Discovering novel chemotherapeutic drugs for the third millennium

There is enormous potential for the discovery of innovative cancer drugs with improved efficacy and selectivity for the third millennium. In this review we show how novel mechanism-based agents are being discovered by focusing on the molecular targets and pathways that are causally involved in cancer formation, maintenance and progression. We also show how new technologies, from genomics through high throughput bioscience, combinatorial chemistry, rational drug design and molecular pharmacodynamic and imaging techniques, are accelerating the pace of cancer drug discovery. The process of contemporary small molecule drug discovery is described and progress and current issues are reviewed. New and potential targets and pathways for therapeutic intervention are illustrated. The first examples of a new generation of molecular therapeutics are now entering hypothesis-testing clinical trials and showing activity. The early years of the new millennium will see a range of exciting new agents moving from bench to bedside and beginning to impact on the management and cure of cancer.     

Recent developments in nanomedicine for melanoma treatment

Melanoma is a most aggressive skin cancer with limited therapeutic options and its incidence is increasing rapidly in recent years. The discovery and application of new targeted therapy agents have shown significant benefits. However, adverse side‐effects and resistance to chemotherapy remain formidable challenges in the clinical treatment of malignant melanoma. Nanotherapeutics offers an important prospect of overcoming these drawbacks. The anti‐tumoral applications of nanomedicine are varied, including those in chemotherapy, RNA interference, photothermal therapy, and photodynamic therapy. Furthermore, nanomedicine allows delivery of the effector structures into the tumor site via passive or active targeting, thereby allowing increased therapeutic specificity and reduced side effects. In this review, we summarize the latest developments in the application of nanocarrier‐mediated targeted drug delivery to melanoma and nanomedicine‐related clinical trials in melanoma treatment. We also discuss existing problems and opportunities for future developments, providing direction and new thoughts for further studies.     

Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer

The estrogen receptor (ER) pathway plays a critical role in breast cancer development and progression. Endocrine therapy targeting estrogen action is the most important systemic therapy for ER positive breast cancer. However its efficacy is limited by intrinsic and acquired resistance. Mechanisms responsible for endocrine resistance include deregulation of the ER pathway itself, including loss of ER expression, post-translational modification of ER, deregulation of ER co-activators; increased receptor tyrosine kinase signaling leading to activation of various intracellular pathways involved in signal transduction, proliferation and cell survival, including growth factor receptor tyrosine kinases human epidermal growth factor receptor-2, epidermal growth factor receptor, PI3K/AKT/mammalian target of rapamycin (mTOR), Mitogen activated kinase (MAPK)/ERK, fibroblast growth factor receptor, insulin-like growth factor-1 receptor; alterations in cell cycle and apoptotic machinery; Epigenetic modification including dysregulation of DNA methylation, histone modification, and nucleosome remodeling; and altered expression of specific microRNAs. Functional genomics has helped us identify a catalog of genetic and epigenetic alterations that may be exploited as potential therapeutic targets and biomarkers of response. New treatment combinations targeting ER and such oncogenic signaling pathways which block the crosstalk between these pathways have been proven effective in preclinical models. Results of recent clinical studies suggest that subsets of patients benefit from the combination of inhibitor targeting certain oncogenic signaling pathway with endocrine therapy. Especially, inhibition of the mTOR signaling pathway, a key component implicated in mediating multiple signaling cascades, offers a promising approach to restore sensitivity to endocrine therapy in breast cancer. We systematically reviewed important publications cited in PubMed, recent abstracts from ASCO annual meetings and San Antonio Breast Cancer Symposium, and relevant trials registered at ClinicalTrials.gov. We present the molecular mechanisms contributing to endocrine resistance, in particular focusing on the biological rationale for the clinical development of novel targeted agents in endocrine resistant breast cancer. We summarize clinical trials utilizing novel strategies to overcome therapeutic resistance, highlighting the need to better identify the appropriate patients whose diseases are most likely to benefit from these specific strategies.     

Bevacizumab in colorectal cancer: current and future directions

Bevacizumab is a humanized monoclonal antibody to VEGF-A, an important therapeutic target through its proangiogenic effects on a variety of tumors. Bevacizumab has demonstrated clinically meaningful benefit in conjunction with chemotherapy for patients with metastatic colorectal cancer as well as other tumor types. Bevacizumab is a well-tolerated therapy with regard to toxicity, in keeping with its biological vascular effect. In this era of personalized medicine, current Phase II and III trials are further defining its role at various stages of metastatic disease and the optimal sequencing with cytotoxic and other targeted agents to achieve further improvements in patient outcome. Translational research for biomarker discovery and validation and further study into mechanisms of resistance are essential for future development and sustained benefit with this class of therapeutic agents.     

