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.     

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.     

New therapies in soft tissue sarcoma

Importance of the field: Soft tissue sarcomas are rare mesenchymal tumors accounting for <?1% of all adult neoplasia. In the last decade, locally advanced and metastatic soft tissue sarcoma have been managed only through surgery, radiotherapy and standard chemotherapy (mainly based on anthracycline and ifosfamide). Despite the efforts, overall 5-year survival rate in patients with soft tissue sarcomas of all stages remains only 50 – 60%.

Areas covered in this review: In the present article, all the main new molecules under clinical evaluation for the treatment of soft tissue sarcoma are revised by describing the mechanism of action, the biological rationale of their use in sarcoma and by reporting the available data about safety and efficacy, up to 2009.

What the reader will gain: A brief summary of the standard treatments available at the moment and a complete analysis of the state of art about the development of new target therapies in the management of soft tissue sarcoma.

Take home message: The identification of new biological therapies that target soft tissue sarcoma tumorigenesis key points seems to offer a real opportunity of improving the prognosis of this often aggressive disease. In this sense, the best management for soft tissue sarcoma patients is in a clinical trial and participation in clinical trials should be encouraged.     

Therapeutic pipeline for soft-tissue sarcoma

Introduction: Soft-tissue sarcomas (STS) represent a heterogeneous group of malignant tumors originating from connective tissues. Over recent years, this heterogeneity has led to a molecular breakdown of STS and subsequent use of targeted agents in several molecularly defined subgroups. After the initial success of imatinib in gastrointestinal stromal tumors, several other compounds have shown promising activity in some but not all subgroups of sarcoma.

Areas covered: This review discusses the rational and clinical results, when available, that support this subtype-directed approach. In the vast majority of cases, these agents have been tested only in patients with advanced disease; as chemotherapeutic agents are developed as non-histotype-specific therapies, they are not discussed here. The PubMed literature was searched using the terms ‘sarcoma’, ‘angiogenesis’, ‘mTOR’ and ‘targeted agents’. Proceedings of the annual meeting of the American Society of Clinical Oncology as well as those of the Connective Tissue Oncology Society were also searched for relevant information.

Expert opinion: Many agents are currently developed in a subtype-specific manner in STS and this represents a significant leap forward. However, much remains to be done to improve our understanding of the molecular biology of this heterogeneous group of diseases.     

A call to ARMS: targeting the PAX3-FOXO1 gene in alveolar rhabdomyosarcoma

Introduction: Expression of fusion oncoproteins generated by recurrent chromosomal translocations represents a major tumorigenic mechanism characteristic of multiple cancers, including one-third of all sarcomas. Oncogenic fusion genes provide novel targets for therapeutic intervention. The PAX3-FOXO1 oncoprotein in alveolar rhabdomyosarcoma (ARMS) is presented as a paradigm to examine therapeutic strategies for targeting sarcoma-associated fusion genes.

Areas covered: This review discusses the role of PAX3-FOXO1 in ARMS tumors. Besides evaluating various approaches to molecularly target PAX3-FOXO1 itself, this review highlights therapeutically attractive downstream genes activated by PAX3-FOXO1.

Expert opinion: Oncogenic fusion proteins represent desirable therapeutic targets because their expression is specific to tumor cells, but these fusions generally characterize rare malignancies. Full development and testing of potential drugs targeted to these fusions are complicated by the small numbers of patients in these disease categories. Although efforts to develop targeted therapies against fusion proteins should continue, molecular targets that are applicable to a broader tumor landscape should be pursued. A shift of the traditional paradigm to view therapeutic intervention as target-specific rather than tumor-specific will help to circumvent the challenges posed by rare tumors and maximize the possibility of developing successful new treatments for patients with these rare translocation-associated sarcomas.     

Targeted therapy in sarcomas: mammalian target of rapamycin inhibitors from bench to bedside

Introduction: Sarcomas are rare heterogeneous malignancies of mesenchymal origin relatively common during childhood. Disruption of the mammalian target of rapamycin (mTOR) pathway is a very common event during the tumorigenesis of several types of cancer. In particular, strong preclinical evidences suggest pivotal roles of this pathway during the sarcomagenesis. Therefore, the inhibition of mTOR via rapamycin, rapamycin analogs (rapalogs) and ATP-competitive inhibitors seems to be a promising path to follow for a fully tailored therapy.

Areas covered: The aim of the present review is to summarize the available data about the mechanisms of mTOR pathway, its biological implications and its possible role in the pathogenesis of soft tissue sarcoma. Moreover, preclinical and clinical evidences of different mTOR inhibitors in the treatment of sarcomas are reported.

