Molecularly targeted therapies in adult soft tissue sarcomas: present approach and future directions

Background: Sarcomas are rare neoplasms. Given the overwhelming chemotherapy resistance of the disease, patients with progressive and metastatic soft tissue sarcomas are ideal candidates for trials of investigational new drugs. Objective: The authors review the molecular mechanisms underlying soft tissue sarcomas and discuss molecularly targeted therapies developed to improve the poor outcome of these uncommon tumors. Methods: A Medline and American Society of Clinical Oncology abstract search was conducted using the keyword ‘soft tissue sarcoma’. Articles and abstracts were reviewed and eligible for inclusion if they used targeted therapies for the treatment of patients with soft tissue sarcomas. Results/conclusion: Phase II clinical trials for patients with soft tissue sarcomas using novel targets and present recognized targets are ongoing and planned.     

Targeting pancreatic expressed PAX genes for the treatment of diabetes mellitus and pancreatic neuroendocrine tumors

Introduction: Four members of the PAX family, PAX2, PAX4, PAX6 and PAX8 are known to be expressed in the pancreas. Accumulated evidences indicate that several pancreatic expressed PAX genes play a significant role in pancreatic development/functionality and alterations in these genes are involved in the pathogenesis of pancreatic diseases.

Areas covered: In this review, we summarize the ongoing research related to pancreatic PAX genes in diabetes mellitus and pancreatic neuroendocrine tumors. We dissect the current knowledge at different levels; from mechanistic studies in cell lines performed to understand the molecular processes controlled by pancreatic PAX genes, to in vivo studies using rodent models that over-express or lack specific PAX genes. Finally, we describe human studies associating variants on pancreatic-expressed PAX genes with pancreatic diseases.

Expert opinion: Based on the current literature, we propose that future interventions to treat pancreatic neuroendocrine tumors and diabetes mellitus could be developed via the modulation of PAX4 and/or PAX6 regulated pathways.     

Therapeutic targets for neuroblastomas

Introduction: Neuroblastoma (NB) is the most common and deadly solid tumor in children. Despite recent improvements, the long-term outlook for high-risk NB is still < 50%. Further, there is considerable short- and long-term toxicity. More effective, less toxic therapy is needed, and the development of targeted therapies offers great promise.

Areas covered: Relevant literature was reviewed to identify current and future therapeutic targets that are critical to malignant transformation and progression of NB. The potential or actual NB therapeutic targets are classified into four categories: i) genes activated by amplification, mutation, translocation or autocrine overexpression; ii) genes inactivated by deletion, mutation or epigenetic silencing; iii) membrane-associated genes expressed on most NBs but few other tissues; or iv) common target genes relevant to NB as well as other tumors.

Expert opinion: Therapeutic approaches have been developed to some of these targets, but many remain untargeted at the present time. It is unlikely that single targeted agents will be sufficient for long-term cure, at least for high-risk NBs. The challenge will be how to integrate targeted agents with each other and with conventional therapy to enhance their efficacy, while simultaneously reducing systemic toxicity.     

Xenograft and genetically engineered mouse model systems of osteosarcoma and Ewing's sarcoma: tumor models for cancer drug discovery

Introduction: There are > 75 histological types of solid tumors that are classified into two major groups: bone and soft-tissue sarcomas. These diseases are more prevalent in children, and pediatric sarcomas tend to be highly aggressive and rapidly progressive. Sarcomas in adults may follow a more indolent course, but aggressive tumors are also common. Sarcomas that are metastatic at diagnosis, or recurrent following therapy, remain refractory to current treatment options with dismal overall survival rates. A major focus of clinical trials, for patients with sarcoma, is to identify novel and more effective therapeutic strategies targeted to genomic or proteomic aberrations specific to the malignant cells. Critical to the understanding of the potential for targeted therapies are models of disease that are representative of clinical disease and predictive of relevant clinical responses.

Areas covered: In this article, the authors discuss the use of mouse xenograft models and genetically engineered mice in cancer drug discovery. The authors provide a special focus on models for the two most common bone sarcomas: osteosarcoma (OS) and Ewing's sarcoma (ES).