Reverse phase protein microarrays advance to use in clinical trials

Individualizing cancer therapy for molecular targeted inhibitors requires a new class of molecular profiling technology that can map the functional state of the cancer cell signal pathways containing the drug targets. Reverse phase protein microarrays (RPMA) are a technology platform designed for quantitative, multiplexed analysis of specific phosphorylated, cleaved, or total (phosphorylated and non-phosphorylated) forms of cellular proteins from a limited amount of sample. This class of microarray can be used to interrogate tissue samples, cells, serum, or body fluids. RPMA were previously a research tool; now this technology has graduated to use in research clinical trials with clinical grade sensitivity and precision. In this review we describe the application of RPMA for multiplexed signal pathway analysis in therapeutic monitoring, biomarker discovery, and evaluation of pharmaceutical targets, and conclude with a summary of the technical aspects of RPMA construction and analysis.     

Role of Apoptosis in Colon Cancer Biology, Therapy, and Prevention

Deregulation of apoptosis is a hallmark of human cancer and contributes to therapeutic resistance. Recent advances in cancer genomics have revealed a myriad of alterations in key pathways that directly or indirectly increase tumor cell survival. This review outlines the pathways of apoptosis in mammalian cells, and highlights the common alterations of apoptosis regulators found in colon cancer, the role of apoptosis, and underlying mechanisms in colon cancer treatment and prevention, including recent advances in investigational agents, such as kinase inhibitors, proteasome inhibitors, heat shock protein 90 inhibitors, BH3 mimetics, tumor necrosis factor related apoptosis-inducing ligand, and inhibitor of apoptosis protein antagonists. The topics also include novel concepts as well as opportunities and challenges for drug discovery and combination therapy by exploring cancer-specific genetic defects, and therefore selective induction of apoptosis in cancer cells. Although the emphasis is on colon cancer, the main theme and many of the aspects are applicable to other solid tumors.     

Functional genomic analysis of drug sensitivity pathways to guide adjuvant strategies in breast cancer

The widespread introduction of high throughput RNA interference screening technology has revealed tumour drug sensitivity pathways to common cytotoxics such as paclitaxel, doxorubicin and 5-fluorouracil, targeted agents such as trastuzumab and inhibitors of AKT and Poly(ADP-ribose) polymerase (PARP) as well as endocrine therapies such as tamoxifen. Given the limited power of microarray signatures to predict therapeutic response in associative studies of small clinical trial cohorts, the use of functional genomic data combined with expression or sequence analysis of genes and microRNAs implicated in drug response in human tumours may provide a more robust method to guide adjuvant treatment strategies in breast cancer that are transferable across different expression platforms and patient cohorts.     

Genomic and proteomic technologies for individualisation and improvement of cancer treatment

The development of microarray-based technologies for characterising tumours, both at the genomic and proteomic levels, has had a significant impact on the field of oncology. Gene expression profiling of various human tumour tissues has led to the identification of expression patterns related to disease outcome and drug resistance, as well as to the discovery of new therapeutic targets and insights into disease pathogenesis. Protein microarray technologies, such as reverse-phase protein arrays, provide the unique opportunity to profile tissues and assess the activity of signalling pathways within isolated cell populations. This technology can be used to identify patients likely to benefit from specific treatment modalities and also to monitor therapeutic response in samples obtained during and after treatment. Routine application of genomic and proteomic microarray technologies in clinical practice will require significant efforts to standardise the techniques, controls and reference standards, and analytical tools used. Extensive, independent validation using large, statistically-powered datasets will also be necessary. Inclusion of concomitant genomic and proteomic-based molecular profiling techniques into clinical trial protocols will bring us closer to the reality of patient-tailored therapy.     

Clinical trial design for target-based therapy

Anticancer drug discovery has shifted from an empiric random screening directed approach to a more rational and mechanistic, target-based approach, which reflects our rapidly expanding knowledge of the pathogenesis of a variety of forms of cancer at the molecular level, providing new targets for drug discovery and development. The clinical development of target-based anticancer drugs will require fundamental changes to the traditional clinical trial design and end points that have been used for conventional cytotoxic drugs. In the phase I and II settings, traditional end points (toxicity and response) may not be suitable for more selective, cytostatic target-based agents, and these end points may be replaced by biological or pharmacokinetic end points to define the optimal doses and the therapeutic effects of these drugs on their targets. For phase III trials, measurable clinical benefit will continue to be the primary end point. As our understanding of the complex pathways and networks controlling cell signaling, proliferation, and cell death expands, we must learn how and when to use agents to target specific steps in malignant transformation and proliferation, and we must adapt clinical trial design to test the clinical utility of this promising new class of anticancer drugs.     

