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.     

Advancing therapies in metastatic castration-resistant prostate cancer

ABSTRACT

Introduction: Prostate cancer is the second most common cause of cancer worldwide and is the most frequently detected cancer in the European Union in men over 50 years of age. Androgen deprivation therapy remains the cornerstone of treatment for recurrent or metastatic disease. Unfortunately, nearly all patients will develop resistance to androgen blockade leading to castration-resistant prostate cancer (CRPC). Over the last 10 years, new treatments have dramatically improved overall survival of men with mCRPC. Current therapies are based on AR-axis inhibitors and taxane-based chemotherapies, as well as radiopharmaceuticals and Sipuleucel T.

Areas covered: The authors provide a review of the current field of systemic therapy in metastatic CRPC. This is followed by an in-depth analysis of recent developments in treatment, and the biological rationale behind these therapies.

Expert opinion: Since several trials with docetaxel or novel hormonal agents showed improvement in overall survival in metastatic castration-sensitive prostate cancer, as well as in non-metastatic castration-resistant patients, it is expected that a growing subgroup of patients will be exposed earlier to chemotherapy and to AR targeted agents. It becomes then fundamental to find novel strategies to overcome drug resistance and further improve survival.     

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.     

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.     

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.     

Targeting angiogenesis in endometrial cancer - new agents for tailored treatments

Introduction: Endometrial carcinoma represents the most frequent gynecologic tumor in developed countries. The majority of women presents with low-grade tumors but a significant subset of women experience recurrence and do not survive their disease. Patients with stage III/ IV or recurrent endometrial cancer have a poor prognosis. Identification of active and tolerable new targeted agents versus specific molecular targets is a priority objective. Angiogenesis is a complex process that plays a crucial role in the development of many types of cancer and in particular endometrial cancer.

Areas covered: In this review, the authors highlight the main angiogenetic molecular pathways and the anti-angiogenic agents in Phase II clinical trials for endometrial cancer treatment. The authors focus on reports from recent years on angiogenesis inhibitors used in endometrial cancer, including anti- vascular endothelial growth factor (VEGF) monoclonal antibodies (bevacizumab and aflibercept), mammalian target of rapamycin inhibitors (mTORi) (everolimus, temsirolimus and ridaforolimus), PI3 K inhibitors (BKM120), tyrosine kinase inhibitors (brivanib, sunitinib, dovitinib and nintedanib) and thalidomide.

Expert opinion: These anti-angiogenic drugs, while used either alone or in combination with chemotherapy, have presented mixed results in treating endometrial cancer patients. Challenges for the future include the identification of new pathways, early identification and overcoming resistance and the use of these molecules in combination with old and new chemotherapeutic and targeted agents.     

Safety of available treatment options for renal cell carcinoma

ABSTRACT

Introduction: For many years, cytokines (high-dose interleukin (IL)-2 and interferon (IFN)) have been the unique available treatment options for metastatic renal cell carcinoma (mRCC) and they provided durable but modest responses at the cost of significant toxicities. To date, targeted therapies have replaced cytokine therapy due to higher response rates and more favorable toxicity profiles. The major classes of targeted therapy for mRCC include tyrosine kinase inhibitors, monoclonal antibody against vascular endothelial grow factors and inhibitors of the mammalian target of rapamycin. Thanks to these new strategies, the prognosis for the mRCC is shifting toward a chronic disease and the new challenges are the adequate treatment of adverse events (AEs) and the care for quality of life, which is crucial. Emerging immunotherapies targeting the programmed death-1 (PD-1) receptor and the programmed death ligand-1 (PD-L1) ligand have shown promising results in both efficacy and safety profiles.

Areas covered: Safety data published on available treatment options for renal cell carcinoma RCC are reviewed.

Expert opinion: Various toxicities are associated with targeted agents; these toxicities are generally well tolerated but careful monitoring and appropriate management are needed to optimize the use of these strategies.     

Treatment of head and neck cancer in the elderly

Introduction: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and the majority of patients present with advanced stage disease. Chemotherapy is an important component of head and neck cancer treatment regimens and has shown beneficial effects in locally advanced and recurrent/metastatic stages of disease. Approximately 25% of HNSCC patients are aged 70 and older, often associated with co-morbid medical conditions. Most clinical trials exclude patients of advanced chronological age such that valid information about the efficacy and safety of drugs and treatment regimens in elderly patients is not available.

