenic agents accordingly aim to restrain cancer progression by blocking the formation of new vessels, improving the delivery of chemotherapeutic agents to the tumor site and reducing the shedding of metastatic cells into the circulation. This review article addresses some key issues in the use of angiogenesis inhibitors in cancer.

Areas covered: The authors review the complex interactions between cell signaling pathways involved in tumor angiogenesis, and focus in particular on the molecular mechanisms that may induce resistance to angiogenesis inhibitors. They will also discuss some novel therapeutic strategies evolving within anti-angiogenic therapy such as the targeting of VEGFR-3, endothelial integrins and hepatocyte growth factor-MET signaling.

Expert opinion: Although anti-angiogenic therapy is targeted at the non-malignant part of the tumor, the intricate network of growth promoting signaling pathways and in particular the redundancy when single pathways are targeted in endothelial cells represents a major therapeutic obstacle. A key challenge will be to develop more efficient inhibitors, combined with an individualized approach based on each tumor's own endothelial signaling profile. Furthermore, reliable biomarkers which pinpoint those patients that will benefit from anti-angiogenic therapy need to be identified.     

Stimulation of Brain Nicotinic Acetylcholine Receptors (nAChR) and Inhibition of Brain Acetylcholinesterase (AChE) Activity

Introduction: The Fas/FasL system plays a significant role in tumorigenesis. Research has shown that its impairment in cancer cells may lead to apoptosis resistance and contribute to tumor progression. Thus, the development of effective therapies targeting the Fas/FasL system may play an important role in the fight against cancer.

Areas covered: In this review the recent literature on targeting the Fas/FasL system for therapeutic exploitation at different levels is reviewed. Promising pre-clinical approaches and various exceptions are highlighted. The potential of combined therapies is also explored, whereby tumor sensitivity to Fas-mediated apoptosis is restored, before an effective targeted therapy is employed.

Expert opinion: The success of the Fas/FasL system targeting for therapeutics will require a better understanding of the alterations conferring resistance, in order to use the most appropriate sensitizing chemotherapeutic or radiotherapeutic agents in combination with effective targeted therapies.     

Metformin in lung cancer: rationale for a combination therapy

Introduction: Metformin is a widely used antidiabetic drug, which also displays significant growth inhibitory and proapoptotic effects in several cancer models, including lung cancer, alone or in combination with chemotherapeutic drugs.

Areas covered: The role of metformin as a chemopreventive drug in lung cancer is still an object of debate as epidemiological studies have shown contrasting results. More preclinical data support its role as an adjuvant drug in the treatment of lung cancer, in combination with chemotherapy or targeted molecular drugs, although the complete mechanism of action of metformin is still unclear, and potentially may exert unexpected effects with contradictory clinical implications.

Expert opinion: Future perspective studies are required in nonsmall-cell lung cancer (NSCLC) patients to better investigate the effect of metformin action on the RAS/RAF/MAPK pathway and the best context in which to use metformin in combination with molecularly targeted agents.     

The achievement of ligand-functionalized organic/polymeric nanoparticles for treating multidrug resistant cancer

Introduction: The effectiveness of conventional cancer chemotherapy is hampered by the occurrence of multidrug resistance (MDR) in tumor cells. Although many studies have reported the development of novel MDR chemotherapeutic agents, clinical success is lacking owing to the high associated toxicity. Nanoparticle-based delivery of chemotherapeutic drugs has emerged as alternative approach to treat MDR cancers via exploitation of leaky vasculature in the tumor microenvironment. Accordingly, functionalization of nanoparticles with target specific ligands can be employed to achieve significant improvements in the treatment of MDR cancer.

Areas covered: This review focuses on the recent advances in the functionalization of nanocarriers with specific ligands, including antibodies, transferrin, folate, and peptides to overcome MDR cancer. The limitations of effective ligand-functionalized nanoparticles as well as therapeutic successes in ligand targeting are covered in the review.

