Efficacy of trabectedin for the treatment of liposarcoma

Introduction: Trabectedin (ET-743) is a synthetic marine derived alkylating agent, extracted originally from a Caribbean Sea sponge. It is approved for the treatment of Soft Tissue sarcomas (STS) in Europe and recently by the FDA for liposarcomas and leiomyosarcomas.

Areas covered: Trabectedin has multiple mechanisms of action, including one targeting the FUS-CHOP oncogene in Myxoid/Round cell Liposarcomas. Numerous Phase I, II and III clinical trials have been conducted with Trabectedin. It has been studied as monotherapy or in combination with other chemotherapeutic agents. The recommended dose based on clinical trials is 1.5 milligrams/m² continuous infusion over 24 hours once every 3 weeks for STS with evidence of disease control in multiple clinical trials at this dose. The most common Grade 3/4 toxicities include neutropenia and transient noncumulative elevations of ALT and AST. Steroid pretreatment has shown efficacy in reducing liver and bone marrow toxicity. In phase III testing comparing trabectedin to dacarbazine, trabectedin was associated with a significantly improved progression free survival rate in patients with advanced lipo- and leiomyosarcomas.

Expert opinion: Trabectedin is an important new addition to the limited treatment options currently available for STS, especially for patients with liposarcoma that have progressed on standard chemotherapeutic regimens.     

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.     

The challenge of targeted therapies for gastric cancer patients: the beginning of a long journey

Introduction: Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced disease remains dismal. Collaborative, high-quality research and advances in high-throughput technologies have contributed to elucidate molecular pathways underpinning disease progression and have stimulated many clinical studies testing target therapies in the advanced disease setting. Although progress has been made thanks to trastuzumab in HER2 positive tumours, antiangiogenic drugs have produced conflicting results and EGFR-inhibitors have failed to show major improvements.

Areas covered: While commenting on the results of many key Phase III randomized trials, the Authors discuss the most promising classes of novel targeted agents and present the current challenges toward a customized treatment.

Expert opinion: Palliative chemotherapy became the worldwide standard of care for patients with advanced gastric cancers, producing significant life prolongation and improvement of life quality. Nevertheless, long-term outcomes of those patients remain poor. Because of the encouraging advancement in novel targeted therapies, such a disappointing scenario is now evolving. While results serve as a springboard for future research, more comprehensive efforts are needed to clarify the biological mechanisms underpinning cancer progression and help clinicians to develop new effective treatments.     

Targeted therapy of hepatocellular cancer

Importance of the field: Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide and third leading cause of cancer death. HCC is highly resistant to conventional systemic therapies, and prognosis for advanced HCC patients remains poor. However, identification of signaling pathways responsible for HCC growth and progression such as RAS/RAF/MEK/ERK or PI3K/AKT/mTOR has determined crucial molecular targets and led to development of novel promising targeted therapies.

Areas covered in this review: This article presents molecular mechanisms responsible for development and progression of HCC and strategies aimed to block important molecules involved in signal transduction. It also reviews the clinical studies evaluating efficacy and safety of novel targeted approaches for treatment of this malignancy.

What the reader will gain: Inhibition of molecular targets (ligands, membrane receptors and receptor-associated kinases) represents a promising strategy for treatment of HCC; in the case of sorafenib, this has already been demonstrated to significantly improve survival of advanced HCC patients. This article reviews novel therapeutic approaches that are based on combinations of different targeted agents with or without classic cytotoxic drugs.

Take home message: Despite significant progress, advanced HCC remains an incurable disease, and the overall efficacy of recently approved targeted therapy (sorafenib) remains moderate. It is to be hoped that several ongoing clinical trials evaluating novel targeted approaches for treatment of HCC will lead to further improvement in the management of advanced disease.     

Investigational therapies in phase II clinical trials for the treatment of soft tissue sarcoma

Introduction: Soft-tissue sarcomas (STS) are a heterogeneous group of diseases that are characterized by a historic lack of active treatment options. However, several new drugs and indications have become available in recent years.

