Section Review: Oncologic,Endocrine & Metabolic: Treatments,topics, and trends in ovarian cancer

Long-term survival is now a reality for patients diagnosed with advanced ovarian cancer. Although cisplatin-based chemotherapy has been the standard therapy for the 1990s, new data suggest that combination chemotherapy, including initial treatment with pacli-taxel, is superior to cisplatin/cyclophosphamide. Other areas of progress include the use of the tumour marker, CA125, the recognition of prognostic factors, the impact of dose, intraperitoneal treatment, the role of surgery, and new drugs. However, many questions are unresolved. For example, what is the best dose and scheduling of paclitaxel? Is it better to treat recurrent disease as soon as possible or to wait until symptoms occur? What will be the new standard chemotherapy in the next decade? What is the best end-point for future clinical trials? These are questions that can only partly be answered from the literature; the final answer will come from performing the necessary trials. A number of new agents with activity during platinum therapy in patients with progressive disease have recently become available, including docetaxel, 2′,2′-difluorodeoxy-cytidine, topoisomerase I inhibitors, and lobaplatin. The results of studies with these drugs will certainly have an impact on future clinical practice and research.     

Clinical perspectives on platinum resistance

The platinum compounds cisplatin and carboplatin are widely used in the treatment of a number of solid malignancies. Although some platinum-sensitive tumours may be cured by combination chemotherapy (e.g. testicular cancer), most will relapse and subsequently prove resistant to platinum compounds. The mechanisms of platinum resistance in patients are still poorly understood. Clearly, when a tumour relapses a long time after successful first-line treatment, there is a high chance that it will still be sensitive to platinum compounds. A number of studies have attempted to assess the role of drug transport, the glutathione system, DNA repair and apoptosis genes in the development of resistance in tumours, but no conclusive evidence is available. Approaches to increasing the potency of platinum therapy (to overcome resistance) have been devised and some have proved to be effective; in particular, intraperitoneal administration of cisplatin has shown superiority over intravenous administration in selected patients with ovarian cancer. The development of drugs and techniques to reduce the adverse effects of platinum chemotherapy has greatly improved their administration. Investigations attempting to modulate platinum activity and toxicity have also been performed. Further investigation of in vivo resistance mechanisms should be valuable in allowing prediction of clinical response to chemotherapy and may identify new treatments with the potential to improve outcomes for patients with a variety of platinum-resistant tumour types.     

胃癌靶向治疗药物新进展

胃癌是我国高发的消化道恶性肿瘤,总体预后不佳。近些年,虽然晚期胃癌患者生活质量得到了一定的改善以及生存期的延长,但晚期胃癌患者5年生存率较低,化疗的疗效也很局限。随着分子生物学的发展,人们对于胃癌的发生发展有了深入的认识,胃癌治疗已进入个体化靶向治疗的新时代,靶向药物通过与癌症发生、肿瘤生长所必需的特定分子靶点的作用来阻止癌细胞的生长。许多大型胃癌临床试验评估了靶向药物在晚期胃癌患者中的疗效及安全性。及早筛查靶向治疗相关生物标志物,及早分类并有的放矢开展治疗,将成为今后胃癌规范治疗的主要方向。     

Novel chemotherapeutic and targeted agents in metastatic colorectal cancer: the time has arrived

Colorectal cancer is a common disease with a high rate of mortality and very well-understood genetics. Primary therapy still consists of relatively non-specific treatments: surgery, radiotherapy and chemotherapy. In this article, recent data in the now fast-moving field of treatment of unresectable metastatic colorectal cancer are reviewed, beginning with new developments in conventional cytotoxic therapies. A number of new cytotoxic agents appear to have at least some activity in this disease, including classes of drugs that have been effective to date. The very rapidly growing area of targeted therapy will also be expanded upon. This year, for the first time, there has been a targeted therapy shown convincingly to prolong survival for patients with unresectable metastatic colorectal cancer in a well-performed Phase III trial. This agent is bevacizumab, a humanised monoclonal antibody targeting the circulating proangiogenic growth factor vascular endothelial growth factor. Results with bevacizumab should lead to rapid expansion of the number of strategies targeting tumour neovasculature. Additionally, an antibody against the epidermal growth factor, cetuximab, has been shown to have both single-agent activity and the potential ability to partially reverse resistance to a chemotherapy drug. These advancements, as well as data on other novel treatment agents that have been studied specifically in patients with colorectal neoplasms, are discussed in detail.     

