Effects of sunitinib and bevacizumab on VEGF and miRNA levels on corneal neovascularization

Aim: To evaluate the effects of sunitinib (0.5?mg/ml) and bevacizumab (5?mg/ml) on VEGF-A, VEGFR-2 and microRNA (miRNA) levels on corneal neovascularization (CNV).

Methods: In this study, CNV was induced by silver nitrate application to the cornea, and 40 Albino male rats were equally divided into four subgroups:

Group 1 (sunitinib): After silver nitrate application to the cornea, 0.5?mg/ml sunitinib eyedrop was administered twice daily for two weeks (n?=?10).

Group 2 (bevacizumab): After silver nitrate application to the cornea, 5?mg/ml bevacizumab eyedrop was administered twice daily for two weeks (n?=?10).

Group 3 (control): After silver nitrate application to the cornea, normal saline eyedrop was administered twice daily for two weeks (n?=?10).

Group 4 (vehicle): After silver nitrate application to the cornea, 1% DMSO eyedrop was administered twice daily for two weeks (n?=?10).

After two weeks from the silver nitrate application, corneas were evaluated by hand-held biomicroscope for their vascularization status. Then, corneas were excised and the expression levels of VEGFR-2, VEGF-A and the common miRNA markers for neovascularization (miR-15?b, miR-16, miR-23a, miR-126, miR-188, miR-210, miR-221, miR-222, miR-410 and miR-423) were evaluated by real-time PCR.

Results: It was seen that the CNV was decreased in sunitinib- and bevacizumab-administered groups compared to the control and DMSO groups. Also, in comparison with the control group; VEGF-A expression was downregulated by nearly 0.75 times in sunitinib group and nearly 0.52 times in bevacizumab group. VEGFR-2 expression was downregulated by 0.89 times in sunitinib group and 0.68 times in bevacizumab group, compared to the control group. miR-15?b, miR-16 and miR-126 levels were statistically lower in sunitinib and bevacizumab groups, but miR-188 and miR-410 levels were two-fold higher compared to the control group. The miR-210 level was found higher only in sunitinib group compared to the control group. There were no statistically significant changes in miR-23a, miR-221, miR-222 and miR-423 levels among the groups.

Conclusion: Topical application of bevacizumab (5?mg/ml) and sunitinib (0.5?mg/ml) decreases the levels of VEGFR-2 and VEGF-A in CNV. Further studies are needed for detailed analysis of genes which are targeted by up- or downregulated miRNAs in this study.     

Advances in malignant glioma drug discovery

Introduction: Outcome for patients with glioblastoma (GBM), the most common malignant primary brain tumor among adults, remains poor. However, two key treatment options have recently generated meaningful improvements in outcome for GBM patients. The addition of temozolomide (a methylating chemotherapeutic agent) to surgical resection and radiation therapy increases survival and is the first evidence that systemic chemotherapy can benefit GBM patients. Also, bevacizumab (a humanized mAb against VEGF) has significant antitumor activity among recurrent GBM patients. Additional areas of ongoing research are generating more therapeutic options that offer exciting potential to build on these results and further improve the outcome for malignant glioma patients.

Areas covered: This review describes three foci of advanced clinical research aimed at improving the outcome of GBM patients: protracted temozolomide dosing, VEGF-inhibiting agents and integrin inhibitors. This review also discusses potential clinical trial strategies to evaluate irreversible EGFR inhibitors as well as therapeutics targeting PI3K and the hedgehog signaling pathway.

Expert opinion: Several factors limit the efficacy of therapeutics targeting GBM. However, significant advances from basic science laboratories have recently generated important insights into the pathophysiology and molecular genetic abnormalities of these tumors. Efforts to translate these findings into innovative treatment strategies offer substantial promise to overcome therapeutic hurdles and treat individual patients more effectively. Improved understanding of malignant glioma biology and factors associated with treatment response will probably lead to improved therapeutic options and a better patient outcome.     

