Cellular and soluble markers of tumor angiogenesis: From patient selection to the identification of the most appropriate postresistance therapy

Antiangiogenic drugs are now intensively used in clinical oncology, but some drawbacks still hamper their development. First, it is frequently unclear what patient subpopulation is likely to gain clinical benefit from these expensive therapies; second, there is evidence of (sometimes rapid) development of drug resistance in many patients; third, the results of some preclinical and clinical studies have suggested acceleration of malignant cell aggressiveness when some antiangiogenic therapies are terminated. Here we discuss the role of soluble molecules and cellular markers of neoplastic angiogenesis for patient selection and follow-up during treatment. These markers should help clinicians to decide the right therapy, advise them of the generation of mechanisms of drug resistance during antiangiogenic treatment, and finally suggest the most appropriate next line of therapy according to the new patterns of cancer vascularization induced by antiangiogenic therapies.     

Cancer pharmacogenomics: current and future applications

Heterogeneity in patient response to chemotherapy is consistently observed across patient populations. Pharmacogenomics is the study of inherited differences in interindividual drug disposition and effects, with the goal of selecting the optimal drug therapy and dosage for each patient. Pharmacogenomics is especially important for oncology, as severe systemic toxicity and unpredictable efficacy are hallmarks of cancer therapies. In addition, genetic polymorphisms in drug metabolizing enzymes and other molecules are responsible for much of the interindividual differences in the efficacy and toxicity of many chemotherapy agents. This review will discuss clinically relevant examples of gene polymorphisms that influence the outcome of cancer therapy, and whole-genome expression studies using microarray technology that have shown tremendous potential for benefiting cancer pharmacogenomics. The power and utility of the mouse as an experimental system for pharmacogenomic discovery will also be discussed in the context of cancer therapy.     

Species differences in tumour responses to cancer chemotherapy

Despite advances in chemotherapy, radiotherapy and targeted drug development, cancer remains a disease of high morbidity and mortality. The treatment of human cancer patients with chemotherapy has become commonplace and accepted over the past 100 years. In recent years, and with a similar incidence of cancer to people, the use of cancer chemotherapy drugs in veterinary patients such as the dog has also become accepted clinical practice. The poor predictability of tumour responses to cancer chemotherapy drugs in rodent models means that the standard drug development pathway is costly, both in terms of money and time, leading to many drugs failing in Phase I and II clinical trials. This has led to the suggestion that naturally occurring cancers in pet dogs may offer an alternative model system to inform rational drug development in human oncology. In this review, we will explore the species variation in tumour responses to conventional chemotherapy and highlight our understanding of the differences in pharmacodynamics, pharmacokinetics and pharmacogenomics between humans and dogs. Finally, we explore the potential hurdles that need to be overcome to gain the greatest value from comparative oncology studies.     

Pharmacogenetics and pharmacogenomics in oncology therapeutic antibody development

Pharmacogenetics and pharmacogenomics are keys to the success of personalized medicine, prescribing drugs based on a patient's individual genetic and biological profile. In this review, we will focus on the application of pharmacogenetics and pharmacogenomics in developing monoclonal antibody (MAb) therapeutics in oncology. The significance of pharmacogenomics in MAb therapeutics is highlighted by the association between polymorphisms in Fc receptors and clinical response to anti-CD20 MAb rituximab (Rituxan) or anti-ganglioside GD2 MAb 3F8, as well as the potential link between polymorphisms in HER2 and cardiac toxicity in patients treated with the anti-HER2 MAb trastuzumab (Herceptin). The dependence on gene copy number or expression levels of HER2 and epidermal growth factor receptor (EGFR) for therapeutic efficacy of trastuzumab and cetuximab (Erbitux), respectively, supports the importance of selecting suitable patient populations based on their pharmacogenetic profile. In addition, a better understanding of target mutation status and biological consequences will benefit MAAb development and may guide clinical development and use of these innovative therapeutics. The application of pharmacogenetics and pharmacogenomics in developing MAb therapeutics will be largely dependent on the discovery of novel surrogate biomarkers and identification of disease- and therapeutics-relevant polymorphisms. Challenges and opportunities in biomarker discovery and validation, and in implementing clinical pharmacogenetics and pharmacogenomics in oncology MAb development and clinical practice will also be discussed.     