单药或联合方案二线治疗进展期胃癌研究进展

进展期胃癌的药物治疗随着时代发展取得一定进展。多项临床试验表明伊立替康或紫杉醇单药作为二线化疗可以提高进展期胃癌患者生存质量并延长生存时间,同时两药联合化疗方案、化疗联合靶向药物临床研究也在开展。但直到现在,标准的二线治疗方案仍有待确立。该文将对近几年进展期胃癌二线治疗的单药和联合方案临床研究进行汇总,希望能为二线治疗方案的选择提供参考。     

Chemotherapy individualization

The current practice of dosing patients with anticancer drugs based on body size, leads to a large degree of inter-patient variation in clinical outcome following standard doses of chemotherapy. Some patients may fail to respond to treatment, whilst others experience unacceptable side effects. Recent studies have identified more rational approaches to drug dosing, based on patient characteristics such as renal function, pharmacogenetic factors, and drug metabolizing activity. These can be used together with therapeutic drug monitoring and adaptive dosing to achieve a targeted systemic drug exposure in each patient, which may lead to more consistent clinical outcomes in patients receiving comparable chemotherapy dosing regimens. The purpose of this review is to present some approaches to chemotherapy individualization, examples of how this might be applied, and speculation as to how recent advances in pharmacogenetics may lead to further dose-optimization.Whilst it is hoped that the design of new agents, targeted to specific genes involved in oncogenesis, will lead to increased success in the treatment of cancer patients, it is essential that the drugs currently available are used to their maximum potential.     

Current status and future of target-based therapeutics

With the beginning of the 21st century, a new and exciting era for cancer therapy has begun with the appearance of molecular targeted drugs. Numerous drugs for chemotherapy have been discovered following careful screening of natural and synthetic components. After screening, candidate chemotherapy drugs are examined to determine if they have sufficiently cytotoxic to function as an anti-tumor therapeutic. However, the development of molecular targeted drugs is based on more logical methodologies. First, the target is determined then a search is conducted for molecules able to inhibit the target molecule. Some molecular targeting drugs, such as Glivec (Imatinib, STI571), have shown amazing effects when compared to currently used chemotherapy drugs, whereas few others have completely failed to inhibit tumor development in clinical trials. Thus, an efficient method for finding effective molecular targeted drugs is needed. An important question is whether the target molecule is responsible for tumor growth or metastasis. In addition, the clinical administration schedule must be suitable for the component used. The drugs will not be completely successful in clinical trials if any of the key points are overlooked. Translational studies are necessary for a complete evaluation of molecular targeted drugs and, based on the results observed in clinical applications, the testers must return to their basic laboratory if necessary and improve the drugs for more advanced therapy. In this review we discuss on the current and future status of molecular target drugs.     

阿帕替尼在肺癌中的应用及研究进展

近年来,肺癌的发病率及死亡率居高不下,成为癌症死亡的主要原因之一。当前,对晚期肺癌患者主要以化疗及靶向药物治疗为主,但是二线治疗进展后可供选择的药物很少。阿帕替尼是一种新型小分子酪氨酸激酶抑制剂,是中国研发的第1代口服抗血管生成药物,通过抑制多种信号转导通路,抑制血管生成,进而控制肿瘤发生,延长晚期肺癌患者的无进展生存期(Progression free survival,PFS)和总生存期(Overall survival,OS),已成为晚期肺癌化疗或其他靶向治疗失败后的一种选择。本文旨在回顾性研究国内外关于阿帕替尼的作用机制、在不同类型肺癌中的有效性、不良反应、最新进展等,以期能为肺癌的临床治疗提供帮助。     

Antibody‐Drug Conjugates: A Clinical Pharmacy Perspective on an Emerging Cancer Therapy