Expert opinion: Early studies with mTOR inhibitors have demonstrated promising antitumor activity in patients with metastatic sarcoma who have failed standard treatments: that is why mTOR inhibitors represents today a promising chance to improve the prognosis of those patients affected by these rare disease, which is today still extremely poor.     

Investigational therapies for Ewing sarcoma: a search without a clear finding

Introduction: Ewing sarcoma family tumors (ESFT) are a group of aggressive diseases, characterized histologically by small, round, blue cells and genetically by translocation involving EWS and ETS partner genes. The current treatment of localized Ewing sarcoma (ES) requires a multi-disciplinary approach, including multidrug chemotherapy, administrated before and after local treatment, surgery and radiation therapy. Unfortunately, the cure rate of metastatic or refractory/recurrent disease is still very poor.

Areas covered: In this review, the authors summarize the new types of therapy and strategies aimed to improve the prognosis or cure ES. Herein, the authors discuss several preclinical and phase I-II studies with new-targeted therapies. The most studied therapies are insulin-like growth factor receptor (IGF1R) inhibitors but have limited efficacy. Other strategies include Mammalian Target of Rapamycin (mTOR) Inhibition, poly ADP ribose polymerase (PARP) inhibition, vascular endothelial growth factor (VEGF) inhibition, tyrosine kinase inhibitors and telomerase inhibitors, all with limited effectiveness.

Expert opinion: Future treatment strategies should combine one or more targeted therapies with conventional chemotherapy. Some combined modality treatments are under clinical study. However, treatment breakthroughs are still needed to improve the relatively poor prognosis of recurrent/metastatic ESFT.     

Current and advancing systemic treatment options for soft tissue sarcomas

Introduction: Soft tissue sarcomas are a collection of rare malignancies, the treatment of which has evolved over time. Although cytotoxic chemotherapy remains the cornerstone of management of metastatic disease, many new treatments have been developed or show great promise in the treatment of soft tissue sarcoma. Research into the different underlying pathogenesis of individual subtypes has driven progress in treatment. This has allowed development of treatments targeted to specific subtypes of sarcoma.

Areas covered: We provide a review of the current field of systemic therapy in soft tissue sarcoma. This is followed by an in-depth analysis of recent developments in treatment, as well as new treatments that are aimed at specific subtypes of sarcoma, and the biological rationale behind these therapies. We also look in detail at the promising new agents currently in development.

Expert opinion: Much progression has been made in treatment of soft tissue sarcomas with multiple exciting new treatments in development. However outcomes in general remain poor. Further research into the underlying pathogenesis of soft tissue sarcomas may help deliver more effective systemic therapies. Increased collaboration between basic science, translational and clinical investigators is required at national and international levels to maximise progress.     

Experimental therapies in Ewing's sarcoma

Background: Ewing's sarcoma/primitive neuroectodermal tumours (ES/PNET) are aggressive musculoskeletal tumours with a predilection for young people. With current treatments, significant numbers of patients relapse and survival is poor for those with metastatic disease. Objective: To review current experimental treatment strategies in ES/PNET and prospects for the future. Methods: A review of the literature and recent meeting presentations on established and experimental cytotoxic and biological therapies in the treatment of ES/PNET was performed. Results/conclusion: New combinations of conventional and emerging cytotoxics show some promise. Molecular techniques are being used to identify high-risk patients and potential cellular targets. Several novel biologically targeted agents have demonstrated encouraging preliminary clinical efficacy; it is hoped these combined with current chemotherapeutic agents may improve outcome in ES/PNET.     

Novel bone cancer drugs: investigational agents and control paradigms for primary bone sarcomas (Ewing's sarcoma and osteosarcoma)

Background: New investigational agents and chemotherapy regimens including cyclophosphamide + topotecan, temozolomide + irinotecan, and anti-IGF-1R antibodies in Ewing's sarcoma (ES) and liposomal muramyltripeptide phosphatidylethanolamine (L-MTP-PE), aerosol therapy, and bone-specific agents in osteosarcoma (OS) may improve survival and/or quality of life on ‘continuation’ therapy. Objective: Review of investigational approaches and control paradigms for recurrent or metastatic primary bone tumors. Methods: Analyze temozolomide + irinotecan data and review in the context of other newer approaches including antiangiogenesis, anti-IGF-1R antibodies and bisphosphonates for ES. Review some current state-of-the-art approaches for OS including L-MTP-PE, anti-IGF-1R inhibition, aerosol therapies and bone specific agents. Results/conclusion: L-MTP-PE with chemotherapy in OS has been shown to improve survival; compassionate access is available for recurrence and/or metastases. Aerosol therapy (granulocyte–macrophage colony stimulating factor, cisplatin, gemcitabine) for lung metastases is a promising approach to reduce systemic toxicity. The bone-specific agents including denosumab (anti-receptor activator of NF-κB ligand antibody) and bisphosphonates may have benefit against giant cell tumor, ES and OS. Anti-IGF-1R antibody SCH717454 has preclinical activity in OS but best effectiveness will most likely be in combination with chemotherapy earlier in therapy. Both temozolomide + irinotecan and cyclophosphamide + topotecan combinations are very active in ES and are likely to be tested with anti-IGF-1R antibodies against ES.     