Expert opinion: Predicting whether a new anticancer agent will have a positive therapeutic index in patients with OS and ES remains a challenge. The use of mouse sarcoma models for understanding the mechanisms involved in the response of tumors to new treatments is an important step in the process of drug discovery and the development of clinically relevant therapeutic strategies for these diseases.     

Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers

Tropomyosin receptor kinase A, B and C (TRKA, TRKB and TRKC), which are well-known members of the cell surface receptor tyrosine kinase (RTK) family, are encoded by the neurotrophic receptor tyrosine kinase 1, 2 and 3 (NTRK1, NTRK2 and NTRK3) genes, respectively. TRKs can regulate cell proliferation, differentiation and even apoptosis through the RAS/MAPKs, PI3K/AKT and PLCγ pathways. Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors, and TRKs have become promising antitumor targets. Therefore, achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications. This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins, the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity, and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.KEY WORDS: Tropomyosin receptor kinase, Neurotrophic receptor tyrosine kinase fusions, Small-molecule inhibitor, NTRK fusion cancer     

DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors

Malignant brain tumors, which are the leading cause of cancer-related morbidity and mortality in children, span a wide spectrum of diseases with distinct clinical phenotypes but may share remarkably similar morphologic features. Until recently, few molecular markers of childhood brain tumors have been identified, which has limited therapeutic advances. Recent global genomic studies have enabled robust molecular classification of childhood brain tumors and the identification and consolidation of rare, seemingly disparate clinical entities. It is now increasingly evident that deregulation of epigenetic processes contributes substantially to heterogeneity in tumor phenotypes and comprise significant drivers of cancer initiation and progression. Specifically, DNA hypermethylation and silencing of critical tumor suppressor genes by DNA methyltransferases (DNMT) has emerged as an important and fundamental mechanism in brain tumor pathogenesis. These observations have been underscored by the recent discovery of TTYH1-C19MC gene fusions in an aggressive pediatric embryonal brain tumor, which results in deregulation and increased expression of a neural-specific DNMT3B isoform in C19MC-associated brain tumors. Our observations that pharmacological inhibitors of DNMTs and histone deacetylases significantly inhibit growth of cells derived from C19MC-associated tumors indicate targeting of epigenomic modifiers as a novel therapeutic approach for these highly treatment-resistant tumors.     

The sonic hedgehog-GLI1 signaling pathway in brain tumor development

Introduction: The sonic hedgehog (Shh) pathway is a regulatory network involved in development and cancer. Proteins like Ptch, SMO, and Gli are central to the Shh pathway. Other proteins like HHIP, SUFU, Bmi-1, Cyclin D2, Plakoglobin, PAX6, Nkx2.2, and SFRP1 are not so well understood in Shh regulation as Gli-1 downstream target genes.

Areas covered: In this review we try to explain the Shh pathway components and their role in development and cancer, mainly of the brain. A summary of each of the proteins is presented together with an overview of their involvement in cancer.

Expert opinion: Genetic alterations of the Shh pathway have been detected in cancer stem cells, a subgroup of tumor cells implicated in the origin and maintenance of tumors, being responsible for cancer recurrence and chemotherapy resistance. Cancer stem cells constitute a novel target for biomedical researchers. Specifically, the Shh pathway is being explored as a new opportunity for targeted therapies against tumors. Therefore, a better knowledge of every of the regulators of the Shh pathway is needed.     

New approaches for pediatric rhabdomyosarcoma drug discovery: targeting combinatorial signaling

Introduction: Rhabdomyosarcomas (RMS) are rare heterogeneous pediatric tumors that are treated by surgery, chemotherapy and irradiation. New therapeutic approaches are needed, especially in the advanced stages to target the pro-oncogenic signals. Exploring the molecular interactions of the regulatory signals and their roles in the developmental aspects of different subtypes of RMS is essential to identify potential targets and develop new therapeutic drugs.

Areas covered: Insights into different drug discovery approaches are discussed with specific emphasis on gene expression profiling, fusion protein, role of small interfering RNA (siRNA)- and microRNA (miRNA)-based discovery approaches, targeting cancer stem cells, and in vitro and in vivo model systems. Targeting some overexpressed signals along with the possibilities of combination therapy of validated drug targets is discussed. Additionally, methods to overcome the limitations of discovery-based research are briefly discussed.