Areas covered: This article reviews the most relevant phase II studies that utilize chemotherapy agents (aldoxorubicin, amrubicin, trabectedin alone or in combination with doxorubicin, and gemcitabine plus docetaxel), targeted therapies (Imatinib, dasatinib, regorafenib, tivozanib, palbociclib and selinexor), a combination of chemotherapy plus targeted therapies (fucusing on doxorubicin plus olaratumab) and immunotherapies (pembrolizumab, combination of nivolumab plus ipilimumab and adaptive cell therapy) in STS (other than gastrointestinal stromal tumors) (GIST) published from 2015. Some of these strategies are under further clinical development or will likely be assessed in future phase III studies.

Expert opinion: A series of novel treatments have shown encouraging results in STS in recent years. The most important is the combination of the standard cytotoxic agent doxorubicin plus the platelet-derived growth factor receptor (PDGFR) inhibitor olaratumab, although definitive results from a phase III trial are expected. Immunotherapy has not been as successful in STS so far. However, further investigations are ongoing.     

Systemic therapy for the treatment of endometrial cancer

ABSTRACT

Introduction: Endometrial cancer (EC) is one of the most frequent gynecological cancers worldwide. The gold standard treatment of EC is most certainly surgery and may very well be the only therapy in the early stages of disease. To improve outcomes in non-early EC, adjuvant therapy is often employed but this is not standardized. Adjuvant options can include radiotherapy, chemotherapy or a combination of both. Adjuvant chemotherapy could be indicated in high-risk stage I and II or advanced stage EC. Several clinical trials are ongoing in an attempt to define the optimal adjuvant treatment. Furthermore, chemotherapy is the front-line therapy in advanced unresectable, metastatic or recurrent endometrial cancer.

Areas covered: Herein, the authors review the first-line chemotherapy for the treatment of endometrial cancer and provide their expert perspectives on these therapies.

Expert opinion: Chemotherapy is fundamental in advanced/recurrent EC. Further evidence is needed to characterize the role of adjuvant chemotherapy. Future studies should consider genomic and molecular heterogeneities to identify even more efficient tailored therapies.     

Novel targeted therapies for the treatment of penile cancer

Introduction: The treatment of penile cancer has changed over the past decade in that it was primarily a surgically managed disease and those with locally advanced or metastatic disease uniformly had a very poor prognosis. However, with the use of better traditional systemic chemotherapeutic agents in the neoadjuvant and adjuvant settings, the disease-specific survival and general outlook has improved. However, there is still a large group of patients who will progress even while on systemic therapy. It is in those patients where the application of targeted therapies has been investigated with some experiencing partial or even complete responses. With the improvement seen in patients with chemotherapy refractory disease, the application of novel targeted agents in the neoadjuvant setting may have a resultant positive impact on patient survival.

Areas covered: This review includes research pertaining to targeted therapies, biomarkers and signaling pathways involved with penile cancer. The article was based on a literature search using the keywords ‘penile cancer’ and ‘targeted therapies’.

Expert opinion: Penile cancer at the advanced stages of the disease has a high mortality. The utilization of novel targeted therapies in these situations is warranted in combination with, or sequentially with, traditional cytotoxic chemotherapy to improve the patient survival rate. Personalized therapy is nearly here for penile cancer and should be made real within the next decade.     

Novel targets for the treatment of autosomal dominant polycystic kidney disease

Importance of the field: Autosomal dominant (AD) polycystic kidney disease (PKD) is the most common life-threatening hereditary disorder. There is currently no therapy that slows or prevents cyst formation and kidney enlargement in humans. An increasing number of animal studies have advanced our understanding of molecular and cellular targets of PKD.

Areas covered in the review: The purpose of this review is to summarize the molecular and cellular targets involved in cystogenesis and to update on the promising therapies that are being developed and tested based on knowledge of these molecular and cellular targets.