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.     

Pharmacotherapy of sarcoma

Background: Comprising < 1% of adult malignancies and approximately 12% of pediatric malignancies, sarcomas are derived from a variety of connective tissues and exhibit highly variable responsiveness to therapy. The clinical and biologic heterogeneity of the > 50 histologic subtypes of sarcomas often require different therapeutic approaches. Objective: This review describes the use of therapeutic agents in the management of bone and soft-tissue sarcomas. Methods: Relevant literature is identified and presented from major conference proceedings, as well as using the PubMed search engine. Results/conclusions: Chemotherapy has improved outcomes over the past few decade, particularly in patients with certain bone sarcomas and gastrointestinal stromal tumors; while in the majority of patients, additional strategies are necessary.     

An overview of the mTOR pathway as a target in cancer therapy

Introduction: The mammalian target of rapamycin (mTOR) signaling cascade is a key regulatory pathway controlling initiation of mRNA translation in mammalian cells. The mTOR inhibitor rapamycin and its derivatives have shown potent antineoplastic activities in many preclinical models and clinical trials. First-generation mTOR inhibitors are now FDA-approved for the treatment of renal cell carcinoma.

Areas covered: This article reviews the components of the mTOR pathway and their normal functions, highlighting the most common alterations in the pathway, seen in various human malignancies. It also discusses elements and effectors of this signaling cascade and reviews the therapeutic relevance of pharmacological inhibitors of the pathway in several malignancies, including lymphomas, leukemias, sarcomas, renal cell carcinoma, and breast cancer.

Expert opinion: mTOR targeting is a highly promising therapeutic approach. First-generation mTOR inhibitors have already shown substantial activity in the treatment of certain tumors, while the emergence of second-generation catalytic mTOR inhibitors provides a better approach to target the pathway in malignant cells and has raised the potential for better clinical outcomes in the future.     

分子靶向药物治疗晚期胃肠道间质瘤的安全性及有效性分析

目的 系统评价分子靶向药物——伊马替尼、舒尼替尼、瑞戈非尼、尼洛替尼和帕唑帕尼对比安慰剂或最佳支持治疗治疗晚期或转移性胃肠道间质瘤（gastrointestinal stromal tumour,GIST）的有效性与安全性。方法 计算机检索Pubmed、Embase、Cochrane Library、中国知网、万方数据库和维普等数据库,按照文献纳入标准和排除标准选择应用分子靶向药物治疗GIST的临床研究,RevMan 5.3软件进行meta分析。其中,试验组为近年来相继上市的酪氨酸激酶抑制剂分子靶向药物——伊马替尼、舒尼替尼、瑞戈非尼、尼洛替尼和帕唑帕尼,对照组为安慰剂或最佳支持治疗。观察终点包括无进展生存期（progression-free survival,PFS）、总生存期（overall survival,OS）和3~4级不良反应发生率。结果 共纳入7项临床研究,总样本量为1 528例。Meta分析结果显示,分子靶向药物与对照组相比,PFS时间（HR=0.34,95%CI：0.26~0.44,P<0.001）,OS时间（HR=0.38,95%CI：0.17~0.85,P<0.02）均明显延长。在不良反应方面,分子靶向药物组可使3~4级不良反应（RR=4.47,95%CI：2.12~9.39,P<0.000 1）的发生率明显增高,主要是中性粒细胞减少、高血压、手足综合征、皮疹、腹泻和疲劳。结论 分子靶向药物治疗晚期或转移性GIST可以延长患者的PFS和OS。虽然其不良反应发生率高于对照组,但患者仍可耐受。     

Evaluation of geranylgeranyl diphosphate synthase inhibition as a novel strategy for the treatment of osteosarcoma and Ewing sarcoma

