Docking: successes and challenges

The state of the art of various computational aspects of docking-based virtual screening of database of small molecules is presented. The review encompasses the different search algorithms and the scoring functions used in docking methods and their applications to protein and nucleic acid drug targets. Recent progress made in the development and application of methods to include target flexibility are summarized. The fundamental issues and challenges involved in comparing various docking methods are discussed. Limitations of current technologies as well as future prospects are presented.     

Targeting cancer: the challenges and successes of structure-based drug design against the human purinome

Purine-binding proteins are of critical importance to all living organisms. Approximately 13% of the human genome is devoted to coding for purine-binding proteins. Given their importance, purine-binding proteins are attractive targets for chemotherapeutic intervention against a variety of disease states, particularly cancer. Modern computational and biophysical techniques, combined together in a structure-based drug design approach, aid immensely in the discovery of inhibitors of these targets. This review covers the process of modern structure-based drug design and gives examples of its use in discovery and development of drugs that target purine-binding proteins. The targets reviewed are human purine nucleoside phosphorylase, human epidermal growth factor receptor kinase, and human kinesin spindle protein.     

New drug targets for genomic cancer therapy: successes,limitations, opportunities and future challenges

Cancer drug therapy is undergoing a major transition from the previous pregenomic cytotoxic era to the new postgenomic era. Future mechanism-based therapeutic agents will increasingly be designed to act on molecular targets that are causally involved in the malignant progression of human cancers. Such agents are predicted to show greater therapeutic selectivity for cancer versus normal cells. New cancer drug targets are identified and validated in various ways. The determination of the normal human genome sequence, followed by that of multiple cancer genomes, is accelerating target discovery. Other new technologies, particularly high throughput screening, combinatorial chemistry and gene expression microarrays, are increasing the speed and efficiency of drug development. Examples of new molecular therapeutics showing promising activity in the clinic include Herceptin, Glivec and Iressa. However, many challenges remain as we test the vision of individualised combinatorial genome-based therapy, using drugs targeted to every significant molecular abnormality in cancer.     

Safety and secondary pharmacology: successes, threats, challenges and opportunities

This review summarises the lecture of Dr Tim Hammond, recipient of the Distinguished Service Award of the Safety Pharmacology Society, given on 20 September 2007 in Edinburgh. The lecture discussed the rationale behind the need for optimal non-clinical Safety and Secondary Pharmacology testing; the evolution of Safety and Secondary Pharmacology over the last decade; its impact on drug discovery and development; the value of adopting an integrated risk assessment approach; the translation of non-clinical findings to humans and finally the future challenges and opportunities facing these disciplines.     

Perceived successes and challenges of clinical pharmacist practitioners in North Carolina

ObjectivesTo describe the successes and challenges reported by current (active) and formerly practicing (inactive) CPPs and to determine the reasons why inactive CPPs discontinued advanced practice.MethodsA sampling frame, consisting of all active and inactive CPPs, was obtained from the North Carolina Boards of Medicine and Pharmacy. An electronic survey was sent to 84 active and 32 inactive CPPs. Respondents were queried regarding qualifications, experience, and practice characteristics, perceived successes, and perceived challenges.Results54 active and 22 inactive CPPs responded. Among active CPPs, 28 (51.9%) reported improved patient care outcomes and 27 (50.0%) reported an expanded scope of practice. Regarding challenges, 30 (55.6%) identified billing for services and 19 (35.2%) noted reimbursement through third parties. Among inactive CPPs, 14 (63.6%) experienced improved patient care outcomes and 11 (50.0%) said their licensure created a practice model for learners. Billing (54.5%) and reimbursement (31.8%) were the top challenges experienced by inactive CPPs. A total of 12 inactive CPPs (54.5%) discontinued CPP licensure because it was not a requirement of their current position. Three (13.6%) discontinued because of insurmountable challenges that made it difficult to continue practice.ConclusionAlthough CPPs held a perception of improved patient care outcomes, billing for services and obtaining reimbursement were reported as the most prevalent challenges and may have played a major role in CPPs becoming inactive.     

Cationic transfection lipids in gene therapy: successes,set-backs,challenges and promises

The clinical success of gene therapy is critically dependent on the development of efficient and safe gene delivery reagents, popularly known as "Transfection Vectors". The transfection vectors commonly used in gene therapy are mainly of two types: viral and non-viral. The efficiencies of viral transfection vectors are, in general, superior to their non-viral counterparts. However, the myriads of potentially adverse immunogenic aftermaths associated with the use of viral vectors are increasingly making the non-viral gene delivery reagents as the vectors of choice. Among the existing arsenal of non-viral gene delivery reagents, the distinct advantages associated with the use of cationic transfection lipids include their: (a) robust manufacture; (b) ease in handling & preparation techniques; (c) ability to inject large lipid:DNA complexes and (d) low immunogenic response. The present review will highlight the successes, set-backs, challenges and future promises of cationic transfection lipids in non-viral gene therapy.     