Sulfonamides: a patent review (2008 – 2012)

Introduction: The primary sulfonamide moiety is present in many clinically used drugs, such as diuretics (furosemide, indapamide, chlorthalidone, thiazides); carbonic anhydrase (CA) inhibitors (CAIs) (including acetazolamide, dichlorophenamide, dorzolamide and brinzolamide); antiepileptics (zonisamide and sulthiame); the antipsychotic sulpiride and the cycloxygenase 2 (COX2) inhibitors celecoxib and valdecoxib. Recently, novel drugs have been launched, such as apricoxib and pazopanib, which also incorporate this group.

Areas covered: The article presents the main classes of sulfonamides investigated between 2008 and 2012. Specifically, the authors review the scientific and patent literature on CAIs, COX2 inhibitors, pazopanib and its congeners, which are multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit.

Expert opinion: Most patents deal with sulfonamide CAIs incorporating NO-donating moieties as antiglaucoma agents, or with compounds targeting the tumor-associated isoforms CA IX/XII. The antidandruff actions of sulphonamides, which inhibit yeast CAs, were also claimed. Apricoxib (a COX2 inhibitor) and pazopanib, a tyrosine kinase inhibitor, show significant antitumor activity and several patents deal with these drugs. There is a constant need of novel sulfonamides to act as selective antiglaucoma drugs (targeting CA II), as antitumor agents/diagnostic tools (targeting CA IX/XII), and to treat and diagnose other disease. This privileged structural motif is likely to be present in other drugs in the future.     

Ramucirumab for the treatment of gastric cancers,colorectal adenocarcinomas,and other gastrointestinal malignancies

Introduction: The use of antiangiogenic strategy in the treatment of advanced colorectal cancers has been largely evidence-based. More recently, novel vascular endothelial growth factor receptor (VEGFR) inhibitors have been studied in other gastrointestinal diseases. Ramucirumab, a recombinant monoclonal antibody that binds to VEGFR2 extracellular domain with a much greater affinity compared to its natural ligand, showed second-line effectiveness for patients with gastric or colorectal carcinomas.

Areas covered: We perform a narrative literature review. The aims of our work are to recall the current evidence of its efficacy in the treatment of gastric, hepatocellular and colorectal cancers and to present the ongoing studies enrolling gastrointestinal cancer patients in which ramucirumab is being tested.

Expert commentary: The landscape of angiogenesis-inhibition for the treatment of GI malignancies is rapidly evolving. The results of the REGARD and RAINBOW trials renewed the interest for antiangiogenic agents in gastric cancer and determined a swift change in the treating paradigm for this disease. Accordingly, ramucirumab was shown to be effective in pretreated colorectal cancer patients and it is being tested in other gastrointestinal malignancies.     

Emerging growth factor receptor antagonists for the treatment of renal cell carcinoma

Introduction: The landscape of systemic treatment for metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of targeted agents including vascular endothelial growth factor (VEGF) inhibitors. Recently, multiple new agents including growth factor receptor antagonists and a checkpoint inhibitor were approved for the treatment of refractory metastatic RCC based on encouraging benefit shown in clinical trials.

Areas covered: The background and biological rationale of existing treatment options including a brief discussion of clinical trials which led to their approval, is presented. This is followed by reviewing the limitations of these therapeutic options, medical need to develop new treatments and major goals of ongoing research. We then discuss two recently approved growth factor receptor antagonists i.e. cabozantinib and lenvatinib, and a recently approved checkpoint inhibitor, nivolumab, and issues pertaining to drug development, and future directions in treatment of metastatic RCC.

Expert opinion: Recently approved growth factor receptor antagonists have shown encouraging survival benefit but associated drug toxicity is a major issue. Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, has similarly shown survival benefit and is well tolerated. With multiple options now available in this patient population, the right sequence of these agents remains to be determined.     

Molecular targeted therapy of advanced hepatocellular carcinoma beyond sorafenib

Importance of the field: With the recent advances in the knowledge of molecular biology of hepatocellular carcinoma (HCC), there have been encouraging developments in targeted therapy for advanced HCC.

