Antiangiogenesis: current clinical data and future perspectives

Neovascularization is a prerequisite for progressive growth of solid tumors and their metastases. This process is tightly regulated by a large number of proangiogenic and antiangiogenic factors such as VEGF, bFGF and matrix-metalloproteinases. The inhibition of angiogenesis is an innovative therapeutic approach and could represent a powerful adjunct to traditional therapy of malignant tumors. Preclinical trials have been very successful but in clinical studies meaningful response rates could only be shown in some cases. This might indicate the existence of different angiogenic phenotypes in humans. It seems that at present only a part of the interactions between the angiogenic cytokines are known. In addition, new receptor/ligand systems which regulate the neovascularization are being described. This article presents an overview of the most important angiogenically active substances, preclinical and clinical data, surrogate markers as well as future perspectives.     

Quantitative imaging biomarkers in the clinical development of targeted therapeutics: current and future perspectives

Targeted therapeutics have challenged how imaging techniques assess tumour response to treatment because many new agents are thought to cause cytostasis rather than cytotoxicity. Advanced tracer development, image acquisition, and image analysis have been used to produce quantitative biomarkers of pathophysiology, with particular focus on measurement of tumour vascular characteristics. Here, we critically appraise strategies available to generate imaging biomarkers for use in development of targeted therapeutics. We consider important practical and technical features of data acquisition and analysis because these factors determine the precise physiological meaning of every biomarker. We discuss the merits of volume-based and other size-based metrics for assessment of targeted therapeutics, and we examine the strengths and weaknesses of CT, MRI, and PET biomarkers derived from conventional clinical data. We review imaging biomarkers of tumour microvasculature and discuss imaging strategies that probe other physiological processes including cell proliferation, apoptosis, and tumour invasion. We conclude on the need to develop comprehensive compound-specific imaging biomarkers that are appropriate for every class of targeted therapeutics, and to investigate the complementary information given in multimodality imaging studies of targeted therapeutics.     

Preclinical and clinical strategies for development of telomerase and telomere inhibitors

Background: Telomerase is an important enzyme whose activity has been convincingly demonstrated in humans recently. It is required for maintenance of ends of chromosomes (telomeres) during cell division. Since its presence has been selectively demonstrated in dividing cells including tumor cells, it has generated considerable excitement as a potential anti-cancer strategy.Design: In this article, we review the current relevant biology of the enzyme, the challenges encountered in the preclinical phase of target development and the current efforts that focus on telomeres and telomerase as therapeutic targets. We also speculate on the potential toxicities and mechanisms of resistance that may be encountered during use of such therapies.     

The clinical development of vaccines for HER2+ breast cancer: Current landscape and future perspectives

Human epidermal growth factor receptor 2 (HER2) is a tumor associated antigen over-expressed in 20–30% of cases of breast cancer. Passive immune therapy with HER2-directed monoclonal antibodies (mabs) has changed the natural history of this subset of breast tumors both in the localized and metastatic settings. The safety and efficacy of HER2 vaccines have been assessed in early phase clinical trials but to date clinically relevant results in late phase trials remain an elusive target. Here, we review the recent translational discoveries related to the interactions between the adaptive immune system and the HER2 antigen in breast cancer, results of published clinical trials, and future directions in the field of HER2 vaccine treatment development.     

Antibody–cytotoxic drug conjugates in clinical trials and future perspectives: the development of Trojan horses

Chemotherapy and targeted agents, such as small molecules and monoclonal antibodies, have individually improved cancer medical therapeutics, yet there is still an unmet need for resistant or refractory disease. Drug combinations are usually more effective, but dose-limiting toxicities are of concern. The idea of developing a “smart bomb” treatment dates many years back. Nowadays, the development of biotechnology and the deeper knowledge of molecular biology have made possible the engineering of tumor-specific antibodies bearing cytotoxins directly and solely targeting the tumor cell, thus minimizing toxicity and increasing efficacy. Approved agents include trastuzumab emtansine (T-DM1) for breast cancer, brentuximab vedotin for Hodgkins’ disease, and gemtuzumab ozogamacin for relapsed acute myeloid leukemia. The present short review presents several newer antibody–drug conjugates (ADCs) in clinical studies and discusses ways to optimize ADC future design.     

Lapatinib in breast cancer: clinical experiences and future perspectives

Lapatinib, an orally available dual inhibitor targeting the tyrosine-kinase domain of both epidermal growth factor receptor-1 and 2, has been introduced for the treatment of advanced/metastatic HER2+ breast cancer in combination with capacitabine after chemotherapy regimens containing anthracycline, taxanes and trastuzumab. Moreover, lapatinib is under investigation in combination with anthracycline and taxanes in neoadjuvant and adjuvant settings. Another potential field of investigation for this drug is related to its ability to restore hormonal sensitivity of HER2-, hormone-receptor positive breast cancer cells. This paper reviews the current use of lapatinib in breast cancer and its future perspectives.     