Expert opinion: Targeting MDR tumors with ligand-functionalized nanoparticles is a promising approach to improve the treatment of cancer. With this approach, higher drug concentrations at targeted sites would be achieved with lower dosage frequencies and reduced side effects in comparison to existing formulations of chemotherapeutic drugs. However, potential toxicities and immunological responses to ligands should be carefully reviewed for viable options in for future MDR cancer treatment.     

Targeting L-type amino acid transporter 1 for anticancer therapy: clinical impact from diagnostics to therapeutics

Introduction: L-type amino acid transporter 1 (LAT1) is one of the amino acid transporters. It is overexpressed in various types of cancer cells, while it is produced restrictedly in normal tissues.

Areas covered: We discuss its characteristics in cancer cells compared with normal cells. We also mention the current applications to target LAT1 for anticancer therapy focusing on prognostic biomarkers, radio-labeled tumor imaging reagents, amino acid-stapled prodrugs, LAT1-mediated enhanced transport of anticancer drugs and LAT1 inhibitors.

Expert opinion: LAT1 can be a versatile target to promisingly develop transporter-based drugs with enhanced drug delivery potential for anticancer therapy.     

Molecular targets for selective killing of TRAIL-resistant leukemic cells

Introduction: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, and shows promising therapeutic activity against solid tumors and lymphomas, in a variety of Phase I and II clinical trials. In contrast, primary leukemias have shown poor susceptibility to TRAIL-mediated cytotoxicity, suggesting the need for sensitizing TRAIL-resistant leukemic cells, by combining soluble recombinant TRAIL either with chemotherapeutic drugs, or with targeted small molecules.

Areas covered: This review discusses potential therapeutic applications of combinations able to restore the sensitivity of leukemic cells to either recombinant TRAIL or anti-TRAIL-receptor agonistic antibodies for the treatment of hematological malignancies.

Expert opinion: Up-to-date knowledge of the most innovative anti-leukemic therapies including functional screening of specific-sensitizers, enhancing TRAIL-mediated cytotoxicity. Strategies aimed to enhance TRAIL-mediated apoptosis, include the combination of novel sensitizers, functionally identified from libraries of pharmaceutically active, synthetic or naturally derived compounds. Other approaches aim to employ the administration of stem cells engineered to express TRAIL, in the leukemic stem cell niche, and promise to be a successful treatment with reduced specific toxicity.     

Ovarian cancer targeted hyaluronic acid-based nanoparticle system for paclitaxel delivery to overcome drug resistance

Abstract

Objective: Most primary human ovarian tumors and peritoneal implants, as well as tumor vascular endothelial cells, express the CD44 family of cell surface proteoglycans, the natural ligand for which is hyaluronic acid (HA). Paclitaxel (PTX) is an effective chemotherapeutic agent that is widely used for the treatment of several cancers, including ovarian cancer. This study aimed to develop a HA-based PTX-loaded nanoparticle system to improve the ovarian cancer therapeutic effects.

Methods: PTX-loaded cationic nanostructured lipid nanoparticles (PTX-NLCs) were prepared. HA-PE was then coated onto the PTX-NLCs by electrostatic adsorption to form HA-PTX-NLCs. In vitro tumor cell inhibition efficiency was analyzed on SKOV3 human ovarian cancer cells (SKOV3 cells) and PTX-resistant SKOV3 cells (SKOV3/PTX cells). In vivo anticancer ability was evaluated with mice bearing SKOV3 ovarian cancer cells xenografts.

Results: HA-PTX-NLCs had an average diameter of 163?nm, and PTX was incorporated with an efficiency of over 80%. The in vitro viability of SKOV3 cells and SKOV3/PTX cells was obviously inhibited by HA-PTX-NLCs. In the ovarian cancer cells model, significant reduction in tumor growth was observed, whereas the conventional PTX injection group did not achieve significance.