Expert opinion: Due to drug resistance, ineffective therapy in advanced stages and relapse, there is a demand to explore new drug targets and discovery approaches. Implementing miRNA-based profiling would reveal the extent of miR-based regulation, various biomarkers and potential targets in RMS. A suitable combination of innovative techniques and the use of model systems might assist the identification and validation of novel targets and drug discovery methods. Combining specific drugs along with type-specific target inhibition of overexpressed mRNAs through siRNA approaches would enable the development of personalized therapy.     

Clinical trial design methodologies for advanced sarcoma therapy

Abstract

Sarcomas are rare and heterogeneous mesenchymal tumors affecting connective tissue. For many years, doxorubicin-based chemotherapy has been the main systemic therapy option for patients with metastatic soft tissue sarcoma. This ‘one size fits all’ approach has led to marginal benefit, but the introduction of tyrosine kinase inhibitors in gastrointestinal stromal tumors has shown that sub-type-specific, molecularly targeted therapy can lead to significant advances. Next generation sequencing has led to the discovery of the biologic nature of many histological sub-types of sarcomas, and now an emphasis has been placed on assessment of novel therapies for each sub-group. However, the transition into the clinic is both challenging and protracted due to the rarity and heterogeneity of these tumors. The high failure rate of phase III trials in oncology has shown that clinical trials can be difficult to run, especially in rare forms of cancer like sarcomas. In this review, the authors provide an evaluation of the potential approaches toward better clinical trial design in sarcoma studies.     

Emerging protein kinase inhibitors for non-small cell lung cancer

Introduction: In the current paradigm of precision medicine in non-small cell lung cancer (NSCLC), the therapeutic strategy is determined by the molecular characteristics. The best examples of this approach are the kinase inhibitors that selectively target tumors bearing an epidermal growth factor receptor (EGFR) mutation or an anaplastic lymphoma kinase (ALK) rearrangement. Emerging protein kinase inhibitors may enhance our ability to effectively treat these and other genomic subtypes of NSCLC.

Areas covered: This article reviews the next-generation kinase inhibitors targeting EGFR and ALK-positive NSCLC. In addition, targeted kinase inhibitors in clinical development for other specific molecular subtypes of NSCLC are covered, including ROS1, BRAF, RET, HER2, KRAS (upstream of the MEK kinase), MET, PIK3CA, FGFR1, DDR2, VEGFR and AAK.

Expert opinion: In EGFR-mutant NSCLC, there are several kinase inhibitors with promising activity, most notably dacomitinib and CO-1686 in tumors with acquired resistance to EGFR-targeted therapy. Next-generation ALK inhibitors appear to have greater potency than crizotinib and several ongoing trials may shed light on their role in both ALK- and ROS1-positive NSCLC. While there is optimism regarding the role of kinase inhibitors in other molecular subtypes, the available evidence is too immature to make recommendations and results from prospective trials are needed.     

Targeting the RAS oncogene

Introduction: The Ras proteins (K-Ras, N-Ras, and H-Ras) are GTPases that function as molecular switches for a variety of critical cellular activities and their function is tightly and temporally regulated in normal cells. Oncogenic mutations in the RAS genes, which create constitutively-active Ras proteins, can result in uncontrolled proliferation or survival in tumor cells.

Areas covered: The paper discusses three therapeutic approaches targeting the Ras pathway in cancer: i) Ras itself, ii) Ras downstream pathways, and iii) synthetic lethality. The most adopted approach is targeting Ras downstream signaling, and specifically the PI₃K-AKT-mTOR and Raf-MEK pathways, as they are frequently major oncogenic drivers in cancers with high Ras signaling. Although direct targeting of Ras has not been successful clinically, newer approaches being investigated in preclinical studies, such as RNA interference-based and synthetic lethal approaches, promise great potential for clinical application.

Expert opinion: The challenges of current and emerging therapeutics include the lack of “tumor specificity” and their limitation to those cancers which are “dependent” on aberrant Ras signaling for survival. While the newer approaches have the potential to overcome these limitations, they also highlight the importance of robust preclinical studies and bidirectional translational research for successful clinical development of Ras-related targeted therapies.     