Antibody‐drug conjugates (ADCs) combine highly specific monoclonal antibodies with potent cytotoxic drugs. Their synergy allows for targeted delivery of toxic drugs to cancer cells while sparing systemic exposure. In this review, we focus on the history and clinical applications of ADCs approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer and highlight new ADCs in the drug development pipeline. Three ADCs have received FDA approval thus far. Gemtuzumab ozogamicin, although withdrawn from the U.S. market, may still be an effective treatment modality in subsets of patients with acute myeloid leukemia. Brentuximab vedotin and ado‐trastuzumab emtansine have shown improved efficacy and safety data compared with standard chemotherapy for the treatment of advanced lymphoma and breast cancer, respectively. With a number of ADCs with promising preliminary data in the clinical trial pipeline, cancer therapy is moving forward from traditional chemotherapy to targeted treatment modalities driven by the specificity of monoclonal antibodies and advancing biotechnology.     

去势抵抗前列腺癌中的非激素信号通路作用机制及其相关药物研究进展

前列腺癌是男性泌尿生殖系统常见的恶性肿瘤之一,近十年来我国前列腺癌的发病率呈明显上升的趋势。目前,以雄激素阻断为主的内分泌治疗是除根治手术和放疗或化疗之外临床上比较主流的前列腺癌治疗方案,虽然在治疗前期能获得良好的临床收益,但近九成的患者仍会进入去势抵抗阶段,且其中又有近九成的患者会发生骨转移,患者的生活质量随着疾病进程急剧降低。有研究表明在形成去势抵抗的过程中,除雄激素信号通路外还涉及了多种其他分子信号的变化,包括经典的致癌信号通路和免疫炎症致癌信号通路等。了解这些独立于雄激素信号通路的其他信号通路在去势抵抗形成中的作用机制,将有助于了解雄激素阻断治疗在去势抵抗中的脱靶效应以及引入新的治疗靶点和治疗策略,推动去势抵抗摆脱临床"无药可用"的困境。     

Novel platinum agents and mesenchymal stromal cells for thoracic malignancies: state of the art and future perspectives

ABSTRACT

Introduction: Non-small cell lung cancer and malignant pleural mesothelioma represent two of the most intriguing and scrutinized thoracic malignancies, presenting interesting perspectives of experimental development and clinical applications.

Areas covered: In advanced non-small cell lung cancer, molecular targeted therapy is the standard first-line treatment for patients with identified driver mutations; on the other hand, chemotherapy is the standard treatment for patients without EGFR mutations or ALK rearrangement or those with unknown mutation status. Once considered an ineffective therapy in pulmonary neoplasms, immunotherapy has been now established as one of the most promising therapeutic options.

Mesenchymal stromal cells are able to migrate specifically toward solid neoplasms and their metastatic localizations when injected intravenously. This peculiar cancer tropism has opened up an emerging field to use them as vectors to deliver antineoplastic drugs for targeted therapies.

Expert opinion: Molecular targeted therapy and immunotherapy are the new alternatives to standard chemotherapy. Mesenchymal stromal cells are a new promising tool in oncology and—although not yet utilized in the clinical practice, we think they will represent another main tool for cancer therapy and will probably play a leading role in the field of nanovectors and molecular medicine.     

Oncologists' current opinion on the treatment of colon carcinoma

Colorectal cancer is a major global health problem with more than a million new cases diagnosed worldwide in 2005. In the United States, this malignancy is the third most common with 145,000 new cases and the second most lethal with 56,000 deaths in 2005. Unfortunately, preclinical diagnostic screening in the U.S. population is less than 30-40 percent. The last decade has ushered in exciting new advances for medical oncologists caring for patients with colorectal cancer. The older cytotoxic chemotherapy drug 5-fluorouracil underwent new formulation, and two new drugs, oxaliplatine and irinotecan, were investigated as adjunctive therapies. Finally, targeted therapies, including monoclonal antibodies against vascular endothelial growth factor (bevacizumab) and the epidermal growth factor receptor (cetuximab), are now standard treatment for metastatic colorectal carcinoma. Systemic adjuvant chemotherapy can be lifesaving in patients with locally advanced colorectal carcinomas, which represent 60-70 percent of cases. For patients with metastatic colorectal cancer, the survival rate has doubled. With more effective drugs in the therapeutic armamentarium, new controversies have arisen. Questions regarding the best schedules for classical cytotoxic chemotherapy were largely answered by contemporary clinical trials. The potential of molecular genetic markers for prognosis or prediction of drug-specific toxicity and efficacy have been explored, but their utility for clinical practice is still being investigated. We will review the rapidly changing, state-of-the-art combination chemotherapy for adjuvant and metastatic disease. We will discuss in detail the c-ERBB family of tyrosine kinases as therapeutic targets in colorectal cancer.     