CAR-T的发展历程及实体瘤治疗难点

随着人们对肿瘤研究的深入,肿瘤疗法也越来越多元化,免疫疗法逐渐成为研究的热点。嵌合抗原受体T细胞疗法（Chimeric Antigen Receptor T cell,CAR-T）是当今肿瘤治疗领域最具研究前景的方向之一,在血液瘤治疗方面取得了重大突破,但在实体瘤中一直未有突破。本文就CAR-T的结构发展历程和在实体瘤治疗中遇到的困难展开讨论。     

降低亲和力提高HER2-CAR-T细胞治疗的安全性

目的 探讨降低CAR-T细胞亲和力是否能有效提高其杀伤特异性,减少"脱靶效应"。方法 构建靶向HER2的中等亲和力和高亲和力的La-G3HER2-CAR和Ha-G3HER2-CAR并电穿孔转染T细胞,采用Western Blot、FCM技术和xCELLigence RTCA DP进行CAR载体表达和杀伤功能检测。结果 La-G3HER2-CAR-T细胞和Ha-G3HER2-CAR-T细胞分别表达43000和58000的外源CAR载体片段,转染效率分别为58.1%和69.0%。高亲和力的Ha-G3HER2-CAR-T细胞对高、中、低水平表达HER2的6种靶细胞均有效杀伤,而低亲和力的La-G3HER2-CAR-T细胞高效杀伤HER2高表达的SK-OV-3和BT474细胞,对HER2中表达的MDA-MB-231和HCC-202的杀伤作用较弱,而对低水平表达HER2的MCF-7和293细胞不杀伤。进一步的机制研究发现,HER2中水平表达的MDA-MB-231细胞共培养对La-G3HER2-CAR-T细胞和Ha-G3HER2-CAR-T细胞激活和细胞因子分泌诱导水平不同(CD107a:8.2% vs 71.6%; IFN-γ:66.3% vs 83.4%; TNF-α:73.4% vs 94.1%)。结论 中等亲和力La-G3HER2-CAR-T细胞比高亲和力的Ha-G3HER2-CAR-T细胞的杀伤作用特异性更强,降低CAR-T细胞的亲和力可以提高治疗的安全性。     

Hepatitis C: recent successes and continuing challenges in the development of improved treatment modalities

Despite the progress being made toward development of less-toxic and simpler alternatives to the current peg-IFN standard-of-care therapy for chronic hepatitis C, the highly replicative nature of HCV infection and the error-prone nature of its viral RNA synthesis pose extraordinary challenges to drug development. Peg-IFN is likely to remain a mainstay of therapy for the foreseeable future, or until such time that multiple direct-acting STAT-C inhibitors are available and shown to provide a sufficiently high barrier to resistance when used in combination.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Overcoming the challenges in the effective delivery of chemotherapies to CNS solid tumors

Locoregional therapies, such as surgery and intratumoral chemotherapy, do not effectively treat infiltrative primary CNS solid tumors and multifocal metastatic solid tumor disease of the CNS. It also remains a challenge to treat such CNS malignant solid tumor disease with systemic chemotherapies, although these lipid-soluble small-molecule drugs demonstrate potent cytotoxicity in vitro. Even in the setting of a 'normalized' tumor microenvironment, small-molecule drugs do not accumulate to effective concentrations in the vast majority of tumor cells, which is due to the fact that small-molecule drugs have short blood half-lives. It has been recently shown that drug-conjugated spherical lipid-insoluble nanoparticles within the 7-10 nm size range can deliver therapeutic concentrations of drug fraction directly into individual tumor cells following systemic administration, since these functionalized particles maintain peak blood concentrations for several hours and are smaller than the physiologic upper limit of pore size in the VEGF-derived blood capillaries of solid tumors, which is approximately 12 nm. In this article, the physiologic and ultrastructural basis of this novel translational approach for the treatment of CNS, as well as non-CNS, solid cancers is reviewed.     

Understanding and targeting cancer stem cells: therapeutic implications and challenges

Cancer stem cells (CSCs) have been identified as rare cell populations in many cancers, including leukemia and solid tumors. Accumulating evidence has suggested that CSCs are capable of self-renewal and differentiation into various types of cancer cells. Aberrant regulation of gene expression and some signaling pathways has been observed in CSCs compared to other tumor cells. CSCs are thought to be responsible for cancer initiation, progression, metastasis, recurrence and drug resistance. The CSC hypothesis has recently attracted much attention due to the potential for discovery and development of CSC-related therapies and the identification of key molecules involved in controlling the unique properties of CSC populations. Over the past several years, a tremendous amount of effort has been invested in the development of new drugs, such as nanomedicines, that can take advantage of the “Achilles'' heel” of CSCs by targeting cell-surface molecular markers or various signaling pathways. Novel compounds and therapeutic strategies that selectively target CSCs have been identified, some of which have been evaluated in preclinical and clinical studies. In this article, we review new findings related to the investigation of the CSC hypothesis, and discuss the crucial pathways involved in regulating the development of CSC populations and the advances in studies of drug resistance. In addition, we review new CSC-targeted therapeutic strategies aiming to eradicate malignancies.     