Areas covered: Surgery, radiotherapy and particularly chemotherapy with the six FDA-approved chemotherapeutic agents for head and neck cancer treatment are discussed with a focus on age, performance status, comorbidities. New targeted therapies and the field of immune checkpoint inhibitors are evaluated in the context of elderly populations.

Expert opinion: Surgery, radiotherapy and administration of cytotoxic chemotherapeutic agents are largely safe and effective in elderly patients. Targeted therapies are mostly well tolerated. Clinical studies should be designed to include elderly patients (>70 years). Immune checkpoint inhibitor therapies may exert age-related effects, since substantial functional changes in T cell responses increase during the aging process.     

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.     

An update: emerging drugs to treat squamous cell carcinomas of the head and neck

ABSTRACT

Introduction: Subsequent to the 2006 FDA approval of cetuximab, a variety of molecular targeting agents have been evaluated in head and neck squamous cell carcinoma (HNSCC). The treatment outcomes of recurrent and/or metastatic (R/M) HNSCC, in particular, remain dismal. The 2016 FDA approval of PD-1 immune checkpoint inhibitors has expanded the treatment options for R/M HNSCC and highlights the potential for immune-based therapies.

Areas covered: We will review the clinical application of EGFR-targeted agents, alone and in combination with other drugs. Molecular targeting agents directed against the IL6/PI3K/STAT3 signaling pathway will be covered. In addition, evaluation of immune checkpoint inhibitors in HNSCC, along with ongoing combination trials incorporating these agents, will be discussed. The expanded indications of emerging drugs and the potential clinical benefit of new drugs and treatment combinations will be summarized.

Expert opinion: In recent years, there has been a major shift toward immunotherapy-based approaches for the treatment of HNSCC, leading to significant improvements in outcomes for a subset of patients. Leveraging the increased understanding of the genetic alterations that characterize individual HNSCC tumors will facilitate precision medicine approaches using targeted agents, immunotherapies, as well as standard chemotherapy and radiation.     

Investigational drugs for the treatment of cervical cancer

Introduction: Cervical cancer (CC) is currently the fourth most common malignant disease of women worldwide. Although the incidence and the mortality rates have been decreasing with screening detection and new treatment strategies, a significant number of metastatic or recurrent disease is still diagnosed. For those patients not amenable to curative treatments, such as surgery and radiation, palliative chemotherapy remains the standard of care. As chemotherapy regimens have limited activity, research is focalized on investigating novel pharmacologic strategies.

Areas covered: This paper aims to give a complete and updated overview on investigated therapies for the treatment of CC. The authors review the results of clinical studies and highlight the ongoing trials.

Expert opinion: Agents targeting various molecular pathways including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), poly ADP-ribose polymerase (PARP), epigenetics and other biological mechanisms represent interesting investigational opportunities. Amongst such drugs, bevacizumab, an anti-VEGF monoclonal antibody, was the first targeted drug recently approved by the FDA for the treatment of patients with metastatic, recurrent, or persistent CC. Another interesting experimental approach is represented by immunotherapy, which is leading to promising results with to the development of therapeutic vaccines and immune checkpoints inhibitors.     

Clinical pharmacokinetics and pharmacodynamics of ramucirumab in the treatment of colorectal cancer

Introduction: Colorectal cancer is the third most common cancer worldwide. The prognosis of colorectal cancer patients still remains dismal and half of them will develop metastatic disease. Angiogenesis plays an essential role in colorectal tumorigenesis, and the VEGF pathway is one of the targets that has been validated up to now. The use of antiangiogenics along with chemotherapy has become an accepted standard for colorectal cancer.

Areas covered: This review discusses the efficacy and safety profile of ramucirumab, a fully human immunoglobulin G1 monoclonal antibody against the vascular endothelial growth factor receptor-2 (VEGFR-2), for the treatment of second-line metastatic colorectal cancer upon progression to first-line chemotherapy including anti-angiogenics.

Expert opinion: Ramucirumab in combination with chemotherapy represents a valid option in second-line treatment of advanced colorectal cancer patients, who progressed on previous bevacizumab-based combinations. This agent demonstrates a similar benefit in terms of overall survival to other angiogenesis inhibitors (bevacizumab and ziv-aflibercept) used in this setting.     