晚期非小细胞肺癌治疗的新趋势

当今肺癌研究的热点是以与肿瘤发生、发展相关的驱动基因为靶点,研发新的药物,进行有针对性的个体化分子靶向治疗,从而改善患者预后。靶向药物、新型化疗药物、抗血管新生药物以及治疗性疫苗等各种治疗手段在晚期非小细胞肺癌(NSCLC)患者的治疗中均取得了显著的进展。其中表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)对于EGFR突变阳性NSCLC患者无论在一线、维持还是二线治疗中疗效均得到肯定;替吉奥胶囊有望成为晚期NSCLC一线、二线治疗新的选择;克唑替尼是棘皮动物微管结合蛋白4与间变淋巴瘤激酶融合基因(EML4-ALK)阳性患者治疗的新标准;抗血管新生药物在NSCLC的治疗疗效得到了进一步证实;EGF疫苗在晚期NSCLC治疗中的结果值得期待。这些成果将会改变目前晚期NSCLC的治疗策略,而基于患者临床特点及分子分型的个体化治疗将成为晚期非小细胞肺癌治疗的新趋势。     

Anti-vascular tumor therapy: recent advances, pitfalls and clinical perspectives.

Anti-vascular tumor therapy represents a promising new strategy for cancer treatment. Anti-vascular treatment may be divided in anti-angiogenic and vascular targeting therapy. Whereas anti-angiogenic drugs aim on the inhibition of new vessel formation, vascular targeting compounds are designed to selectively destruct preexisting tumor blood vessels leading to secondary tumor cell death. Both anti-angiogenic drugs and vascular targeting agents have proven effective anti-tumoral activity in numerous preclinical studies over the last decade. In vivo, a combination with anti-vascular tumor therapy enhances the effects of other treatment modalities as chemo- and radiotherapy. Phase I clinical studies revealed a number of well-tolerated candidates. As monotherapy, however, anti-angiogenic treatment lacked efficacy in randomized clinical studies so far. In contrast, combination of anti-angiogenic therapy with chemotherapy was highly effective in an encouraging, large randomized phase III trial on metastatic colorectal cancer. This review will outline recent advances in the preclinical and clinical development of anti-vascular therapy with focus on vascular targeting. Conceptual differences between anti-angiogenic and vascular targeting therapies will be discussed with emphasis on specific problems and pitfalls in the conversion into the clinic.     

Point mutations of protein kinases and individualised cancer therapy

The treatment of cancer is rapidly changing, with an increasing focus on converting our improved understanding of the molecular basis of disease into clinical benefit for patients. Protein kinases that are mutated in cancer represent attractive targets, as they may result in cellular dependency on the mutant kinase or its associated pathway for survival, a condition known as ‘oncogene addiction’. Early clinical experiences have demonstrated dramatic clinical benefit of targeting oncogenic mutations in diseases that have been largely resistant to traditional cytotoxic chemotherapy. Further, mutational activation of kinases can indicate which patients are likely to respond to targeted therapeutics. However, these experiences have also illuminated a number of critical challenges that will have to be addressed in the development of effective drugs across different cancers, to fully realise the potential of individualised molecular therapy. This review utilises examples of genetic activation of kinases to illustrate many of the lessons learned, as well as those yet to be implemented.     