Areas covered in this review: This review discusses the development of targeted therapy for advanced HCC patient since 2006. Among the newly identified targets, promising results have been shown in targeting the anti-angiogenic pathway. Pure anti-angiogenic agents such as bevacizumab and PTK 787 demonstrate modest activity in treating patients with advanced HCC. Sorafenib, a multi-targeted tyrosine kinase inhibitor with both anti-angiogenic and anti-proliferative effects, has been shown to prolong the overall survival of patients with advanced HCC in two Phase III randomized trials. Like sorafenib, other anti-angiogenic multi-targeted tyrosine kinase inhibitors, such as sunitinib, pazopanib, brivanib and linifanib, also show promising activity in various stages of clinical trials. Other on-going early-phase studies are exploring the activities of drugs targeting novel pathways, such as PI3K/AKT/m TOR, hepatocyte growth factor/mesenchymal epithelial transition factor and insulin-like growth factor.

What the reader will gain: After reading this review, the reader should have an in-depth understanding of the latest developments in the molecular targeted therapy of advanced HCC.

Take home message: The development of sorafenib in the treatment of advanced HCC proves the concept that molecular targeted therapies, especially anti-angiogenic agents, play a pivotal role in the treatment of this otherwise chemoresistant neoplasm. Future progress depends on further unraveling more molecular mechanisms of HCC for therapeutic intervention.     

Targeting angiopoietin-2 signaling in cancer therapy

Introdcution: Over the past decade, several anti-angiogenic strategies have been devised to target a wide spectrum of malignancies. The most widely utilized approach involves abrogation of vascular endothelial growth factor receptor signaling through either consumption of ligand (i.e., with the monoclonal antibody bevacizumab) or through direct inhibition of the receptor tyrosine kinase domain (i.e., with small molecules such as sunitinib or sorafenib). While these agents do appear to delay cancer progression in the clinic, they are not curative approaches.

Areas covered: A novel anti-angiogenic strategy involves inhibition of signaling along the Ang/Tie-2 axis, a pathway critical for mediating endothelial and perivascular cell interactions. While several agents (i.e., AMG-386 and regorafenib) have reached late stages of clinical development, others (i.e., ARRY614 and CEP-11981) are in their relative infancy. Herein, we will outline the clinical trajectory of wide spectrum Ang/Tie-2 inhibitors, with attention to data evaluating combinations with cytotoxic therapy or other targeted agents.

Expert opinion: Provided that these approaches to not drastically augment toxicity, they may represent the ideal path for further development of this class of agents.     

BIBF 1120/nintedanib: a new triple angiokinase inhibitor-directed therapy in patients with non-small cell lung cancer

Introduction: Several new targeted agents with anti-angiogenic properties have been developed recently, including vandetanib, sunitinib, sorafenib, bevacizumab and others. Tumor development, progression, metastasis are strongly linked to angiogenesis. Targeted agents like bevacizumab, a monoclonal antibody which targets VEGF, have been fully developed in several solid tumors. These new agents strongly advocate that targeting angiogenesis is one of the best approaches for cancer therapy.

Areas covered: Those agents that target additional pro-angiogenic intracellular signaling pathways beyond VEGF signaling have also the potential to contribute to anticancer therapies. The authors present here nintedanib (BIBF 1120), a triple angiokinase inhibitor. It targets not only VEGFRs, but also FGFR and PDGFR. All the available clinical information regarding Phase I – II trials and the toxicity and efficacy of BIBF 1120 both as single agent and in combination with cytotoxic agents in non-small cell lung cancer (NSCLC) is reviewed and discussed here.

Expert opinion: Up till now, Phase I and II trials with nintedanib showed an improvement for survival of advanced NSCLC patients. Tolerability profile seems to be acceptable in these clinical trials. However, Phase III trials are mandatory to translate these findings into clinical practice. The research for predictive biomarkers could improve the success of these anti-angiogenic agents.     

Investigational drugs for the treatment of Zika virus infection: a preclinical and clinical update

ABSTRACT

Introduction: The Zika virus (ZIKV) infection results in severe neurological complications and has emerged as a threat to public health worldwide. No drugs or vaccines are available for use in the clinic and the need for novel and effective therapeutic agents is urgent.

Areas covered: This review describes the latest progress of antiviral development for the treatment of ZIKV infection; it primarily focuses on the literature describing 20 potential anti-ZIKV drugs/agents currently being tested in vivo or in clinical trials. The paper also discusses the need for novel ZIKV inhibitors and the critical issues for successful antiviral drug development.