Initial systemic chemotherapeutic and targeted therapy strategies for the treatment of colorectal cancer patients with liver metastases

ABSTRACT

Introduction: The liver is the most common metastatic site in colorectal cancer with more than half the patients developing a liver metastasis either at the time of their diagnosis (synchronous) or later (metachronous). Surgical resection remains the principal curative approach that offers significant survival improvements. However, upfront surgery is only possible in about 10–20% of patients at the time of diagnosis, making the consideration of other treatment modalities essential.

Areas covered: In this review, the authors provide an overview of the standard approaches for the initial management of patients with colorectal cancer with liver metastases. They then provide an up-to-date discussion of first-line systemic chemotherapy/targeted therapy options in the contexts of initially resectable and unresectable disease and review toxicities and complications following these options.

Expert opinion: Advances in chemotherapeutic agents and biological targeted therapies have improved the prognosis of colorectal cancer with liver metastases. However, there is still no ‘single best approach’, making further trials necessary to provide more evidence.     

The prospects for combination therapy with capecitabine in the rapidly evolving treatment landscape of renal cell carcinoma

Introduction: Although significant advances have been made in the treatment of advanced renal cell carcinoma (RCC), patients still develop resistance to standard therapies and require the administration of subsequent lines of treatment. New therapeutic approaches are thus imperative to improve the prognosis for patients with RCC.

Areas covered: Based on the current literature, we summarize the treatment of metastatic RCC, including the use of cytotoxic chemotherapy, in this review article. We also review the existing scientific literature regarding the role of capecitabine in the treatment of RCC.

Expert opinion: Currently, targeted therapies including vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors are widely used in the treatment of metastatic RCC. More recently, the role of immune checkpoint inhibitors has been established in the treatment of advanced RCC. Traditionally, the use of cytotoxic chemotherapy in the treatment of RCC is limited. However, cytotoxic chemotherapy may have benefit in different types of RCC, such as variant histology. Furthermore, new combinations of chemotherapy with immune checkpoint inhibitors may provide new treatment options for our patients.     

Fulvestrant for the treatment of endometrial cancer

Introduction: About one third of patients with endometrial cancer (EC) relapse and face a limited prognosis, if surgery or radiotherapy are not feasible. The remaining therapeutic options are chemotherapy and endocrine therapy.

Areas covered: This review summarizes the development of the first selective estrogen receptor (ER) down-regulator fulvestrant. This article provides its mechanism of action, pharmacokinetics and the available preclinical and clinical data. Furthermore, this review provides an overview of the market of treatments for recurrent or metastatic EC (RMEC) while also taking into account studies of fulvestrant in metastatic breast cancer.

Expert opinion: Even if fulvestrant showed only marginal activity in two phase II trials, it shouldn’t be abandoned but instead further developed in EC. Firstly, the dose of fulvestrant used in these trials was too low from today’s point of view. Secondly, the available literature on other endocrine agents is full of limitations and does not provide a gold standard. Furthermore, given the activity of mTOR inhibitors in EC, there may also be synergistic effects, given the cross-regulation of ER and the PI3K/AKT/mTOR pathway. The authors suggest that a prospective, phase II trial in ER positive RMEC would help to further explore the efficacy and tolerability of fulvestrant together with a mTOR inhibitor.     

Advances in systemic delivery of anti-cancer agents for the treatment of metastatic cancer

ABSTRACT

Introduction: The successful treatment of metastatic cancer is refractory to strategies employed to treat confined, primary lesions, such as surgical resection and radiation therapy, and thus must be addressed by systemic delivery of anti-cancer agents. Conventional systemically administered chemotherapeutics are often ineffective and come with severe dose-limiting toxicities.

Areas covered: This review focuses on the recent developments in systemic therapy for metastatic cancer. Firstly, the strategies employed to improve the efficacy of conventional chemotherapeutics by ‘passively’ and ‘actively’ targeting them to tumors are discussed. Secondly, recent advances in the use of biologics to better target cancer and to instigate anti-tumor immunity are reviewed. Under the label of ‘biologics’, antibody-therapies, T cell engaging therapies, oncolytic virotherapies and cell-based therapies are examined and evaluated.

Expert opinion: Improving specificity of action, and engaging the immune system appear to be key goals in the development of novel or reformulated anti-cancer agents for the treatment of metastatic cancer. One of the largest areas of opportunity in this field will be the identification of robust predictive biomarkers for use in conjunction with these agents. Treatment regimens that combine an agent to elicit an immune response (such as an oncolytic virus), and an agent to potentiate/mediate that immune response (such as immune checkpoint inhibitors) are predicted to be more effective than treatment with either agent alone.     

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.