Novel targeted treatment options for advanced cholangiocarcinoma

Introduction: Surgical resection remains the mainstay of potentially curative treatment in the early stages of cholangiocarcinoma, whereas for the advanced stage, systemic chemotherapeutics and experimental targeted therapies are the primary treatment options. The molecular heterogeneity of the tumor is based on location, liver dysfunction, and relative rarity of the disease and confers challenges for clinical trial enrollment. The advancements in the understanding of molecular pathogenesis of cholangiocarcinoma have led to the development of targeted therapies that are currently being evaluated in the clinical trials.

Areas covered: This review summarizes the current understanding and future directions of targeted therapeutic options in the management of advanced cholangiocarcinoma.

Expert opinion: Advanced cholangiocarcinoma has a dismal prognosis; improved understanding of the molecular pathogenesis and advancements in development of targeted therapy offers hope that we may improve outcomes in this rare, but highly lethal cancer. Among the newly discovered molecular alterations, targeting FGFR2 fusions, IDH1/2 mutations and HER2 receptors hold great promise for improving the future management of cholangiocarcinoma. Immunotherapy in combination with targeted agents and chemotherapy may improve outcomes. In addition, drugs targeting the MEK, EGFR, KRAS, BRAF, and ROS1 pathways and neo-angiogenesis may also provide new horizons in the management of cholangiocarcinoma.     

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

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

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

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

Molecularly targeted therapies in adult soft tissue sarcomas: present approach and future directions

BACKGROUND: Sarcomas are rare neoplasms. Given the overwhelming chemotherapy resistance of the disease, patients with progressive and metastatic soft tissue sarcomas are ideal candidates for trials of investigational new drugs. OBJECTIVE: The authors review the molecular mechanisms underlying soft tissue sarcomas and discuss molecularly targeted therapies developed to improve the poor outcome of these uncommon tumors. METHODS: A Medline and American Society of Clinical Oncology abstract search was conducted using the keyword 'soft tissue sarcoma'. Articles and abstracts were reviewed and eligible for inclusion if they used targeted therapies for the treatment of patients with soft tissue sarcomas. Results/conclusion: Phase II clinical trials for patients with soft tissue sarcomas using novel targets and present recognized targets are ongoing and planned.     

Targeted therapy and promising novel agents for the treatment of advanced soft tissue sarcomas

Introduction: Soft tissue sarcomas (STS) are a rare and difficult to treat malignancy. Efforts to utilize targeted therapy have been ongoing for the last decade and have resulted in the approval of pazopanib for treatment of advanced disease. Although several other agents have been investigated, the inability to predict responses remains a limiting factor to the incorporation of these agents into treatment.

Areas covered: The authors summarize recent clinical findings from studies focused on targeted agents in STS. The authors also discuss the potential approaches and ongoing clinical trials with novel agents.

Expert opinion: A major challenge in the treatment of advanced STS remains a lack of predictive biomarkers to guide therapy and the heterogeneity of response among different histologies of sarcoma. Incorporation of predictive biomarker analysis into clinical trials is warranted. Additionally, mechanisms of treatment resistance and parallel pathways of tumor growth pose challenges in how we treat these tumors. An active area of research in STS is the use of novel combinations of agents, such as chemotherapy combined with multi-targeted agents. The potential of immune check point inhibitors is being explored in advanced STS and is hoped to further expand our treatment armamentarium.     

Treatment strategies for DNA repair-deficient prostate cancer

Introduction: Common recurrent genetic alterations have been identified in prostate cancer through comprehensive sequencing efforts, and the prevalence of mutations in DNA repair pathway genes in patients with advanced and metastatic disease approaches 20–25%. Identification of these underlying DNA repair defects may present unique treatment opportunities for patients, both in terms of standard-of-care treatments and selected investigational agents.

Areas covered: We review our current understanding of the genomic landscape of prostate cancer, with special attention to alterations in DNA repair pathway genes in metastatic castration-resistant disease. For patients with tumors deficient in homologous recombination repair, potential opportunities for treatment include platinum chemotherapy, poly(ADP) ribose polymerase (PARP) inhibitors, bipolar androgen therapy, and maybe immune checkpoint blockade therapy. In addition, tumors with mismatch repair defects (i.e. microsatellite instability) may be particularly susceptible to checkpoint blockade immunotherapy.