Preclinical applications of imaging for cancer gene therapy

Gene therapy is a very attractive strategy in experimental cancer therapy. Ideally, the approach aims to deliver therapeutic genes selectively to cancer cells. However, progress in the improvement of gene therapy formulations has been hampered by difficulties in measuring transgene delivery and in quantifying transgene expression in vivo. In clinical trials, endpoints rely almost exclusively on the analysis of biopsies by molecular and histopathological methods, which provide limited information. Therefore, to ensure the rational development of gene therapy, a crucial issue is the utilisation of technologies for the non-invasive monitoring of spatial and temporal gene expression in vivo upon administration of a gene delivery vector. Such imaging technologies would allow the generation of quantitative information about gene expression and the assessment of cancer gene therapy efficacy. In the past decade, progress has been made in the field of in vivo molecular imaging. This review highlights the various methods currently being developed in preclinical models.     

Pharmacogenomics of breast cancer targeted therapy: focus on recent patents

Adjuvant endocrine therapy as well as other forms of targeted therapy such as HER2 inhibitors and antiangiogenic agents reduce the risk of recurrence and improve survival among women with hormone receptor positive breast cancer. However, a significant percentage of women who receive targeted therapy as adjuvant or metastatic treatment do not benefit from this therapy, while a number of women who initially respond will eventually develop disease progression and relapse while on therapy. The observed variability in treatment response to targeted breast cancer treatment could be partly explained by pharmacogenomics. This paper reviews evidence on the role of pharmacogenomics of breast targeted therapy focusing on the clinical relevance of genetic variation. In particular, this article reviews the role of pharmacogenomics of tamoxifen, aromatase inhibitors, HER-2 inhibitors and anti-angiogenic agents. In addition, recent patents in the field are presented that provide promising steps in the field of personalized treatment of breast cancer, although future studies are needed for determining the clinical benefit of the proposed inventions. Finally, we present a testable hypothesis to aide the search for biologically meaningful genetic variation Specifically, we suggest the publication of negative results in the field of pharmacogenomics and pharmacoproteomics, will benefit future research in the field.     

The multiple personality disorder phenotype(s) of circulating endothelial cells in cancer

Circulating endothelial cells (CECs) and circulating endothelial progenitors (CEPs) are currently being investigated in a variety of diseases as markers of vascular turnover or damage and, also in the case of CEPs, vasculogenesis. CEPs appear to have a “catalytic” role in different steps of cancer progression and recurrence after therapy, and there are preclinical and clinical data suggesting that CEC enumeration might be useful to select and stratify patients who are candidates for anti-angiogenic treatments. In some types of cancer, CECs and CEPs might be one of the possible hidden identities of cancer stem cells. The definition of CEC and CEP phenotype and the standardization of CEC and CEP enumeration strategies are highly desirable goals in order to exploit these cells as reliable biomarkers in oncology clinical trials.     

卵巢癌的靶向药物治疗研究进展

卵巢癌死亡率居女性生殖系统恶性肿瘤之首,早期诊断困难,晚期患者治疗效果差,分子靶向药物成为近年的研究热点。目前许多靶向药物已经进入临床试验阶段,给卵巢癌特别是术后复发及化疗耐药患者的治疗带来新的希望。本文主要对单克隆抗体,酪氨酸激酶抑制剂等几种药物在卵巢癌的研究进行综述。     

Optimizing preclinical study design in oncology research

The current drug development pathway in oncology research has led to a large attrition rate for new drugs, in part due to a general lack of appropriate preclinical studies that are capable of accurately predicting efficacy and/or toxicity in the target population. Because of an obvious need for novel therapeutics in many types of cancer, new compounds are being investigated in human Phase I and Phase II clinical trials before a complete understanding of their toxicity and efficacy profiles is obtained. In fact, for newer targeted molecular agents that are often cytostatic in nature, the conventional preclinical evaluation used for traditional cytotoxic chemotherapies utilizing primary tumor shrinkage as an endpoint may not be appropriate. By utilizing an integrated pharmacokinetic/pharmacodynamic approach, along with proper selection of a model system, the drug development process in oncology research may be improved leading to a better understanding of the determinants of efficacy and toxicity, and ultimately fewer drugs that fail once they reach human clinical trials.     

