Emerging drugs for endometrial cancer

Introduction: From the dualistic classification that divides endometrial cancer (EC) into two types with distinct underlying molecular profiling, histopathology and clinical behavior, arises a deeper understanding of the carcinogenesis pathways. EC treatment comprises different and multimodal therapeutic approaches, such as chemotherapy, radiation therapy or combinations of novel drugs; however, few of these regimens have truly improved progression-free or survival rates in advanced and metastatic settings.

Areas covered: We reviewed the main molecular pathways involved in EC carcinogenesis through a wide literature search of novel compounds that alone or in combination with traditional drugs have been investigated or are currently under investigation in randomized clinical trials.

Expert opinion: The molecular therapies mainly discussed in this review are potential therapeutic candidates for more effective and specific treatments. In the genomic era, a deeper knowledge about molecular characteristics of cancer provides the hope for the development of better therapeutic approaches. Targeting both genetic and epigenetic alterations, attacking tumor cells using cell-surface markers overexpressed in tumor tissue, reactivating antitumor immune responses and identifying predictive biomarkers represent the emerging strategies and the major challenges.     

Emerging drugs for urothelial (bladder) cancer

Introduction: Metastatic urothelial carcinoma has been associated with poor prognosis and a median survival of approximately 12–14 months with standard therapy. Treatment options for decades have been limited to platinum based chemotherapy as first line with few therapeutic options available to the majority who will ultimately progress beyond platinum.

Areas covered: This review focuses on the various targeted, antiangiogenic, chemotherapeutic and immunotherapeutic agents currently being developed for the treatment of urothelial carcinoma.

Expert opinion: Incorporation of systemic immunotherapy into the treatment of urothelial carcinoma has already fundamentally changed the treatment of this disease. The landscape is rapidly changing and it is likely that immunotherapy will be incorporated into therapy in earlier disease states and in novel combinations. Outcomes in urothelial carcinoma have improved and likely to improve further with ongoing and future clinical research that is discussed in this review.     

Emerging drugs for non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases and is the leading cause of cancer mortality. Despite the optimization of chemotherapy regimens, treatment outcomes for advanced disease are still disappointing. The EGFR tyrosine kinase inhibitor, erlotinib, and the recombinant monoclonal antibody against the VEGF, bevacizumab, have proven active in NSCLC. In the BR.21 trial, a 2-month benefit in overall survival was observed for previously treated NSCLC patients who received erlotinib versus placebo. The combination of chemotherapy plus bevacizumab yielded superior overall survival or progression-free survival in one randomized trial in advanced non-squamous NSCLC patients. However, despite the introduction of more effective agents, new treatment strategies are clearly needed in lung cancer management.

The review focuses on a number of new targeted agents/chemotherapy drugs now in clinical trials directed at improving NSCLC management. Mature results regarding their activity and usefulness can be expected in the near future.     

Emerging drugs for malaria

Introduction: Malaria remains one of the most important infectious diseases, causing around 655 000 deaths annually, mostly among children in Sub-Saharan Africa. Plasmodium falciparum, the parasite responsible for the most severe form of malaria, has developed resistance against almost all drugs in clinical use. Development of new drugs, preferably acting by mechanisms distinct from those of established treatment, is thus urgently needed.

Areas covered: Non-artemisinin drug candidates currently in pre-registration clinical trials are reviewed covering published data available until December 2011.

Expert opinion: Although promising compounds are presently undergoing clinical evaluation, the lack of new treatments for severe malaria and the predominance of artemisinin-based combination therapy for uncomplicated malaria is concerning. Future research should be directed towards the discovery of new therapeutic principles.     

Emerging sublingual immunotherapy drugs

Importance of the field: There is epidemiological evidence that respiratory allergy has reached epidemic proportions; owing to the related socio-economic impact, this topic deserves particular attention. An integrated approach involving pharmacotherapy and the immunomodulatory effect of immunotherapy is expected to optimize the management of respiratory allergy, reducing its clinical and economic burdens. Sublingual immunotherapy (SLIT) has gained increasing interest for its efficacy comparable to traditional subcutaneous immunotherapy and its good safety profile.

Areas covered in this review: A review of the up-to-date state of the art concerning the key aspects of SLIT is provided; the critical issues are discussed in the light of the comprehensive revision of the recent World Allergy Organization position paper and the subsequent literature, paying particular attention to efficacy, safety, additional effects, adherence and clinical developments.

What the reader will gain: The overview of current certainties and concerns, related to the use of SLIT, allows the reader's insight into the future directions of research and clinical applications of SLIT, aimed at covering current unmet needs.

Take home message: A large amount of experimental evidence sustains the use of SLIT, though some aspects still need to be clarified to provide clear, evidence-based recommendations. Unmet needs represent the basis for future research, while clinical hypotheses would open the search for new indications and modalities.     

