Cancer vaccines: on the threshold of success

Background: Cancer vaccines are a unique approach to cancer therapy. They exert an antitumor effect by engaging the host immune response, and have great potential for circumventing the intrinsic drug resistance that limits standard cancer management. Additional advantages of cancer vaccines are exquisite specificity, low toxicity, and the potential for a durable treatment effect due to immunologic memory. Objectives: This review aims to consider the promise of cancer vaccines, review the current state of cancer vaccine development, and suggest directions for future research. Methods: The scope of this review was defined peer-reviewed information found on Medline, and information found on the Internet about Phase III clinical trials that are ongoing and not yet published. Results/conclusions: Multiple Phase III clinical trials have demonstrated the promise and challenges posed by therapeutic vaccines, and defined the next steps in their clinical development. Determining the optimal integration of cancer vaccines with chemotherapy, radiation, surgery, and biologically targeted therapies, defining predictive biomarkers of immunologic and clinical response, and combining tumor vaccines with new drugs that effectively modulate the antitumor immune response, will ensure that cancer vaccines become part of standard cancer therapy and prevention.     

Vandetanib for the treatment of non-small-cell lung cancer

Introduction: The use of targeted therapies in the treatment of advanced non-small-cell lung cancer (NSCLC) is increasing, especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity. Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). Vandetanib is an orally available inhibitor of VEGFR and EGFR signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways.

Areas covered: This review encompasses the clinical efficacy, safety and tolerability of vandetanib in advanced NSCLC. Of particular interest are the randomized Phase III clinical trials, which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens.

Expert opinion: Vandetanib has anti-tumour activity in NSCLC, with improved objective responses and disease control. However, significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC.     

Tirapazamine: a novel agent targeting hypoxic tumor cells

Background: Tumor hypoxia remains one of the greatest challenges in the treatment of solid tumors, as cancer cells in these regions are resistant to killing by radiation therapy and most anticancer drugs. Tirapazamine (TPZ) is a newer class of cytotoxic drugs with selective toxicity towards hypoxic mammalian cells. Objective: This article reviews the mechanism of action, toxicity and antitumor activity of the drug and provides insights into factors that may have contributed to the disappointing results in some of the Phase III trials. It also identifies the need to explore dependable markers of tumor hypoxia and limit future trials of this agent to patients who have significant populations of hypoxic tumor cells. Methods: We reviewed all clinical trials published to date and present a summary of the results. There are also several ongoing studies, the results of which are pending and may yet impact the clinical use of the drug. Results/conclusion: Despite the very promising results obtained in various preclinical studies and early-Phase clinical trials, several Phase III trials have failed to demonstrate any survival benefit of adding TPZ to chemotherapy or radiation therapy in non-small cell lung cancer or head and neck cancer. Several clinical trials have yet to be completed and reported.     

Emerging drugs in pancreatic cancer

Improving survival in patients with pancreatic cancer remains a formidable challenge. For the few patients with localised stages of the disease, intra-operative radiotherapy, adjuvant chemoradiotherapy and neo-adjuvant therapies remain non-validated and the survival benefit conferred by 5-fluorouracil-folinic acid adjuvant chemotherapy over radical surgery alone is still a matter of debate. Gemcitabine has recently emerged as the standard single agent in advanced stages of the disease and pharmacokinetic refinements such as the use of a fixed-dose infusion rate may further improve still rather modest result figures. At present, most efforts deal with the development of more effective doublet or triplet therapies, combining gemcitabine with either conventional cytotoxic drugs--the most promising being oxaliplatin--or more innovative, targeted therapeutic agents. Among these agents, matrix metalloprotease inhibitors and farnesyltransferase inhibitors have already undergone Phase III trials, alone or in combination with gemcitabine, with rather disappointing results. However, preclinical and Phase I and II studies of cyclooxygenase-2 or lipoxygenase inhibitors, various immunotherapeutic approaches and several tyrosine kinase inhibitors or monoclonal antibodies against growth factors or their receptors are encouraging and may provide some hope for patients with pancreatic cancer.     

Emerging drugs in the treatment of advanced gastric cancer

Background: Gastroesopheal cancer is one of the most common cancers worldwide. If detected early, curative treatment is possible. Often, gastroesophageal cancer is detected at an advanced stage when therapy is palliative. Objectives: To provide a critical evaluation of historic and recently developed chemotherapy regimens for the treatment of advanced gastroesophageal cancer (AGC). Methods: Published clinical trials in AGC as well as selected abstracts presented at international oncology meetings were selected. Results/conclusion: Chemotherapy has demonstrated a benefit over best supportive care alone by improving the quality and quantity of life for patients with advanced disease. Recent Phase III trials investigating cytotoxic chemotherapy and Phase II trials incorporating biotherapy for the treatment of AGC show promise for the future.     