Expert opinion: So far, 20 compounds have been tested in vivo and three in the clinical trials; progressing these compounds to the clinic is a challenge. Novel ZIKV inhibitors that target virus or host factors are urgently needed. Knowledge-driven drug repurposing, structure-based discovery, RNA interference, long noncoding RNAs, miRNAs, and peptide inhibitors may pave the way for the discovery of such novel agents.     

The use of single chain Fv as targeting agents for immunoliposomes: an update on immunoliposomal drugs for cancer treatment

Importance of the field: Targeted liposomal drugs represent the next evolution of liposomal drug delivery in cancer treatment. In various preclinical cancer models, antibody-targeted PEGylated liposomal drugs have demonstrated superior therapeutic effects over their non-targeted counterparts. Single chain Fv (scFv) has gained popularity in recent years as the targeting agent of choice over traditional targeting agents such as monoclonal antibodies (mAb) and antibody fragments (e.g., Fab′).

Areas covered in this review: This review is focused mainly on advances in scFv-targeted liposomal drug delivery for the treatment of cancers, based on a survey of the recent literature, and on experiments done in a murine model of human B-lymphoma, using anti-CD19 targeted liposomes targeted with whole mAb, Fab′ fragments and scFv fragments.

What the reader will gain: This review examines the recent advances in PEGylated immunoliposomal drug delivery, focusing on scFv fragments as targeting agents, in comparison with Fab′ and mAb.

Take home message: For clinical development, scFv are potentially preferred targeting agents for PEGylated liposomes over mAb and Fab′, owing to factors such as decreased immunogenicity, and pharmacokinetics/biodistribution profiles that are similar to non-targeted PEGylated (Stealth^®) liposomes.     

VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012-2016)

Introduction: Angiogenesis is an important component of certain normal physiological processes, but aberrant angiogenesis contributes to some pathological disorders and in particular to tumor growth. Activation of vascular endothelial growth factor receptor-2 (VEGFR-2) by vascular endothelial growth factor (VEGF) is a critical step in the signal transduction pathway that initiates tumor angiogenesis. Inhibition of angiogenesis via blocking VEGF/VEGFR-2 signaling pathway has emerged as a potential approach to anticancer therapy. Indeed, this approach has recently been clinically validated with the approvals of VEGFR-2 inhibitors.

Areas covered: This review accounts for small-molecule inhibitors and antibodies of VEGFR-2 reported in the patent literature covering between January 2012 and June 2016, and their potential use as therapeutics for cancers, angiogenesis-related disorders and inflammatory diseases.

Expert opinion: Despite the attractiveness of anti-angiogenic therapy by VEGF inhibition alone, several issues may limit this approach. VEGF expression levels can be elevated by numerous diverse stimuli such as the activation of other RTK signaling transduction pathway. Therefore, the development of multi-targeted tyrosine kinase inhibitors and the strategy of using these agents in conjunction with other anti-cancer agents are recent interesting therapeutic approaches that could give promising results.     

Emerging VEGF-receptor inhibitors for colorectal cancer

Introduction: Targeted agents have dramatically improved and enriched the therapeutical choices for patients with metastatic colorectal cancer (mCRC). By better understanding the role of the angiogenic pathway in colorectal cancer (CRC), new therapies have been developed. Bevacizumab, the first anti-angiogenetic agent approved for the treatment of mCRC provide a proof of concept since it has improved the progression-free survival and overall survival when combined with cytotoxic chemotherapy.

Areas covered: This review is focused on the most recent findings on the VEGF signaling pathway and new therapeutic drugs explored in clinical trials.

Expert opinion: Despite the advantage offered by bevacizumab, the median overall survival of mCRC patient exceeds 21 months; thus, investigational efforts are needed. Several antiangiogenic agents for the treatment of mCRC are being tested in preclinical and clinical Phase I/II trials. Unfortunately a discrete number of Phase III trials produced negative results. Recently aflibercept and regorafenib, two new antiangiogenic drugs, have been approved as the new-targeted agents for the treatment of mCRC, according to the positive findings from the VELOUR and the CORRECT studies. In order to maximize clinical impact it will be important to validate predictive biomarkers and best combination treatments to offer for mCRC patients; further research and intense investigation is still required.     