What the reader will gain: Insight into the pathogenesis of PKD and how a better understanding of the pathogenesis of PKD has led to the development of potential therapies to inhibit cyst formation and/or growth and improve kidney function.

Take home message: The results of animal studies in PKD have led to the development of clinical trials testing potential new therapies to reduce cyst formation and/or growth. A vasopressin V2 receptor antagonist, mTOR inhibitors, blockade of the renin–angiotensin system and statins that reduce cyst formation and improve renal function in animal models of PKD are being tested in interventional studies in humans.     

QSAR studies in the discovery of novel type-II diabetic therapies

Introduction: Type-II diabetes mellitus (T2DM) is a complex chronic disease that represents a major therapeutic challenge. Despite extensive efforts in T2DM drug development, therapies remain unsatisfactory. Currently, there are many novel and important antidiabetic drug targets under investigation by many research groups worldwide. One of the main challenges to develop effective orally active hypoglycemic agents is off-target effects. Computational tools have impacted drug discovery at many levels. One of the earliest methods is quantitative structure–activity relationship (QSAR) studies. QSAR strategies help medicinal chemists understand the relationship between hypoglycemic activity and molecular properties. Hence, QSAR may hold promise in guiding the synthesis of specifically designed novel ligands that demonstrate high potency and target selectivity.

Areas covered: This review aims to provide an overview of the QSAR strategies used to model antidiabetic agents. In particular, this review focuses on drug targets that raised recent scientific interest and/or led to successful antidiabetic agents in the market. Special emphasis has been made on studies that led to the identification of novel antidiabetic scaffolds.

Expert opinion: Computer-aided molecular design and discovery techniques like QSAR have a great potential in designing leads against complex diseases such as T2DM. Combined with other in silico techniques, QSAR can provide more useful and rational insights to facilitate the discovery of novel compounds. However, since T2DM is a complex disease that includes several faulty biological targets, multi-target QSAR studies are recommended in the future to achieve efficient antidiabetic therapies.     

Update on the pharmacotherapy for myelodysplastic syndromes

Introduction: For many decades, myelodysplastic syndromes (MDS) were a poorly understood disease group with no approved therapies, and patient management largely relied upon supportive care and intensive chemotherapy. The last decade has seen many scientific and therapeutic advances culminating in the US FDA approval of three drugs for the treatment of these complex malignancies: lenalidomide, azacitidine and decitabine.

Areas covered: This review summarizes the major prognostic risk models that guide treatment decisions and examines the available literature on the mechanism of action and efficacy of each of the approved agents. The authors also discuss evidence supporting the use of other therapies that have entered the standard of care including growth factors, immunosuppressive therapy and stem-cell transplantation.

Expert opinion: While significant progress has been made in understanding the molecular basis of MDS, much of this has yet to translate into therapeutic benefit. Each of the available treatment modalities has shortcomings, and both combination strategies and novel agents are under investigation in clinical trials to improve outcomes.     

Pharmacotherapy of neuroblastoma

Importance of the field: Neuroblastoma, a tumor of the sympathetic nervous system, is the most common extracranial solid tumor of early life. High risk disease in older children remains a therapeutic challenge, despite high-intensity therapy with correspondingly significant short- and long-term toxicities.

Areas covered in this review: We have reviewed therapy for neuroblastoma over the last three decades. This includes cytotoxic chemotherapy, immunotherapy, radionuclides, antiangiogenic compounds, and molecularly targeted agents. We provide a perspective on the incorporation of these drugs into therapy for neuroblastoma.

What the reader will gain: The reader will gain a better understanding of these novel agents and their targets in neuroblastoma. The reader will also gain insight into the need to define through sequential, carefully designed clinical trials, the roles and toxicities of these therapies, especially if the combination of targeted and conventional cytotoxic agents is used.

Take home message: Advanced-stage neuroblastoma in older infants and children remains a disease that is difficult to cure. New, targeted agents may improve both the therapeutic index and the outcome, but are, for the most part, in early development and present a challenge for clinical trial design given both the rarity of this disease and its responsiveness (albeit incomplete) to currently used cytotoxic agents.     