Emerging drugs for adrenocortical carcinoma

Background: Adrenocortical carcinoma (ACC) is an extremely rare aggressive disease. Few data are available on the efficacy of systemic antineoplastic treatments (mitotane and cytotoxic therapy) in the treatment of advanced disease. Objective/methods: this paper will review the existing treatment strategies and new perspectives in the management of ACC patients. Results/conclusion: An ongoing randomized international trial aims to define the best combination chemotherapy plus mitotane regimen. Based on the results of a case control study, mitotane is being explored as adjuvant therapy. Genetic and biological studies have identified molecular targets for specific targeted drugs such as IGF receptor inhibitors and antiangiogenetic drugs. Phase II trials are exploring the activity of these drugs either alone or in combination with chemotherapy.     

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.     

Focal adhesion kinase inhibitors in the treatment of metastatic cancer: a patent review

Introduction: Focal adhesion kinase (FAK) plays a prominent role in integrin signaling. FAK activation increases phosphorylation of Tyr397 and other sites of the protein. FAK-dependent activation of signaling pathways implicated in controlling essential cellular functions including growth, proliferation, survival and migration. FERM (F for the 4.1 protein, ezrin, radixin and moesin) domain-enhanced p53 degradation plays a critical role in proliferation and survival. FAK, overexpressed in metastatic tumors, has emerged as an important therapeutic target for the development of selective inhibitors. FAK inhibitors achieved tumor growth inhibition and induced apoptosis. Strategies targeting FAK inhibition using novel compounds have created an exciting opportunity for anticancer therapy.

Areas covered: This review summarizes the current research with available data from early phase clinical trials and discusses the available small-molecule inhibitors of FAK from patents. The importance of inhibiting FAK activity in cancer patients is discussed.

Expert opinion: Emerging data from clinical trials with orally available small-molecule inhibitors of FAK are promising. Although this approach is appropriate as a targeted therapeutic approach against several metastatic cancer types, several compounds in research are yet to prove their preclinical efficacy. This report lays special emphasis on the available patent data of FAK inhibitors for such targeted molecular therapies. This review summarizes current knowledge about FAK inhibition in cancer therapy.     

Principle and evolving role of intraperitoneal chemotherapy in ovarian cancer

Introduction: Intraperitoneal (i.p.) chemotherapy has been extensively studied in the ovarian cancer field. Despite the fact that three large randomized trials that were conducted in the United States showed survival benefit, meta-analysis also showed survival benefit and the National Cancer Institute (NCI) released a clinical announcement recommending i.p. chemotherapy for optimally debulked advanced stage ovarian cancer in 2006, i.p. chemotherapy has not been widely accepted by the gynecologic oncology community, mainly because of its toxicities.

Areas covered: In this review, previously available evidence, new evidence published since the NCI clinical announcement and ongoing clinical trials will be discussed.

Expert opinion: Three currently ongoing randomized Phase III trials will provide extremely important information about whether a less toxic i.p. regimen using carboplatin will be beneficial for patients with advanced ovarian cancer. They are important because it may be possible to solve many of the questions or unmet needs in i.p. chemotherapy by combining these three trials.     

Antivascular agents for non-small-cell lung cancer: current status and future directions

Background: Despite improvements in surgery and chemo(radio)therapy which have allowed for modest advances in the treatment of patients with non-small-cell lung cancer (NSCLC), survival remains poor and further improvements are needed. Attention over recent years has focused, therefore, on targeted therapies, with notable success in the development of antivascular drugs. Objective: To summarize the current knowledge on antivascular therapy in patients with NSCLC. Method: Review of randomized controlled trials exploring treatment of NSCLC patients with antivascular drugs. Results/conclusion: Bevacizumab, a humanized monoclonal antibody against the vascular endothelial growth factor (VEGF), when added to cytotoxic chemotherapy, was the first treatment to prolong the overall survival of patients with advanced NSCLC beyond 12 months, a significant breakthrough in the management of advanced NSCLC. Small-molecule tyrosine kinase inhibitors and alternative antivascular strategies such as VEGF-trap and vascular disrupting agents are also being investigated and have shown promise in clinical trials. This review summarizes the most recent and important findings in antivascular agents in NSCLC.     