Conclusion: This study demonstrated that significantly improved results were obtained by the newly constructed HA-PTX-NLCs, in terms of in vitro and in vivo therapeutic efficacy. These findings strongly support the superiority of HA based nano-system for the PTX delivery, thus enhance the efficacy of ovarian cancer chemotherapy.     

Nanoparticle-mediated co-delivery of chemotherapeutic agent and siRNA for combination cancer therapy

Introduction: Cancer is the leading cause of death worldwide. Current cancer treatments in the clinic mainly include chemotherapy, radiotherapy and surgery, with chemotherapy being the most common.

Areas covered: Cancer treatments based on the single ‘magic-bullet’ concept are often associated with limited therapeutic efficacy, unwanted adverse effects, and drug resistance. The combination of multiple drugs is a promising strategy for effective cancer treatment due to the synergistic or additive effects. Small interfering RNA (siRNA) has the ability to knock down the expression of carcinogenic genes or drug efflux transporter genes, paving the way for cancer treatment. Treatment with both a chemotherapeutic agent and siRNA based on nanoparticle (NP)-mediated co-delivery is a promising approach for combination cancer therapy.

Expert opinion: The combination of chemotherapeutic agents and siRNAs for cancer treatment offers the potential to enhance therapeutic efficacy, decrease side effects, and overcome drug resistance. Co-delivery of chemical drug and siRNA in the same NP would be much more effective in cancer therapy than application of chemical agent or siRNA alone. With the development of material science, NPs have come to be the most widely used platform for co-delivery of chemotherapeutic drugs and siRNAs.     

P53-Derived peptides conjugation to PEI: an approach to producing versatile and highly efficient targeted gene delivery carriers into cancer cells

ABSTRACT

Objectives: Targeted delivery of cytotoxic drugs or therapeutic antisense RNAs into specific cells is a major bottleneck in cancer therapy. To overcome this problem and improve the specificity for cancer cells, we describe a new-targeted delivery system using p53-derived peptides, namely PNC 27 and PNC 28. These peptides target HDM-2 on the surface of cancer cells. HDM-2 is overexpressed on the surface of cancerous cells, but not present on the untransformed cells.

Methods: To determine HDM-2-expressing cells, we used immunocytochemistry and flow cytometry analysis on nine cell lines including MCF-7 and NIH-3t3. Conjugation of peptides to vectors was confirmed using reverse-phase high-pressure liquid chromatography (RP-HPLC). Physicochemical properties of vector/DNA complexes including particle size, surface charge and DNA condensation ability were determined. In transfection studies, three plasmids were used including luciferase, pEGFP and shRNA plasmid against Bcl-XL mRNA. The level of Bcl-XL expression was determined by real-time PCR and western blot techniques.

Results: The results of gene delivery and shRNA-based gene silencing studies indicated that conjugation of PNC peptides could enhance gene delivery efficiently with high-targeted activity exclusively into cancer cells.

Conclusion: Our results strongly indicated that this targeting system could be utilized as an efficient targeting method for most cancer cells.     

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.     

Dendrimer and cancer: a patent review (2006 – present)

Introduction: Dendrimers were widely used in cancer diagnosis and therapy during the past decade. The surface functionalities allow bioactive molecules such as imaging probes, therapeutic compounds, targeting ligands to be present on dendrimer surface in a multivalent fashion. In addition, the interior pockets as well as the charged surface of dendrimer can be encapsulated/bound with anti-cancer drugs or therapeutic DNAs/siRNAs.

Areas covered: The combination of dendrimer chemistry and new cancer therapy techniques such as radiotherapy, photodynamic therapy, neuron capture therapy, and photothermal therapy provides promising strategies in future cancer therapy. Here, we focused on recent advances on this topic in the patents (2006 – present) and discussed the advantages of dendrimer technology in these inventions.

Expert opinion: The challenges and perspectives of dendrimer-based theranostics for cancer diagnosis and therapy are discussed. Future efforts in this area should be focused on designing materials to solve problems such as cancer metastasis, multidrug resistance (MDR) in cancer cells, and early-stage cancer diagnosis.