Preclinical perspectives on bisphosphonate renal safety

Renal insufficiency is not rare in cancer patients who may receive nephrotoxic medications as antineo-plastic agents or for comorbid conditions. Thus, the choice of a particular bisphosphonate for patients with metastatic bone disease should be based not only on efficacy but also on the risk for renal deterioration. Some i.v. bisphosphonates have been associated with occasional renal toxicity in the clinical setting. Preclinical studies have also shown that there may be considerable differences among bisphosphonate renal safety profiles. Comparative studies show variations in the risk for histopathologic damage and the ability to cause cumulative toxicity during intermittent dosing. Reasons for the differences among bisphosphonates are not fully understood; however, research shows that they may be influenced by pharmacokinetic properties such as renal tissue half-life or protein binding and intracellular potency. Further preclinical analyses are needed to confirm and evaluate differences among bisphosphonates.     

Posaconazole for paediatric patients: status of development and future perspectives

Posaconazole is a novel oral antifungal triazole with potent and broad-spectrum antifungal activity, favourable pharmacokinetic properties and a limited spectrum of adverse events. The compound has documented clinical efficacy in the settings of oropharyngeal candidiasis, refractory aspergillosis, fusariosis, zygomycosis, and as antifungal prophylaxis in high-risk patients with acute myeloblastic leukaemia or graft-vs.-host disease. Whereas, posaconazole is approved for use in adults, however, the appropriate dosage and the safety of the compound have not been systematically investigated in paediatric age groups. This paper reviews the relevant pharmacological characteristics of posaconazole, the published data on its use in paediatric patients without therapeutic alternative and perspectives for the clinical development in paediatric patients at risk for invasive fungal infections.     

Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy

Perillyl alcohol (POH) is a naturally occurring dietary monoterpene isolated from the essential oils of lavender, peppermint, and other plants. Medical interest in this compound was generated by research findings showing that POH was able to inhibit the growth of tumor cells in cell culture and exert cancer preventive and therapeutic activity in a variety of animal tumor models. Based on this promising preclinical work, POH was formulated in soft gelatine capsules and orally administered to cancer patients several times a day on a continuous basis. However, such clinical trials in humans yielded disappointing results, also because the large number of capsules that had to be swallowed caused hard-to-tolerate intestinal side effects, causing many patients to withdraw from treatment due to unrelenting nausea, fatigue, and vomiting. As a result, efforts to treat cancer patients with oral POH were abandoned and did not enter clinical practice. Intriguingly, clinical trials in Brazil have explored intranasal POH delivery as an alternative to circumvent the toxic limitations of oral administration. In these trials, patients with recurrent malignant gliomas were given comparatively small doses of POH via simple inhalation through the nose. Results from these studies show this type of long-term, daily chemotherapy to be well tolerated and effective. In this review, we will present the vicissitudes of POH’s evaluation as an anticancer agent, and its most recent success in therapy of patients with malignant brain tumors.     

Statistical methodology of phase III cancer clinical trials: advances and future perspectives

The methodology for conducting cancer clinical trials has undergone enormous changes over the past 25-30 years since the EORTC Data Center was created. The purpose of this paper is to highlight and to provide a historical perspective for the main methodological concepts, both practical and theoretical, which form the basis for the design and analysis of phase III cancer clinical trials within the EORTC Data Center. Some statistical aspects of other associated topics such as quality of life, health economics, meta-analysis and treatment outcome will also be briefly discussed. Finally, some future perspectives and topics for further statistical methodological research will be presented in order to spur statisticians to meet the challenge of efficiently designing and analysing the clinical trials of tomorrow.     

Preclinical and clinical development of novel agents that target the protein kinase C family

Protein kinase C (PKC) family comprises more than 12 serine-/threonine-specific isoenzymes. PKC isoenzymes play a complex role in the transduction of signal from tyrosine kinase receptor modulating proliferation, cell cycle, apoptosis, invasion, differentiation, and senescence in both cancer cells and endothelial cells. Thereby, inhibition and/or activation of specific PKCs is thought to control tumor growth by interacting directly with cancer cells and indirectly by blocking tumor angiogenesis. Furthermore, PKCs are known to modulate multi-drug resistance, providing a rational for the combination of PKCs modulators with classical cytotoxic drugs. During the past few years, preclinical and clinical data with first-generation PKC inhibitors/activators provided insight that PKCs may indeed represent attractive targets for the discovery of small molecules with new anticancer properties. In this review, we will provide an overview on the current understanding of PKC participation in chemotherapeutic resistance, the possible implications in cancer treatment, and the potential of most recent PKC inhibitors in molecular cancer therapeutics.     