Emerging drugs for cancer cachexia

Cachexia is a complex syndrome. The main components of this pathological state are anorexia and metabolic abnormalities such as glucose intolerance, fat depletion and muscle protein catabolism among others. The altered metabolic status generates a high degree of energetic inefficiency that results in weight loss, fatigue and a considerable loss of muscle and, therefore, asthenia. The aim of the present article is to review the different therapeutic approaches and emerging drugs that have been designed to fight and counteract cachexia associated with cancer.     

Emerging drugs for high-grade osteosarcoma

Importance of the field: Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. This review focuses on the most promising therapeutic markers and drugs which may potentially be considered for innovative high-grade OS treatments.

Areas covered in this review: The list of drugs and compounds reviewed has been generated by taking into account those which target markers of potential clinical interest for high-grade OS and have been included in Phase I, II or III clinical trials. The literature search covers the last 40 years, starting from the first OS chemotherapy reports of the early 1970s. Particular relevance was given to reports and reviews on new targeted therapies of possible clinical usefulness for high-grade OS.

What the reader will gain: This review gives an updated overview of novel therapeutic approaches which have been or are going to be evaluated in Phase I/II/III clinical studies for high-grade OS.

Take home message: On the basis of the information that has emerged so far, it can be predicted that in the next 5 – 10 years, new agents to be included in innovative treatment strategies for selected subgroups of high-grade OS patients may become available.     

Emerging drugs for Hodgkin's lymphoma

Importance of the field: Although to date most patients with Hodgkin's lymphoma (HL) can be cured, the current treatment is associated with acute and long-term complications such as infertility, cardiovascular damage and secondary malignancies. Moreover, novel effective therapies are urgently needed for elderly patients and for patients relapsing after high-dose chemotherapy.

Areas covered in this review: Currently emerging promising approaches include drugs targeting cell surface structures by mAbs and immunotoxins, as well as small molecules targeting intracellular proteins. This article includes clinical trials published within the past 3 decades and early results reported in international conferences.

What the reader will gain: This article summarizes the biological basis and early clinical data on emerging drugs for HL.

Take home message: To date, several new drugs are being tested for HL that are expected to change the approach in both first-line and relapsed patients.     

Emerging drugs in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease is one of the most relevant diseases with increasing incidence, morbidity and mortality. Although there have been therapeutic advances in the past decades, there is a lot of room for improvement. There are several new therapeutic strategies and a variety of novel drugs under development that are based on established concepts. These new drugs have the following targets: i) smoking; ii) airways obstruction; iii) inflammation; iv) protease–antiprotease imbalance; and v) regeneration of lung tissue. In the next few years, there will be bronchodilators with longer duration of action that may improve adherence. In addition, there will be fixed combinations of different bronchodilators and bronchodilators with corticosteroids, which may have a positive impact on parameters such as exacerbations, dyspnea and exercise capacity. Novel anti-inflammatory concepts that go beyond corticosteroids are in early phases of development and it remains to be seen how effective they are and what side effects they may carry.     

Emerging drugs for hepatocellular carcinoma

Hepatocellular carcinoma is often diagnosed at an advanced stage, when potentially curative surgical or local ablative therapies are not feasible. There is no effective chemotherapy for hepatocellular carcinoma. Recent advances in cancer biology suggest that a limited number of signalling pathways may be responsible for uncontrolled cell proliferation, the major cellular alteration responsible for the cancer phenotype. Novel anticancer agents target these critical pathways, including the receptor tyrosine kinase pathways, the Wnt/β-catenin signalling pathway, the ubiquitin/proteasome degradation pathway, the DNA methylation and histone deacetylation pathways, the PI3 kinase/AKT/mTOR pathway, angiogenic pathways, telomerase and the cell cycle. These agents hold promise for improving the outcome of patients with intermediate and advanced hepatocellular carcinoma. Because of the high prevalence of liver cirrhosis in hepatocellular carcinoma patients, to achieve long-term survival of the majority of patients, targeted anticancer therapies will need to be coupled with strategies aimed at reversing the progression of chronic liver disease.     

Emerging drugs for the treatment of bone metastasis

Introduction: Bone metastases are virtually incurable resulting in significant disease morbidity, reduced quality of life and mortality. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Increased understanding of the pathogenesis of bone disease has led to the discovery and clinical utility of bone-targeted agents other than bisphosphonates and denosumab, currently, the standard of care in this setting.

Areas covered: In this review, we present the recent advances in molecular targeted therapies focusing on therapies that inhibit bone resorption and/or stimulate bone formation and novel anti-tumoral agents that exerts significant effects on skeletal metastases, nowadays available in clinical practice or in phase of development.