CAR-T cell therapy and its application in clinical cancer treatment

Immunotherapy is regarded as the most significant method for cancer treatment in recent years. Chimeric antigen receptor T cells (CAR-T) technology, one form of target immunotherapy, has made a great breakthrough in hematological malignancies treatment and also a few progress in solid tumor treatment. This article reviews the history and mechanism of CAR-T, as well as the advantages and limitations of CAR-T in clinical cancer treatment. Then the review mainly discussed the clinical trial progress of CAR-T cell therapy in solid tumor treatment. A primary obstacle of CAR-T therapy is the heterogeneity in solid tumors. With an increasing number of solid tumor surface antigens being discovered, different varieties of CARs have been designed to treat solid tumors and have made some progress in clinical trial. In the end, this review puts forward a possible development direction of CAR-T.     

Recent developments in the virus therapy of cancer

Cancer is one of the leading causes of death in the United States. Although there has been significant progress in the areas of cancer etiology, diagnostic techniques, and cancer prevention, adequate therapeutic approaches for many cancers have lagged behind. One promising line of investigation is the virus therapy of cancer. This approach entails the use of viruses, such as retroviruses, adenovirus, and vaccinia virus, to modify tumor cells so that they become more susceptible to being killed by the host immune response, chemotherapeutic agents, or programmed cell death. This review discusses recent advances in the virus therapy of cancer from both basic science and clinical perspectives. Given the potential of viruses to kill tumor cells directly or transduce desired gene products to allow a vigorous host antitumor immune response, the virus therapy of cancer holds great promise in the treatment of cancer.     

药物基因组学对癌症化疗的启示

药物基因组学的研究任务是阐明个体差异的遗传基础,并利用这些遗传信息来预测药物的疗效、毒性和安全性。绝大多数的癌症化疗药物在治疗效果及正常组织毒性上的个体差异一直广为关注。不仅诸多临床因素(如年龄、性别、饮食、药物相互作用等)与药物反应和治疗效果有关,而且药物分布(转运和代谢)和药物靶标的遗传变异同样可导致癌症治疗上的差异。本篇综述主要讨论当前和将来药物基因组学在临床癌症治疗和抗癌药物研制方面的应用。     

Moving forward with metronomic chemotherapy: meeting report of the 2nd International Workshop on Metronomic and Anti-Angiogenic Chemotherapy in Paediatric Oncology

Metronomic chemotherapy, which is defined by the frequent, repetitive administration of chemotherapeutic drugs at relatively low doses, and without prolonged drug-free break, is an emerging strategy to fight cancer. Initially thought to act by targeting tumor angiogenesis, additional mechanisms have been recently unveiled, and metronomic chemotherapy is now considered to represent a form of multitargeted therapy. Despite representing a genuine alternative for advanced and/or high-risk cancer therapy, the development of metronomic approaches in pediatric oncology is still in the early stage. The few numbers of large-scale state-of-the-art clinical trials, issues regarding terminology and the limited understanding of the complex and intertwined mechanisms of action of metronomic treatments have limited progress in this important field of research. On March 18 and 19, 2010, the 2nd International Workshop on Metronomic and Anti-Angiogenic Chemotherapy in Paediatric Oncology was held in Marseille, France, and brought together clinicians, basic scientists, physician-scientists, trainees, and students from all around the world. The main aim of this international meeting was to provide a unique forum to 1) reflect on the major advances that have been made in this field of research since its creation, 2) communicate results from the most recent clinical trials and preclinical studies, 3) discuss the current and future challenges of the field, and 4) set forth a solid framework for future collaborative biologic and clinical studies. The present report documents the main preclinical and clinical data that were presented in the keynote and best abstract sessions and delivers the key messages from the meeting.     