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 therapeutics in refractory renal cell carcinoma

Introduction: Metastatic renal cell carcinoma (mRCC) has seen the introduction of numerous new treatments over the past decade. However, the efficacy of these therapies has plateaued, and new treatment options are needed for the majority of patients with mRCC whose disease inevitably progresses through one or more standard therapies (‘refractory’ mRCC). Recently approved agents in this space have shown great promise.

Areas covered: This article reviews the evidence behind current management strategies for mRCC. After reviewing clinical trials that established current first-line therapies and agents used in the refractory setting, we address new ideas for the treatment of refractory disease including combination therapies and novel targeted agents. In particular, we focus on targeted immunotherapy in refractory mRCC. We conclude by considering future directions in combination treatments utilizing these novel agents.

Expert opinion: Numerous approaches have produced tangible benefits for the treatment of patients with mRCC. These include development of next generation VEGFR/TKIs, targeted immunotherapy agents, and the development of combined regimens. In particular, immunotherapy agents targeting the PD1/PD-L1 pathway have shown great promise with a robust survival advantage seen in patients treated with nivolumab. A tolerable side effect profile of immunotherapy agents makes them amenable for use in combination therapies and ongoing trials are addressing this question.     

Advances in pharmacotherapy of small cell lung cancer

Introduction: Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastatic dissemination and responsiveness to initial therapy. The incidence of SCLC has been declining over the past two decades. Limited-stage SCLC is a potentially curable disease with long-term survival of ～ 20% when treated with platinum-based chemotherapy plus concurrent thoracic radiation and prophylactic cranial irradiation. For patients with extensive-stage SCLC, survival can be increased with combination platinum-based chemotherapy, but the disease remains incurable.

Areas covered: This review looks at the current advances in pharmacotherapy for SCLC.

Expert opinion: Many chemotherapeutic strategies and newer cytotoxic agents have been evaluated in SCLC, and some had promising activity in early clinical trials. However, none have demonstrated consistent improvements in outcome over standard platinum-based treatment. Similarly, although many potential molecular targets have been identified in preclinical studies of SCLC, molecularly targeted therapy has yet to demonstrate any substantial activity in clinical trials. Nonetheless, future advances in this disease will undoubtedly depend on improvements in our understanding of the molecular mechanisms that drive the proliferation and survival of SCLC cells.     

New targeted therapies for renal cell carcinoma

Introduction: The aim of treatment in metastatic renal cell carcinoma is palliation. In the last 5 years, multiple targeted agents have been developed which have resulted in prolongation of patients' lives, but complete responses remain rare. New therapies and approaches are required to further improve the prognosis for patients with this disease.

Areas covered: This review discusses the molecular targets in renal cell carcinoma relevant to the development of new treatments and describes the progress of novel therapies. The evidence is compiled from the PubMed database and proceedings of scientific meetings, searched up to December 2010.

Expert opinion: A multitude of experimental agents are in clinical development and offer theoretical advantages over those currently in use. It is hoped that these treatments will result in better long-term control of metastatic renal cell carcinoma, with improved side effect profiles, but curative treatment in this disease remains elusive until the mechanisms underlying response and resistance to therapy are elucidated. Progress in the field has been limited by inadequate tissue collection within clinical trials; current and future clinical trial design will incorporate a larger translational component in an attempt to establish predictive biomarkers.     

Aldoxorubicin for the treatment of soft tissue sarcoma

Intoduction: Soft tissue sarcomas (STS) encompass a group of rare tumors arising from mesenchymal tissue. Traditionally, anthracycline-based chemotherapy, with doxorubicin, is the main treatment for advanced STS.

Areas covered: Aldoxorubicin is a doxorubicin derivative containing a carboxylic hydrazone and serves as a prodrug of doxorubicin. It covalently binds to albumin in the blood until reaching the acidic tumor environment, which dissolves the hydrazone linker, thus releasing doxorubicin into the tissue. In this review paper, we analyze the pharmacokinetics, current phase I, phase II, and phase III trials, as well as adverse effect profile of aldoxorubicin in patients with advanced STS.