Expert opinion: New emergent bone target therapies radium-223, mTOR inhibitors, anti-androgens have demonstrated the ability to increase overall survival in bone metastatic patients, other compounds, such as ET-1 and SRC inhibitors, up to now failed to clearly confirm in clinical trials their promising preclinical data.     

Emerging drugs for urothelial carcinoma

Introduction: Advanced urothelial carcinoma is associated with a poor prognosis. In the metastatic setting, the response rate to first-line, cisplatin-containing chemotherapy is high, but survival is poor. Second-line treatment options are limited. Advanced age at diagnosis and the presence of comorbidities often preclude treatment with cisplatin-containing regimens.

Areas covered: This review addresses the current therapy of urothelial carcinoma, the unmet needs in treatment and the status of drug development in this disease. The molecular targets identified and efforts to incorporate targeted agents into therapy will be addressed.

Expert opinion: There have been no major advances in the treatment of urothelial carcinoma in three decades. Despite high response rates in the first-line setting, survival is limited. Major impediments to improved outcomes include poor durability of response to first-line chemotherapy and lack of second-line treatments. Better understanding in tumor biology has identified multiple targets in urothelial carcinoma; however, such discoveries have yet to lead to the incorporation of targeted agents into the routine treatment of urothelial carcinoma. Multiple ongoing clinical trials are investigating the use of targeted agents in urothelial carcinoma. Continued efforts are underway to better understand the molecular drivers of disease and such efforts are likely to identify additional therapeutic targets.     

Emerging drugs for allergic conjunctivitis

Introduction: Allergic conjunctivitis (AC) is a very common disease, especially in association with allergic rhinitis but may also occur in isolated presentation. The treatment of AC has long been based on antihistamines, cromones and topical corticosteroids, but none of these drugs completely abolishes the clinical expression of AC.

Areas covered: The development of new drugs for AC is analyzed highlighting the recent insights into the pathophysiological mechanisms of the disease. The major aim of development of drugs for AC is to have agents able to prevent the inflammatory effects of the interaction between the allergen and the specific IgE antibodies on mast cell surface. This may be obtained by blocking the effects of histamine (the main mediator of early allergic response) by H1-receptor antagonists, inhibiting the release of soluble factors able to recruit inflammatory cells (that sustain prolonged inflammation) by mast-cell stabilizers, inhibiting the effects of single mediators, inducing tolerance to the allergen by specific immunotherapy or even acting on factors related to activation and differentiation of T lymphocytes such as the toll-like receptors.

Expert opinion: AC is an underestimated disease for which there is a search of more effective treatments. The availability of the drugs under current evaluation will allow more refined therapeutic strategies to apply according to the characteristics and the clinical severity of AC.     

Emerging drugs for biliary cancer

Biliary cancer comprise carcinoma of the gallbladder as well as the intrahepatic, hilar and extrahepatic bile ducts. Furthermore, many different etiologies and risk factors are contributing to the inhomogeneity of this disease. It is often diagnosed at an advanced stage when potentially curative resection is not feasible. Due to the lack of randomised Phase III studies, there is no standard regimen for chemotherapy in biliary cancer. Recent investigations into the underlying molecular mechanisms involved in biliary carcinogenesis and tumour growth have contributed greatly to our understanding of biliary cancer. Through a better understanding of these mechanisms, improved and more specific diagnostic, therapeutic and preventive strategies may be developed. Although fluoropyrimidines and gemcitabine remain the backbone of routine chemotherapy in advanced disease, new agents such as epidermal growth factor receptor blockers and angiogenesis inhibitors may hold promise for improving the outcome for patients with biliary cancer.     

Emerging growth factor receptor antagonists for ovarian cancer treatment

Introduction: Epithelial Ovarian Cancer (EOC) is the most lethal gynecological malignancy. EOC outcomes remain unsatisfactory despite aggressive surgical approach, disease chemo-sensitivity and recent introduction of agents targeting angiogenesis and tumour genome instability. Advances in EOC research have allowed for a tailored treatment approach and accelerated development of novel treatments strategies from bench to bed side, anticipated to improve patient outcomes.

Areas covered: Comprehensive review of growth factor receptor antagonists for EOC treatment currently in different stages of development was performed. English peer-reviewed articles and abstracts were searched in MEDLINE, PubMed, Embase and major conferences. We focused on agents that antagonize growth factors promoting sustained proliferative signaling, angiogenesis and evasion of immune destruction blocking the receptor or its stimulating factors.

Expert opinion: Receptor signaling has been well characterized for most cancer generating pathways. Growth receptor antagonists are represented by both high receptor affinity monoclonal antibodies as well as tyrosine kinase inhibitors; both are especially effective when a related predictive biomarker of response is identified. Therefore, along with the promising development of novel receptor antagonists or modulators in EOC treatment, targeting essential growth pathways in the tumour and associated microenvironment, is fundamental for biomarker discovery and towards achieving significant improvements in response.     