Drug development for metastatic castration-resistant prostate cancer: current status and future perspectives

Prostate cancer represents a third of all newly diagnosed cancers in men in the USA with an estimated incidence of 192,280 cases and 27,360 deaths in 2009. It continues to be a major cause of cancer-related morbidity and mortality, and there is an urgent need for new treatments. Historically, systemic therapy options were limited after progression on docetaxel-based chemotherapy. This article reviews current data on the novel therapeutics demonstrating activity in metastatic castration-resistant prostate cancer and their future role in the treatment of this disease with a poor prognosis.     

Early phase oncology clinical trials in Malaysia: current status and future perspectives

Historically, the majority of oncology clinical trials are conducted in Western Europe and North America. Globalization of drug development has resulted in sponsors shifting their focus to the Asia-Pacific region. In Malaysia, implementation of various government policies to promote clinical trials has been initiated over a decade ago and includes the establishment of Clinical Research Malaysia, which functions as a facilitator and enabler of industry-sponsored clinical trials on a nationwide basis. Although oncology clinical trials in Malaysia have seen promising growth, there are still only a limited number of early phase oncology studies being conducted. Hence, the Phase 1 Realization Project was initiated to develop Malaysia's early phase clinical trial capabilities. In addition, the adaptation of good practices from other countries contribute to the effective implementation of existing initiatives to drive progress in the development of early phase drug development set up in Malaysia. Furthermore, holistic approaches with emphasis in training and education, infrastructure capacities, strategic alliances, reinforcement of upstream activities in the value chain of drug development, enhanced patient advocacy, coupled with continued commitment from policy makers are imperative in nurturing a resilient clinical research ecosystem in Malaysia.     

Animal models of acute myelogenous leukaemia - development, application and future perspectives.

From the early inception of the transplant models through to contemporary genetic and xenograft models, evolution of murine leukaemic model systems have been critical to our general comprehension and treatment of cancer, and, more specifically, disease states such as acute myelogenous leukaemia (AML). However, even with modern advances in therapeutics and molecular diagnostics, the majority of AML patients die from their disease. Thus, in the absence of definitive in vitro models which precisely recapitulate the in vivo setting of human AMLs and failure of significant numbers of new drugs late in clinical trials, it is essential that murine AML models are developed to exploit more specific, targeted therapeutics. While various model systems are described and discussed in the literature from initial transplant models such as BNML and spontaneous murine leukaemia virus models, to the more definitive genetic and clinically significant NOD/SCID xenograft models, there exists no single compendium which directly assesses, reviews or compares the relevance of these models. Thus, the function of this article is to provide clinicians and experimentalists a chronological, comprehensive appraisal of all AML model systems, critical discussion on the elucidation of their roles in our understanding of AML and consideration to their efficacy in the development of AML chemotherapeutics.     

Rationale for initial clinical trials and future development of radioprotectors

Over the past two decades a number of chemical radioprotectors have been developed which, although toxic, appear to be usable in clinically relevant doses. Because of differences in blood flow, radiochemical action in hypoxic cells, and active concentration in certain normal tissues, these compounds exhibit differential protection of normal tissue versus tumor. The best, currently available protector, WR-2721, is active in skin, intestine, marrow, mucosa, and salivary glands with lesser activity in kidney and lung and none in brain. Clinical trials have been designed in the Radiation Therapy Oncology Group based on this knowledge. Phase I studies involve patients requiring palliative radiotherapy for tumors located in or adjacent to tissues which are known to be protected. These studies use excalating doses of WR-2721, starting at 50 mg/m2 and will determine the maximum tolerated dose of drug, first as single doses and then as 1X, 3X, and 5X weekly for 3 and 6 weeks. Concomitant radiotherapy is given and normal tissue response at conventionl doses observed. Phase II studies will be site specific based on phase I results and doses. They will be radiation dose ranging studies designed to determine the maximum acceptable radiation dose at each site with WR-2721 protection. These new, higher doses will then be compared to conventional radiotherapy without protector, seeking increased tumor control in phase III studies. WR-2721 is not the ideal sensitizer since it does not protect all normal tissues. It is particularly important to develop compounds which can protect the brain, spinal cord, and lung. A large effort in new drug development will be justified if an improved therapeutic ratio is observed with WR-2721.