PARP抑制剂在肿瘤治疗中的研究进展

肿瘤是威胁人类生存与健康的重要原因之一。在肿瘤的药物治疗中,化疗是常用手段之一,但由于其特异性低、不良反应大、长期使用易产生耐药性等问题,应用受到较大限制。基于DNA损伤修复机制开发的新型抗肿瘤药物聚腺苷酸二磷酸核糖聚合酶(poly-ADP ribose polymerase,PARP)抑制剂可能是解决这一问题的关键。PARP抑制剂是一类靶向抑制PARP-1蛋白,诱导BRCA基因突变的肿瘤细胞发生“合成致死”现象的新型抗肿瘤药物,已成功应用于卵巢癌、乳腺癌等肿瘤的治疗。近年来PARP抑制剂更是与各类一线化疗药、靶向制剂及免疫检查点抑制剂等进行联合治疗,扩大了临床适用范围。本文将对PARP抑制剂的药理作用与作用机制、在肿瘤治疗中的应用及其耐药机制等研究进展进行总结,以期为PARP抑制剂的临床应用提供合理指导。     

Point mutations of protein kinases and individualised cancer therapy

The treatment of cancer is rapidly changing, with an increasing focus on converting our improved understanding of the molecular basis of disease into clinical benefit for patients. Protein kinases that are mutated in cancer represent attractive targets, as they may result in cellular dependency on the mutant kinase or its associated pathway for survival, a condition known as 'oncogene addiction'. Early clinical experiences have demonstrated dramatic clinical benefit of targeting oncogenic mutations in diseases that have been largely resistant to traditional cytotoxic chemotherapy. Further, mutational activation of kinases can indicate which patients are likely to respond to targeted therapeutics. However, these experiences have also illuminated a number of critical challenges that will have to be addressed in the development of effective drugs across different cancers, to fully realise the potential of individualised molecular therapy. This review utilises examples of genetic activation of kinases to illustrate many of the lessons learned, as well as those yet to be implemented.     

Novel targets for therapy in paediatric oncology

Although the majority of children with cancer are now cured of their disease, a significant number either have disease resistant to current therapy, or are unable to tolerate the short and long term complications of their treatment. Therefore new therapeutic strategies which optimise existing agents by use of their clinical and molecular pharmacology are needed, along with the development of new agents. Accordingly, the agents chosen for the study need to be prioritized, and are thus selected on the basis of categories such as encouraging pre-clinical data from xenografts of paediatric tumours, novel mechanisms of action, drugs that modify or overcome cellular resistance and drugs that are active in adult studies. In this review, novel targets for chemotherapy such as topoisomerase I, angiogenesis and signal transduction will be discussed. In addition, the circumvention of methotrexate resistance by novel antifolate thymidylate synthase inhibition, and the modulation of alkylating agents by inhibition of 0(6)-alkylDNA-alkyltransferase will be discussed as strategies to overcome potentially important resistance mechanisms in paediatric oncology. Finally, recent advances in biological therapies, tumour vaccination and gene therapy will be highlighted. In the future, investigation of cancer biology, selection of new drugs, and securing of funds to support the conduct of integrated early clinical studies that maximise the pharmacological, cellular biological and molecular pathological information gained, will be the major challenges to be faced by paediatric oncologists.     

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.     

Advances in the approach to novel drug clinical development for breast cancer

Introduction: In the post-genomic era clinical development of new agents to treat breast cancer (BC) can be a real challenge. Different from chemotherapy agents, with a broad but not specific spectrum of activity, novel drugs are being developed as ‘targeted’ agents, potentially benefiting a subgroup of patients. In BC, different clinically identifiable subtypes are now separately addressed in specific clinical trials.

Areas covered: In this review, the authors discuss the clinical development of targeted drugs that have become part of the current treatment of BC. They also highlight the challenges that in other cases determined the failure of promising compounds. Furthermore, the article reports on how combinations of targeted agents have emerged as valid strategies to overcome acquired resistance. It also provides discussion of how ‘old’ therapies can be retargeted to certain patient populations or ‘reinvented’ as safer and more effective with the creation of drug conjugates. They also discuss how novel clinical trial designs are emerging to accelerate the successful matching of targeted drugs to the right patient population.

Expert opinion: It is important not to forget that the development of BC therapeutics is a ‘moving target’, as its biology evolves in time under the pressure of ongoing treatments. There are currently a finite number of resources available for the development of new therapeutics, which means that resources need to be carefully allocated. There is also a need to prioritize clinical trials that can reduce the number of patients who are candidates for expensive treatments.