Emerging drugs and drug targets against tuberculosis

Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, uses various tactics to resist on antibiotics and evade host immunity. To control tuberculosis, antibiotics with novel mechanisms of action are urgently needed. Emerging new antibiotics and underlying novel drug targets are summarized in this paper.     

Advances in emerging drugs for the treatment of neuroblastoma

Introduction: Neuroblastoma is the most common solid extracranial tumor of childhood. Outcome for children with high-risk neuroblastoma remains suboptimal. More than half of children diagnosed with high-risk neuroblastoma either do not respond to conventional therapies or relapse after treatment with dismal prognosis.

Areas covered: This paper presents a short review of the state of the art in the current treatment of high-risk neuroblastoma. An updated review of new targeted therapies in this group of patients is also presented.

Expert opinion: In order to improve prognosis for high-risk patients there is an urgent need to better understand spatial and temporal heterogeneity and obtain new predictive preclinical models in neuroblastoma. Combination strategies with conventional chemotherapy and/or other targeted therapies may overcome current ALK inhibitors resistance. Improvement of international and transatlantic cooperation to speed clinical trials accrual is needed.     

Emerging drugs for esophageal cancer

Background: Cancer of the esophagus and gastro-esophageal junction is a disorder with a poor prognosis and increasing incidence. Objective: To provide a critical evaluation of current treatment strategies and new developments including targeted therapy for esophageal cancer. Methods: Published clinical trials as well as abstracts were selected regarding chemoradiation or targeted therapy for esophageal cancer. Results/conclusions: Preoperative chemotherapy may offer a survival advantage compared to surgery alone, but the evidence is inconclusive. For preoperative chemoradiation, only 2 of 10 randomized trials showed advanced survival compared to surgery alone, and, therefore, more Phase III trials and, consequently, meta-analyses are needed. Until now, for palliative chemotherapy, no survival benefit has been shown. This is largely due to a lack of studies and difficulties in performing randomized trials. The application of targeted therapy is widespread and reported for several tumor types. For esophageal cancer, most studies have been performed with EGFR inhibitors, including cetuximab, gefitinib, erlotinib and trastuzumab. Limited experience is available with angiogenesis inhibitors, apoptosis inhibitors and COX-2 inhibitors. As yet, targeted therapies are proven to be safe often in combination with chemoradiation, but modestly effective for esophageal cancer. Phase III trials have not been published yet and, therefore, for targeted therapies also, possibly using new concepts, more studies are needed.     

Emerging intravesical drugs for the treatment of non muscle-invasive bladder cancer

Introduction: Bladder cancer (BC) is a severe health burden: and has high recurrence and progression rates. Standard treatment starts with TURB followed by intravesical chemotherapy with Mitomycin C or immunotherapy with BCG. However, successful management still remains a challenge, because approximately 30% of patients have recurrence or progression within 5 years, and treatment has considerable side effects. Anticipating on the upcoming BCG shortage emphasizes, moreover, the necessity to develop and study novel treatments. This review explores emerging and novel salvage treatments as well as approaches of current treatments with decrease side-effects for non muscle-invasive bladder cancer (NMIBC).

Areas covered: In this review, the authors provide an overview of the novel and emerging therapies for NMIBC. They also provide the currently available data and ongoing trials.

Expert opinion: Key findings in the field of research on emerging intravesical drugs for the treatment of NMIBC are the promising results for device assisted treatments, treatment with intravesical immunotherapy, and treatments to expedite the immunotherapy checkpoint inhibitors. Other novel therapies are still in an experimental stage and have to make the transition towards the clinical setting to determine the benefit in terms of reduced side-effects, recurrence and progression rates.     

Emerging drugs for bronchiectasis

Introduction: The global burden of disease due to bronchiectasis is high, disproportionately impacting developing countries and disadvantaged populations. Bronchiectasis, the destruction and dilation of airways, is due to a variety of causes and is characterized by a self-perpetuating cycle of airway inflammation, infection and obstruction that results in substantial morbidity and mortality. Although many therapies have been tested that address each of these three components, as well as the diseases that both cause and result from bronchiectasis, there have been few randomized, placebo-controlled trials.

Areas covered: In this review, current knowledge of the clinical features, pathophysiology and epidemiology of bronchiectasis among both adults and children is summarized. We discuss the quality and extent of evidence supporting current treatment strategies, focusing on therapies for which the strongest evidence of efficacy exists. We then identify key goals for future research on the causes and treatments of a variety of types of bronchiectasis.

Expert opinion: Significant advances in the prevention and treatment of bronchiectasis will require substantially improved understanding of the pathogenesis of this orphan disease. A concerted, global effort to coordinate studies of both the pathophysiology and potential treatments of bronchiectasis, in its many forms, could lead to substantial improvements in outcomes.