Establishing a robust chimeric antigen receptor T-cell therapy program in Australia: the Royal Prince Alfred Hospital experience

>himeric antigen receptor (CAR) T-cell therapy is a novel approved cancer treatment that has shown remarkable efficacy in the treatment of patients with relapsed leukemia and lymphoma. Implementation of CAR T-cell therapy in a hospital setting requires careful and detailed planning because of the complexities in delivering this specialist service. A multi-disciplinary approach with dedicated funding is required to meet clinical, scientific, logistic and regulatory requirements. Tisagenlecleucel was the first approved CAR T-cell therapy in Australia. The treatment has been made available to Australian patients in specialist public hospitals through federal and state funding. Royal Prince Alfred Hospital (RPAH) is one of Australia's oldest tertiary referral public health care institutions and was approved for the provision of CAR T-cell therapy service in 2019. A multi-disciplinary clinical program has been established for the collection and cryopreservation of donor cells shipped for manufacturing as well as for the receipt, storage and administration of CAR T-cell therapy and patient management. The program encompasses a Therapeutic Goods Administration-accredited apheresis unit and a state-of-the-art facility for cell processing, cryopreservation and storage. The program's clinical expertise extends to hematology, oncology, intensive care, pharmacy, neurology and radiology services with direct experience in managing patients receiving CAR T-cell therapies. The introduction of CAR T-cell therapies at RPAH was a complex undertaking facilitated by the existing infrastructure and clinical expertise.     

A New Formulation of Calcitriol (DN-101) for High-Dose Pulse Administration in Prostate Cancer Therapy

Although the antineoplastic activity of calcitriol in prostate cancer has been known for many years, the agent's use in oncology has been prevented because of the occurrence of hypercalcemia with daily administration. High-dose pulse administration of calcitriol has the potential to improve the therapeutic index of calcitriol. Results of a phase II study of calcitriol and docetaxel (Taxotere(R)) suggest that this combination may have utility in androgen-independent prostate cancer (AIPC). DN-101, a high-dose (15 mug) formulation of calcitriol suitable for use in oncology, is now being tested in a randomized trial (AIPC Study of Calcitriol Enhancing Taxotere). This formulation of calcitriol could become an important new tool for improving the efficacy of docetaxel in the treatment of AIPC and would join the ranks of other nuclear receptor ligands in cancer treatment. Investigations of DN-101 in the treatment of a broad range of tumor types and in combination with a variety of agents are an exciting new area of research.     

Gene transfer to the vasculature: historical perspective and implication for future research objectives

Cardiovascular diseases are a major cause of fatality, disability, and economic burden in Western civilization. Although the pharmaceutical industry has delivered a plethora of drugs for treatment of diverse cardiovascular complaints, there remain many conditions for which pharmacological regimens are either nonexistent or largely ineffective. In contrast, remarkable progress has been made in the field of vascular gene transfer in the last decade. The vast majority of studies are preclinical, although a number of high profile vascular gene therapy clinical trials are in progress. In principle, vascular gene therapy represents an unprecedented opportunity to treat a host of cardiovascular diseases in humans although many scientific, clinical, and ethical obstacles remain. Here we discuss the rapid progress in preclinical vascular gene therapy, highlight the most appropriate gene delivery vectors, and discuss the advances toward the ultimate goal of an efficient and safe gene therapy for diverse cardiovascular diseases.     