Combinatorial drug screening identifies compensatory pathway interactions and adaptive resistance mechanisms

Constitutively activated signaling molecules are often the primary drivers of malignancy, and are favored targets for therapeutic intervention. However, the effectiveness of targeted inhibition of cell signaling can be blunted by compensatory signaling which generates adaptive resistance mechanisms and reduces therapeutic responses. Therefore, it is important to identify and target these compensatory pathways with combinations of targeted agents to achieve durable clinical benefit. In this report, we demonstrate the use of high-throughput combinatorial drug screening as a discovery tool to identify compensatory pathways that generate resistance to the cytotoxic effects of targeted therapy. We screened 420 drug combinations in 14 different cell lines representing three cancer lineages, and assessed the ability of each combination to cause synergistic cytotoxicity. Drug substitution studies were used to validate the functionally important drug targets. Of the 84 combinations that caused robust synergy in multiple cell lines, none were synergistic in more than half of the lines tested, and we observed no pattern of lineage specificity in the observed synergies. This reflects the plasticity of cell signaling networks, even among cell lines of the same tissue of origin. Mechanistic analysis of one novel synergistic combination identified in the screen, the multi-kinase inhibitor Ro31-8220 and lapatinib, demonstrated compensatory crosstalk between the p70S6 kinase and EGF receptor pathways. In addition, we identified BAD as a node of convergence between these two pathways that may be playing a role in the enhanced apoptosis observed upon combination treatment.     

阿帕替尼治疗恶性肿瘤的临床研究进展

随着抗血管生成靶向治疗的发展,作用于血管内皮生长因子（vascular endothelial growth factor,VEGF）及其血管内皮生长因子受体（vascular endothelial growth factor receptor ,VEGFR）信号通路的抗肿瘤药物越来越受到广泛的关注。血管内皮细胞生长因子受体- 2（vascular endothelial growth factor receptor 2,VEGFR- 2）抑制剂阿帕替尼是一种高效抗血管生成药物,是最新上市的口服分子靶向抗肿瘤药物之一。阿帕替尼在人体生物利用度高,安全性及耐受性良好。上市前后一系列大规模的随机、对照临床试验证实阿帕替尼在多种恶性肿瘤中具有一定的客观有效率和生存获益,如胃癌、非小细胞肺癌（non-small cell lung cancer ,NSCLC ）、乳腺癌等,尤其是在胃癌中。2014年该药在中国批准上市应用于临床治疗晚期胃癌。目前正在进行胃癌、肺癌、肝癌、食管癌、结直肠癌等多种恶性肿瘤的Ⅱ/ Ⅲ期临床试验,以探讨其单独或联合抗肿瘤活性。本文就阿帕替尼抗肿瘤机制、对不同类型肿瘤的临床疗效、安全性及不良反应、药物相互作用、耐药及生物标志物等最新研究进展进行综述,以加深对该药抗肿瘤应用的了解,为临床实践提供参考,并期望为恶性肿瘤患者的治疗带来一些新的选择。      

Bevacizumab for malignant gliomas: current indications,mechanisms of action and resistance,and markers of response

Vascular endothelial growth factor (VEGF) is an attractive target of antiangiogenic therapy in glioblastomas. Bevacizumab (Bev), a humanized anti-VEGF antibody, is associated with the improvement of progression-free survival and performance status in patients with glioblastoma. However, randomized trials uniformly suggest that these favorable clinical effects of Bev do not translate into an overall survival benefit. The mechanisms of action of Bev appear to include the inhibition of tumor angiogenesis, as well as indirect effects such as the depletion of niches for glioma stem cells and stimulation of antitumor immunity. Although several molecules/pathways have been reported to mediate adaptation and resistance to Bev, including the activation of alternative pro-angiogenic pathways, the resistance mechanisms have not been fully elucidated; for example, the mechanism that reinduces tumor hypoxia remains unclarified. The identification of imaging characteristics or biomarkers predicting the response to Bev, as well as the better understanding of the mechanisms of action and resistance, is crucial to improve the overall clinical outcome and optimize individual therapy. In this article, the authors review the results of important clinical trials/studies, the current understanding of the mechanisms of action and resistance, and the knowledge of imaging characteristics and biomarkers predicting the response to Bev.     

RNA interference and potential therapeutic applications of short interfering RNAs

RNA interference is an endogenous gene-silencing mechanism that involves double-stranded RNA-mediated sequence-specific mRNA degradation. The discovery of this pathway together with the elucidation of the structure and function of short interfering RNAs--the effector molecules of RNA interference--has had an enormous impact on experimental biology. RNA interference technologies are currently the most widely utilized techniques in functional genomic studies. Furthermore, there is an intense research effort aimed at developing short interfering RNAs for therapeutic purposes. A number of proof-of-principle experiments have demonstrated the clinical potential of appropriately designed short interfering RNAs in various diseases including viral infections, cancer and neurodegenerative disorders. Already, in such a short time from their discovery, Acuity Pharmaceuticals (August 2004) and Sirna Therapeutics (September 2004) have filed Investigational New Drug applications with the US FDA to begin clinical trials with modified siRNA molecules in patients with age-related macular degeneration. This review will give a brief overview of the mechanism of RNA interference and applications of the pathway in experimental biology will be discussed. The article will focus on recent developments related to the use of RNA interference technologies in mammalian systems and on potential clinical applications of short interfering RNA-mediated RNA interference.