Rab GTPases are critical regulators of protein trafficking in the cell. To ensure proper cellular localization and function, Rab proteins must undergo a posttranslational modification, termed geranylgeranylation. In the isoprenoid biosynthesis pathway, the enzyme geranylgeranyl diphosphate synthase (GGDPS) generates the 20-carbon isoprenoid donor (geranylgeranyl pyrophosphate [GGPP]), which is utilized in the prenylation of Rab proteins. We have pursued the development of GGDPS inhibitors (GGSI) as a novel means to target Rab activity in cancer cells. Osteosarcoma (OS) and Ewing sarcoma (ES) are aggressive childhood bone cancers with stagnant survival statistics and limited treatment options. Here we show that GGSI treatment induces markers of the unfolded protein response (UPR) and triggers apoptotic cell death in a variety of OS and ES cell lines. Confirmation that these effects were secondary to cellular depletion of GGPP and disruption of Rab geranylgeranylation was confirmed via experiments using exogenous GGPP or specific geranylgeranyl transferase inhibitors. Furthermore, GGSI treatment disrupts cellular migration and invasion in vitro. Metabolomic profiles of OS and ES cell lines identify distinct changes in purine metabolism in GGSI-treated cells. Lastly, we demonstrate that GGSI treatment slows tumor growth in a mouse model of ES. Collectively, these studies support further development of GGSIs as a novel treatment for OS and ES.     

Computational modeling in melanoma for novel drug discovery

ABSTRACT

Introduction: There is a growing body of evidence highlighting the applications of computational modeling in the field of biomedicine. It has recently been applied to the in silico analysis of cancer dynamics. In the era of precision medicine, this analysis may allow the discovery of new molecular targets useful for the design of novel therapies and for overcoming resistance to anticancer drugs. According to its molecular behavior, melanoma represents an interesting tumor model in which computational modeling can be applied. Melanoma is an aggressive tumor of the skin with a poor prognosis for patients with advanced disease as it is resistant to current therapeutic approaches.

Areas covered: This review discusses the basics of computational modeling in melanoma drug discovery and development. Discussion includes the in silico discovery of novel molecular drug targets, the optimization of immunotherapies and personalized medicine trials.

Expert opinion: Mathematical and computational models are gradually being used to help understand biomedical data produced by high-throughput analysis. The use of advanced computer models allowing the simulation of complex biological processes provides hypotheses and supports experimental design. The research in fighting aggressive cancers, such as melanoma, is making great strides. Computational models represent the key component to complement these efforts. Due to the combinatorial complexity of new drug discovery, a systematic approach based only on experimentation is not possible. Computational and mathematical models are necessary for bringing cancer drug discovery into the era of omics, big data and personalized medicine.     

Evaluation of Elephantopus scaber on the inhibition of chemical carcinogenesis and tumor development in mice

The effect of the active fraction of Elephantopus scaber L. (Asteraceae) (ES) on skin papillomas induced by 7,12-dimethylbenz(a)anthracene (DMBA) as an initiator and croton oil as promoter was studied in mice. The active fraction of E. scaber (100?mg/kg) on topical application delayed the onset of papilloma formation and reduced the mean number of papillomas and the mean weight of papillomas per mouse. The intraperitoneal administration of the active fraction of E. scaber also had a significant effect on subcutaneous injection of 20-methylcholanthrene (20-MCA)-induced soft tissue sarcomas in mice. It inhibited the incidence of sarcomas and reduced the tumor diameter compared to MCA-treated control animals. The subcutaneous administration of the active fraction of E. scaber significantly inhibited the growth of subcutaneously transplanted DLA and EAC solid tumors, delayed the onset of tumor formation, and increased the life span of tumor bearing mice. The present study thus indicates the tumor inhibitory activity of the active fraction of E. scaber against chemically induced tumors and its ability to inhibit the development of solid tumors.     

The clinical development of p53-reactivating drugs in sarcomas – charting future therapeutic approaches and understanding the clinical molecular toxicology of Nutlins

Introduction: The majority of human sarcomas, particularly soft tissue sarcomas, are relatively resistant to traditional cytotoxic therapies. The proof-of-concept study by Ray-Coquard et al., using the Nutlin human double minute (HDM)2-binding antagonist RG7112, has recently opened a new chapter in the molecular targeting of human sarcomas.

Areas covered: In this review, the authors discuss the challenges and prospective remedies for minimizing the significant haematological toxicities of the cis-imidazole Nutlin HDM2-binding antagonists. Furthermore, they also chart the future direction of the development of p53-reactivating (p53-RA) drugs in 12q13–15 amplicon sarcomas and as potential chemopreventative therapies against sarcomagenesis in germ line mutated TP53 carriers. Drawing lessons from the therapeutic use of Imatinib in gastrointestinal tumours, the authors predict the potential pitfalls, which may lie in ahead for the future clinical development of p53-RA agents, as well as discussing potential non-invasive methods to identify the development of drug resistance.

Expert opinion: Medicinal chemistry strategies, based on structure-based drug design, are required to re-engineer cis-imidazoline Nutlin HDM2-binding antagonists into less haematologically toxic drugs. In silico modelling is also required to predict toxicities of other p53-RA drugs at a much earlier stage in drug development. Whether p53-RA drugs will be therapeutically effective as a monotherapy remains to be determined.