Pazopanib for the treatment of renal cancer

Introduction: Dramatic advances in the care of patients with advanced renal cell carcinoma (RCC) have occurred over the last 10 years. Insights into the molecular pathogenesis of this disease have elucidated the importance of signaling cascades related to angiogenesis in the management of RCC. Pazopanib is a novel, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3; platelet-derived growth factor receptors (PDGFR)-α and -β; and c-kit tyrosine kinases. Pazopanib exhibits distinct pharmacokinetic and toxicity profiles compared with other agents in the class of VEGF signaling pathway inhibitors.

Areas covered: This review discusses the scientific rationale for the development of pazopanib, as well as the preclinical and clinical trials that led to the approval of pazopanib for patients with advanced RCC. The most recent information, including data from the 2010 meeting of the American Society of Clinical Oncology and the design of ongoing Phase III trials, is discussed. Finally, an algorithm utilizing level I evidence for the treatment of patients with this disease is proposed.

Expert opinion: The treatment of metastatic RCC has changed dramatically over the last 5 years. Six novel agents – sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab (used in combination with interferon), and pazopanib (Votrient) – have been approved for the treatment of metastatic RCC. The clinical data to date clearly place pazopanib among the most active of the targeted therapies.     

Novel investigational drugs for constipation-predominant irritable bowel syndrome: a review

Introduction: Constipation-predominant irritable bowel syndrome (IBS-C) is a functional gastrointestinal (GI) disorder with an unknown etiology. A number of the drugs tested for IBS-C have also been applied to chronic constipation and chronic idiopathic constipation. Unfortunately, due to severe adverse effects, many drugs envisioned for IBS-C had been withdrawn from the market. Nevertheless, a number of potential new agents for this indication are now under development.

Areas covered: The following review describes the most recently developed agents in preclinical as well as Phase 1 and Phase 2 clinical studies. Information was obtained from published literature, abstracts and the latest results found in Clinicaltrial.gov database. The authors put a special interest on glucagon-like peptide 1 analogue, bile acid modulators, serotonergic agents, guanylate cyclase C and cannabinoid antagonists.

Expert opinion: To enter the market, a newly-developed drug has to meet several criteria, such as good bioavailability or the absence of drug-related adverse events. Taking into account constipation and abdominal pain as the main symptoms in IBS-C, a novel successful drug is usually able to improve both at the same time. Four out of fifteen investigational drugs described in this paper belong to the serotonergic family and have a good prognosis to reach the market; still, more long-term clinical studies are warranted.     

Belinostat: clinical applications in solid tumors and lymphoma

Introduction: Histone deacetylase (HDAC) inhibitors have recently emerged as a novel and active class of anticancer agents. Belinostat is one member of the class that has been tested as a single agent and in combination with other chemotherapies and biological agents in the treatment of solid tumors and lymphoma.

Areas covered: A literature search of pre-clinical and clinical studies of belinostat was performed. The data from these studies were analysed to summarise the progress of belinostat from Phase I to a current pivotal trial in peripheral T-cell lymphoma. The parallel development of appropriate biomarker analysis is also discussed.

Expert opinion: Belinostat has demonstrated significant clinical activity in T-cell lymphomas. Although its activity as a single agent in solid tumors has been less compelling, the emerging results from combination trials are promising. However, the basis for the activity of belinostat, like that of other HDAC inhibitors, remains to be truly defined and the identification of predictive and prognostic biomarkers of activity should be established to further progress the development of this compound.     

Novel drugs for the treatment of chronic pruritus

ABSTRACT

Introduction: Chronic pruritus (CP) is a multidimensional condition severely affecting the quality of life of those affected. Although a multitude of topical and systemic agents are recommended for CP of different origins, the condition often remains refractory to treatment. However, a deeper understanding of the pathophysiology of CP is leading to the development of novel antipruritic drugs.