Expert opinion: Aldoxorubicin represents a promising drug for treatment of sarcomas. The drug has minimal cardiac toxicity, which represents a significant advantage to doxorubicin. Preliminary phase 3 study results demonstrate PFS advantage in patients with leiomyosarcoma and liposarcoma. However, more studies are needed to establish the role of aldoxorubicin in sarcoma treatment.     

Advances in the pharmacotherapeutic management of dementia with Lewy bodies

ABSTRACT

Introduction: Dementia with Lewy bodies (DLB) is the second most common type of dementia in people over 65 years of age. Given the complex clinical phenotype, the management of DLB may be challenging, especially considering that there is limited evidence about specific interventions, and there are currently no Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved medications.

Areas covered: This article provides an overview of the current pharmacotherapy in DLB and gives review to the most recent drug candidates in clinical trials.

Expert opinion: Commonly prescribed drugs are primarily aimed at treating the most troublesome clinical features of DLB. Although these medications provide some benefit to symptoms, there is, unfortunately, a lack of DLB-specific evidence on effective treatments and their off-label use. Indeed, most treatments used come from clinical trials on patients with Alzheimer’s disease or Parkinson’s disease. Thus, there is an urgent need for randomized clinical trials in DLB patients. Despite several challenges, potential new drugs are in ongoing clinical trials; furthermore, as our understanding of molecular and cellular mechanisms underlying DLB broaden, it is likely that we will identify novel drug targets for the development of better and more effective symptomatic products and disease-modifying therapies.     

Targeting miR-21 in glioma: a small RNA with big potential

Importance of the field: Glioma therapies have produced relatively small improvements over the past decade, highlighting an important need to identify novel ways to target this disease. Targeted therapies against single activated protein kinases have proven effective in some cancers including gastrointestinal stromal cancer and colon cancer, but not yet in gliomas where multiple pathways and targets may be involved. MicroRNAs are emerging as key regulators of multiple pathways involved in cancer development and progression and may become the next targeted therapies in glioma.

Areas covered in this review: This review covers the basics of microRNA biology and specifically focuses on the roles of miR-21 in glioma and its potential as target for glioma therapy.

What the reader will gain: This review will provide the reader with an in depth understanding of how miR-21 functions in glioma. We also review the current state of studies designed to specifically target miR-21 as a potential future therapeutic.

Take home message: Identifying novel targets for the treatment of glioma is critical for advancing the current state of the field. MicroRNAs provide a novel target; and in glioma, targeting miR-21 may have broad consequences for the tumor that make it an attractive potential therapeutic.     

Investigational therapies for squamous cell lung cancer: from animal studies to phase II trials

Introduction: It remains challenging to treat squamous cell lung cancer (SCC) with limited therapeutic options. However, recent breakthroughs in targeted therapies and immunotherapies have shed some light on the management of this deadly disease.

Areas covered: The article first reviews the current treatment options for advanced SCC, especially recent FDA approved molecular agents (afatinib, ramucirumab and necitumumab) and immunotherapies (nivolumab, pembrolizumab and atezolimumab). We then provide an overview on investigational therapies with data ranging from preclinical to phase II studies, focusing on new cytotoxic agents, emerging molecularly targeted agents (including a PARP inhibitor for Homologous Recombinant Deficiency positive SCC) and novel immunotherapeutic strategies.

Expert opinion summary: Identification of potential therapeutic targets, development of novel clinical trials and the rapid approvals of immune checkpoint inhibitors have shifted the management paradigm for squamous cell lung cancer. On the other hand, continued efforts are needed to identify the predictive biomarkers and to investigate novel mechanistically-driven mono- and combination therapies. We need to learn more about the biology behind immune checkpoint blockade and tumor genomics in SCC for better patient selection and future trial design.