Application of monoclonal antibodies as cancer therapy in solid tumors

Monoclonal antibodies have become an important new class of therapeutic agents approved for use in solid tumors. They function through several different mechanisms including inhibition of tumor-related signal transduction, induction of apoptosis, inhibition of angiogenesis, enhancing host immune response against cancer and targeted delivery of cytotoxic agents to the tumor site. Several monoclonal antibodies have now received regulatory approval--trastuzumab, cetuximab, panitumumab, bevacizumab, catumaxomab, ipilimumab and denosumab--across multiple solid tumor types, including breast, colorectal, head and neck, non-small cell lung cancers and melanomas, amongst others. These agents are employed clinically in some neoadjuvant/adjuvant and radical treatment settings, as well as more extensively in the metastatic and palliative settings. Current research is focused on innovative compound design, novel targets, predictive biomarker discovery, enriched patient populations, and combination strategies in order to overcome resistance and prolong disease control. Here we provide an overview of monoclonal antibodies approved for use in clinical oncology and those currently in clinical development.     

Dasatinib in solid tumors

Importance of the field: Dasatinib is an oral, potent adenosine triphosphate-competitive inhibitor of multiple tyrosine kinases including BCR-ABL, c-KIT, platelet-derived growth factor receptor, and Src family kinases (SFKs). It has gained much attention for its use in chronic myeloid leukemia and for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. However, dasatinib is also being explored in solid tumors in ongoing Phase I and II clinical trials.

Areas covered in this review: The clinical efficacy of dasatinib in a wide variety of solid tumors and important Phase I/II studies utilizing dasatinib and the optimal dosage used in solid tumors. A literature search was conducted using PubMed/MEDLINE, www.clinicaltrials.gov, and the American Society of Clinical Oncology websites to find relevant Phase I/II clinical trials during 1987 – 2009.

What the reader will gain: The understanding that the biology and mechanism of Src activation in tumors are not well understood and finding the optimal use of SFK inhibitors in the clinical setting requires further investigation.

Take home message: In reviewing the clinical safety data of dasatinib in its current use as a Src inhibitor in a wide variety of solid malignancies, dasatinib appears to be safe and is a promising agent for the treatment of metastatic solid tumors refractory to standard therapies.     

Sunitinib in solid tumors

Background: Until recently, few treatments were available for renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GIST). Several targeted agents inhibiting key pathogenetic pathways have since been developed for RCC (sunitinib, sorafenib, bevacizumab, temsirolimus, everolimus) and GIST (imatinib, sunitinib). Sunitinib is a multi-kinase inhibitor of VEGFR-2, PDGFR (α,β), FLT-3, KIT, CSF-1 and RET. Objective: To summarize the literature regarding the structure, pharmacokinetics, pharmacodynamics, toxicity and current clinical use of sunitinib. Other potential roles for this drug in RCC, GIST and other tumor types will be discussed. Methods: A literature search identified relevant (pre)clinical studies of sunitinib and other relevant agents. Results/conclusions: Sunitinib revolutionized the management of advanced RCC and GIST. With the realization that cross-resistance between targeted agents is incomplete, evolving strategies include sequential treatment, concurrent treatment, and biomarker development. Sunitinib also shows promise in several other tumor types that lack therapeutic options. What remains less clear is its role in tumors that are not heavily dependent on a central pathogenetic pathway, especially if effective cytotoxic therapies exist. Future clinical trials will clarify whether there is a role for sunitinib in these tumors, possibly in combination with cytotoxic agents.     

NF-kappaB in solid tumors

Cancer is a multistep process during which cells acquire genetic alterations that drive the progressive transformation of normal cells into highly malignant cells. Self-sufficiency in growth, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis, are signatures of transformed cells. NF-kappaB is a key actor in tumorigenesis given its ability to control the expression and the function of a number of genes involved in these processes. Indeed, constitutive activation of NF-kappaB is a common feature of many human tumors, while its sustained activation during inflammation predisposes normal cells to neoplastic transformation. Since suppression of NF-kappaB has been shown to inhibit oncogenic potential of transformed cells, targeting it should be effective in the prevention and treatment of cancer.     

Belinostat: clinical applications in solid tumors and lymphoma

Introduction: Histone deacetylase (HDAC) inhibitors have recently emerged as a novel and active class of anticancer agents. Belinostat is one member of the class that has been tested as a single agent and in combination with other chemotherapies and biological agents in the treatment of solid tumors and lymphoma.

Areas covered: A literature search of pre-clinical and clinical studies of belinostat was performed. The data from these studies were analysed to summarise the progress of belinostat from Phase I to a current pivotal trial in peripheral T-cell lymphoma. The parallel development of appropriate biomarker analysis is also discussed.

Expert opinion: Belinostat has demonstrated significant clinical activity in T-cell lymphomas. Although its activity as a single agent in solid tumors has been less compelling, the emerging results from combination trials are promising. However, the basis for the activity of belinostat, like that of other HDAC inhibitors, remains to be truly defined and the identification of predictive and prognostic biomarkers of activity should be established to further progress the development of this compound.