Areas covered: This paper reviews antipruritic therapies in development by gathering data from recently published articles and clinical trials databases. Interleukin-31 antibodies and other biologics, neurokinin-1 receptor antagonists, opioid-receptor agonists/antagonists, TrkA-antagonists, and ileal bile acid transporter inhibitors are discussed.

Expert opinion: Clinical trials have rendered promising data on the antipruritic efficacy and safety of novel drugs, but further studies are necessary to enhance our understanding of the different conditions associated with CP. High-quality clinical trial data is necessary for these agents to be approved for the treatment. Basic research should be intensified to identify pathways relevant for CP and to further the development of new specific antipruritic drugs.     

Challenges in the development of novel therapeutic strategies for treatment of endometriosis

Introduction: Endometriosis is an estrogen-dependent disease that results in pelvic pain and infertility. Its treatment is often frustrating due to limited medical treatment options, complex surgical treatment and high recurrence rates. Despite the advances in our understanding of the pathogenesis over the last decades and the consequent novel therapeutic strategies, no new drugs have been introduced in daily clinical practice.

Areas covered: In the first part we present an overview of the pathogenesis of endometriosis. In the second part we discuss how new insights have led to the development of novel nonhormonal strategies for the treatment of endometriosis, focusing on anti-inflammatory and anti-angiogenic agents. In the third part we describe the problems encountered in the translation from experimental drugs to routine medicine for the treatment of endometriosis.

Expert Opinion: Despite the multitude of agents that have been tested in preclinical trials, only few drugs have passed to the stage of clinical testing and none have been introduced into clinical practice. It is our opinion that the major challenges in the translation from novel agents for endometriosis is due to the use of inadequate rodent models and a lack of standardization in the design and reporting of preclinical endometriosis models.     

Novel molecular targets for the therapy of urothelial carcinoma

Introduction: First-line platinum-based combinations are active in locally advanced and metastatic urothelial carcinoma; however, long-term outcomes including disease-specific and overall survival remain suboptimal. In addition, approximately 40 – 50% of patients with advanced urothelial carcinoma have coexisting medical issues that preclude the use of cisplatin-based therapy. Improvements in our understanding of the molecular mechanisms of urothelial tumorigenesis have led to first-generation clinical trials evaluating novel agents targeting molecular pathways. These are particularly relevant in regard to subpopulations. Novel trial designs warrant consideration to accelerate accrual.

Areas covered: In this review, novel molecular targets for the therapy of urothelial carcinoma, as well as recently completed and ongoing clinical trials utilizing novel targeted agents, are discussed. A Medline search with key words, abstracts reported at national conferences on urothelial carcinoma and NCI clinical trial identifiers was used for this review.

Expert opinion: Improved understanding of molecular biology has identified a number of new molecular targets, but there is a seeming absence of one dominant molecular driver for urothelial cancer. An adaptive and biomarker-derived strategy may be warranted. Clinical trials utilizing targeted agents are ongoing and results are awaited.     

Update on bevacizumab and other angiogenesis inhibitors for brain cancer

Introduction: Primary and metastatic brain tumors remain a major challenge. The most common primary adult malignant brain tumor, glioblastoma (GBM), confers a dismal prognosis as does the development of CNS metastases for most systemic malignancies. Anti-angiogenic therapy has been a major clinical research focus in neuro-oncology over the past 5 years.

Areas covered: Culmination of this work includes US FDA accelerated approval of bevacizumab for recurrent GBM and the completion of two placebo-controlled Phase III studies of bevacizumab for newly diagnosed GBM. A multitude of anti-angiogenics are in evaluation for neuro-oncology patients but none has thus far surpassed the therapeutic benefit of bevacizumab.

Expert opinion: These agents demonstrate adequate safety and the majority of GBM patients derive benefit. Furthermore, their anti-permeability effect can substantially decrease tumor-associated edema leading to stable or improved neurologic function and quality of life. In particular, anti-angiogenics significantly prolong progression-free survival – a noteworthy achievement in the context of infiltrative and destructive brain tumors like GBM; however, in a manner analogous to other cancers, their impact on overall survival for GBM patients is modest at best. Despite substantial clinical research efforts, many fundamental questions regarding anti-angiogenic agents in brain tumor patients remain unanswered.