Molecular targeted therapy of advanced hepatocellular carcinoma beyond sorafenib

Importance of the field: With the recent advances in the knowledge of molecular biology of hepatocellular carcinoma (HCC), there have been encouraging developments in targeted therapy for advanced HCC.

Areas covered in this review: This review discusses the development of targeted therapy for advanced HCC patient since 2006. Among the newly identified targets, promising results have been shown in targeting the anti-angiogenic pathway. Pure anti-angiogenic agents such as bevacizumab and PTK 787 demonstrate modest activity in treating patients with advanced HCC. Sorafenib, a multi-targeted tyrosine kinase inhibitor with both anti-angiogenic and anti-proliferative effects, has been shown to prolong the overall survival of patients with advanced HCC in two Phase III randomized trials. Like sorafenib, other anti-angiogenic multi-targeted tyrosine kinase inhibitors, such as sunitinib, pazopanib, brivanib and linifanib, also show promising activity in various stages of clinical trials. Other on-going early-phase studies are exploring the activities of drugs targeting novel pathways, such as PI3K/AKT/m TOR, hepatocyte growth factor/mesenchymal epithelial transition factor and insulin-like growth factor.

What the reader will gain: After reading this review, the reader should have an in-depth understanding of the latest developments in the molecular targeted therapy of advanced HCC.

Take home message: The development of sorafenib in the treatment of advanced HCC proves the concept that molecular targeted therapies, especially anti-angiogenic agents, play a pivotal role in the treatment of this otherwise chemoresistant neoplasm. Future progress depends on further unraveling more molecular mechanisms of HCC for therapeutic intervention.     

Vandetanib for the treatment of non-small-cell lung cancer

INTRODUCTION: The use of targeted therapies in the treatment of advanced non-small-cell lung cancer (NSCLC) is increasing, especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity. Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). Vandetanib is an orally available inhibitor of VEGFR and EGFR signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways. AREAS COVERED: This review encompasses the clinical efficacy, safety and tolerability of vandetanib in advanced NSCLC. Of particular interest are the randomized Phase III clinical trials, which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens. EXPERT OPINION: Vandetanib has anti-tumour activity in NSCLC, with improved objective responses and disease control. However, significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC.     

Indications and limitations of third-generation aromatase inhibitors

Background: Use of aromatase inhibitors in postmenopausal breast cancer, initially in advanced disease but recently also for adjuvant therapy, represents a major advance. Objective: To summarize research leading to this success and to review clinical data from large Phase III trials revealing efficacy of novel third-generation aromatase inhibitors in metastatic and early breast cancer. Methods: Literature on PubMed and on ISI Web of Science for the last 10 years was searched using the word ‘aromatase’. Recent key presentations and abstracts are also included. Results/conclusion: Third-generation aromatase inhibitors improve relapse-free survival compared to tamoxifen, and some trials reveal a survival advantage in early breast cancer. Although substantial data now confirm the safety of these potent compounds with respect to bone metabolism and cardiovascular risk, there is a need for continuous long-term follow-up, in particular into potential vascular effects. The mechanisms and optimal treatment of musculoskeletal and joint pain remain to be addressed. Ongoing studies evaluate sequential treatment versus monotherapy, potential differences between individual compounds and optimal duration of treatment, as well as combining aromatase inhibitors with novel targeting agents.     

Pharmacotherapy targeting the EGFR oncogene in NSCLC

Introduction: The EGFR plays a central role in regulating cancer cell growth and survival, representing an attractive therapeutic target in NSCLC.

Areas covered: For the purpose of this review article, data from Phase II and III trials with anti-EGFR agents, including EGFR-tyrosine kinase inhibitors (TKIs) and mAbs, were collected and analysed.

Expert opinion: Eight large Phase III trials demonstrated that EGFR-TKIs are the best option we can offer today as front-line therapy exclusively in EGFR mutant NSCLC. In patients with EGFR wild type or unknown lung cancer, platinum-based chemotherapy remains the standard of care, with no consistent benefit produced by the addition of an anti-EGFR treatment. In pretreated NSCLC, EGFR-TKIs are considered more effective than standard monotherapy with cytotoxics in presence of classical EGFR mutations, whereas in the EGFR wild-type population, a similar efficacy with docetaxel or pemetrexed in terms of survival has been demonstrated. New agents targeting EGFR are under investigation, particularly in individuals with squamous cell histology and those with acquired resistance to EGFR-TKIs.     

The potential for targeting HER2 therapeutically in esophageal cancer – a grasp at straws?