Emerging mechanisms and applications of low-dose IL-2 therapy in autoimmunity

Interleukin 2 (IL-2) is a pleiotropic cytokine that elicits both immunogenic and tolerogenic immune response essential for homeostasis. Initial clinical application of IL-2 based therapy was hampered by its function on broad spectrum of cells expressing corresponding receptors, which exerts uncontrolled side effects in clinical trials. While recent progress on structural modification or adjusted regimen of IL-2, revolutionized the use of IL-2 in immunomodulation process that requires stringent selection of effector cells, such as promotion of T_REG cells for tolerance or invigoration of CD8⁺ T cells against infection and cancer. Low-dose IL-2 therapy is amongst these succuss and is proved to be a promising immunotherapy to treat a broad range of autoimmune and inflammatory diseases. This article will review major recent advances in fundamental research on IL-2 as well as significant progress made in clinical trials where patients received low-dose IL-2 therapy. This knowledge also helps design further optimized IL-2 therapies for a broader application in treating human disease.     

Navigating the clinical development landscape for oncolytic viruses and other cancer therapeutics: No shortcuts on the road to approval

Chemotherapy remains a common mode of anticancer treatment even though in most cancer indications the therapeutic approach is not effective and ultimately associated with the onset of chemoresistance. A better understanding of genetic differences in tumors ushered in the era of targeted therapy which has revolutionized the treatment of certain cancer types. However, generally targeted therapies are only cytostatic and a proportion of the patient population may be non-responsive to targeted therapy due to mutations of other genes in the same pathway (e.g. ras mutations in patients with colorectal cancer treated with EGFR targeted therapy). Therefore, there exists a need for a radically new approach to cancer therapy. Oncolytic viruses (OVs) possess many properties of an ideal cancer therapeutic. OVs are cytotoxic and target cancers via multiple mechanisms of action while at the same time exploiting validated genetic pathways known to be dysregulated in many cancers. Indeed, promising safety and efficacy data has emerged from Phase 1 and Phase 2 trials with diverse OVs (e.g. JX-594, a targeted oncolytic poxvirus). Though the field has lagged behind with pivotal, randomized Phase 3 trials, these are currently being initiated for a number of OVs. In addition, the field must ensure a continued clinical development of newly developed OVs; a strategy for the clinical development of novel cancer therapeutics is outlined.     

The cause of cancer mutations: Improvable bad life or inevitable stochastic replication errors?

Despite substantial progress in understanding the mechanisms of carcinogenesis and fighting oncology diseases, cancer mortality remains rather high. Therefore, there is a striving to reduce this mortality to the level determined by endogenous biological factors. The review analyzes the mutations that lead to cell malignant transformation and describes the contribution that self-renewal of adult tissues makes to tumorigenesis. Cancer progression is considered as a development of a complicated system where cells mutate, evolve, and are subject to selection. Cancer paradoxes are described in conclusion.     

ATP depletion triggers acute myeloid leukemia differentiation through an ATR/Chk1 protein-dependent and p53 protein-independent pathway

Despite advances in oncology drug development, most commonly used cancer therapeutics exhibit serious adverse effects. Often the toxicities of chemotherapeutics are due to the induction of significant DNA damage that is necessary for their ability to kill cancer cells. In some clinical situations, the direct induction of significant cytotoxicity is not a requirement to meet clinical goals. For example, differentiation, growth arrest, and/or senescence is a valuable outcome in some cases. In fact, in the case of acute myeloid leukemia (AML), the use of the differentiation agent all-trans-retinoic acid (ATRA) has revolutionized the therapy for a subset of leukemia patients and led to a dramatic survival improvement. Remarkably, this therapeutic approach is possible even in many elderly patients, who would not be able to tolerate therapy with traditional cytotoxic chemotherapy. Because of the success of ATRA, there is widespread interest in identifying differentiation strategies that may be effective for the 90-95% of AML patients who do not clinically respond to ATRA. Utilizing an AML differentiation agent that is in development, we found that AML differentiation can be induced through ATP depletion and the subsequent activation of DNA damage signaling through an ATR/Chk1-dependent and p53-independent pathway. This study not only reveals mechanisms of AML differentiation but also suggests that further investigation is warranted to investigate the potential clinical use of low dose chemotherapeutics to induce differentiation instead of cytotoxicity. This therapeutic approach may be of particular benefit to patients, such as elderly AML patients, who often cannot tolerate traditional AML chemotherapy.