Expert commentary: We anticipate that genomic profiling of tumors will become necessary to guide treatment of advanced prostate cancer in the coming years. Work is needed to define the optimal tissue to test, and to define the natural history of tumors with specific genetic defects. The prognostic and therapeutic importance of germline vs somatic DNA repair alterations, and mono-allelic vs bi-allelic inactivation, also remains unclear. Finally, optimal strategies to sequence or combine targeted agents for these patients with ‘actionable’ mutations are now needed.     

基于网络药理学和实验验证白藜芦醇治疗类风湿性关节炎的作用机制

目的 通过网络药理学、分子动力学模拟探讨白藜芦醇对类风湿性关节炎的治疗作用及潜在机制,并进行实验验证。方法 使用TCMSP、Batman-TCM、SwissTarget Prediction数据库预测白藜芦醇的作用靶点;使用GeneCards和OMIM数据库预测类风湿性关节炎的潜在治疗靶点;使用STRING和Cytoscape3.8.0构建蛋白相互作用（PPI）网络,并进行MCC分析、MCODE分析、基因本体（GO）功能和京都基因与基因组百科全书（KEGG）富集分析,对KEGG通路和靶点之间绘制网络图;使用分子对接和分子动力学模拟方法对核心靶点与白藜芦醇进行模拟;构建类风湿性关节炎大鼠模型,Western blotting法检测p-磷脂酰肌醇3-激酶（p-PI3K）、p-蛋白激酶B1（p-Akt1）和p-细胞外信号调节激酶（p-ERK）1/2的表达水平。结果 白藜芦醇有310个靶点,与类风湿性关节炎有207个交集靶点,MCC分析发现Akt1、PIK3CA、PIK3CB、促分裂原活化蛋白激酶（MAPK）1、MAPK3、信号传导与转录激活因子3（STAT3）是其中核心基因。GO和KEGG富集分析发现,癌症通路、糖尿病并发症中的晚期糖基化终末产物–晚期糖基化终末产物受体（AGE-RAGE）信号通路、细胞凋亡和PI3K/Akt信号通路可能是白藜芦醇影响类风湿性关节炎的关键通路;分子对接和分子动力学模拟也发现Akt1、PIK3CA和MAPK1与白藜芦醇之间有很强的结合能力。动物实验发现,与对照组相比,模型组大鼠关节炎指数明显增加,而给予白藜芦醇后大鼠的关节炎指数明显下降;p-PI3K、p-AKT表达明显上升,p-ERK1/2的表达明显下降（P＜0.05、0.01）。结论 白藜芦醇能改善类风湿性关节炎大鼠的关节炎指数,并可能通过Akt1、PIK3CA和MAPK1等靶点和PI3K/Akt信号通路来发挥关键治疗作用。     

Molecular targeted therapy for patients with melanoma: the promise of MAPK pathway inhibition and beyond

Importance of the field: Recent discoveries have expanded the understanding of the molecular signaling events critical to melanomagenesis and led to the development of targeted therapeutic agents that are revolutionizing the treatment of patients with advanced melanoma.

Areas covered in this review: This article reviews current therapy and its limitations, describes the key pathogenic mechanisms in melanoma for which inhibitors have been tested, and summarizes the results of clinical trials involving molecularly targeted agents in this disease.

What the reader will gain: There has been an explosion of preclinical and clinical research aimed at targeting the key molecular alterations in melanoma for therapeutic benefit. These findings will be presented and placed in the proper clinical context, affording information regarding the current molecular targets in the melanoma and the activity and limitations of therapeutic agents directed against them.

Take home message: Greater understanding of the pathogenic mechanisms underlying melanoma development has prompted the development of new therapeutic approaches aimed at counteracting these processes. While progress made over the past few years has generated considerable excitement, the benefits of these new therapies are still limited by incomplete and transient tumor regressions. It is hoped that with further investigation, particularly into mechanisms of treatment de novo and acquired treatment resistance, these limitations can be overcome.