Introduction: Human EGFR-2 (HER2) has an impact on cellular proliferation and survival. HER2 overexpression has been shown to be a marker for poorer prognosis in several malignancies. Trastuzumab, a humanized mAb, is successfully used to target HER2 in breast cancer. The effect of targeting HER2 in esophageal cancer (EC) is the focus of current trials.

Areas covered: Basic knowledge, detection techniques and definitions of HER2 overexpression, as well as the molecular mechanisms underlying the effects of trastuzumab on HER2, are reviewed. An overview of research on the prognostic and predictive relevance of HER2 in EC is given, as well as an overview of current trials targeting HER2 in EC.

Expert opinion: The first aim of novel targeted therapies must be perioperative neoadjuvant and adjuvant applications, as surgery is the only option for curative treatment in patients with stage I – III EC. Regarding targeted therapies in EC, HER2 is currently the most promising target. Trials of trimodal neoadjuvant therapy regimes (neoadjuvant radiochemotherapy plus trastuzumab) are currently recruiting. However, the prognostic impact of HER2 overexpression in EC remains ambiguous. Targeting HER2 may have negative and positive impacts on survival, depending on which subgroup of EC patients is treated.     

Angiogenesis inhibitors in the treatment of prostate cancer

Importance of the field: Prostate carcinoma is the most common non-cutaneous malignancy in U.S. men. The efficacy of docetaxel and prednisone in metastatic castrate-resistant prostate cancer (mCRPC) has been shown to improve overall survival; however, its effect is not durable, highlighting the need for new therapies.

Areas covered in this review: We will review the development of some of the leading compounds with direct and indirect antiangiogenic activity in prostate cancer including antibodies to VEGF and its receptors, small-molecule inhibitors of downstream signaling, immunomodulatory drugs with antiangiogenic activity, and compounds thought to directly inhibit or destroy vascular endothelial cells.

What the reader will gain: The reader will gain a basic understanding of the role of angiogenesis in prostate cancer growth and metastasis. Current and potential targets of angiogenesis and their corresponding drugs under development for prostate cancer are discussed.

Take home message: There are now multiple early-phase clinical trials of antiangiogenic agents alone or in combination in prostate cancer. Several of these agents are now in Phase III development. Combined therapy with two antiangiogenic compounds may improve the activity of either compound alone. Multiple targets in the angiogenesis pathway continue to be elucidated and should remain an active area of investigation for the treatment of prostate cancer.     

Novel investigational drugs for gastric cancer

Background: Gastric cancer still represents a leading cause of death worldwide. Several cytotoxic agents have demonstrated activity and combination regimens improve progression-free survival, overall survival and quality of life. Nevertheless, now there is no standard therapy for advanced gastric cancer patients. Objective: To evaluate the role of new investigational agents. Methods: We analysed Phase I, II and III studies that evaluated tailored drugs directed against the epidermal growth factor receptor (EGFR), the c-erbB2, the vascular endothelial growth factor (VEGF), the vascular endothelial growth factor receptor (VEGFR), the matrix metalloproteinases (MMP) and the mammalian target of rapamycin (mTOR). Conclusion: Data from Phase II trials indicate the potential of improved efficacy of chemotherapy when administered in combination with bevacizumab and cetuximab. Trastuzumab results are ongoing, while marimastat has not obtained clinical developments even if it has demonstrated to be an active drug in this setting of patients.     

Targeted therapy in renal cell carcinoma

Hypoxia-regulated genes such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are both important for tumour progression in renal cell carcinoma (RCC). Drugs that block these and other pathways have been examined in Phase I and II clinical trials in patients with advanced or metastatic RCC. Results from a randomised study of an anti-VEGF antibody demonstrate a delay in the time to disease progression, suggesting a biological effect and change in the natural history of the disease. Results using small-molecule inhibitors of VEGF, FLT3, KIT and platelet-derived growth factor receptor tyrosine kinases, such as sunitinib, show a 40% objective response rate. Results from a Phase III clinical trial with sorafenib, an inhibitor of multiple tyrosine kinases, show only a 2% response rate; however, a statistically significant improvement in progression-free survival was observed. Objective responses have also been noted using an inhibitor of the mammalian target of rapamycin. Conversely, EGF receptor inhibitors, proteosome inhibitors, microtubule stabilising agents, cell-cycle inhibitors and imatinib were also examined with few objective responses. Ultimately, identifying the predictive factors for responsiveness to these targeted therapies may improve the clinical benefit; for example, RCC with biallelic mutations in the von Hippel-Lindau gene would have higher levels of hypoxia-inducible factor-1α, and may be more responsive to inhibitors of angiogenesis. Phase III studies comparing the combinations of targeted therapy could lead to a new standard of care for RCC.