Selected highlights from the 27th San Antonio Breast Cancer Symposium

The San Antonio Breast Cancer Symposium is now considered the most important international breast cancer meeting worldwide. On 8 – 11th December 2004, ～ 6700 participants attended the meeting and shared the latest findings from breast cancer research. All the main fields of breast cancer research and treatment were covered. This report will focus on the most relevant advancements in the pharmacotherapy of breast cancer. The selected presentations have been grouped together in separate sections, including the fields of prevention, early disease and advanced disease. The most promising data from translational research have also been included, with particular regard to those who will most likely influence the management of breast cancer patients in the future.     

Selected highlights from the 27th San Antonio Breast Cancer Symposium. San Antonio, TX, USA, 8-11 December 2004

The San Antonio Breast Cancer Symposium is now considered the most important international breast cancer meeting worldwide. On 8-11th December 2004, approximately 6700 participants attended the meeting and shared the latest findings from breast cancer research. All the main fields of breast cancer research and treatment were covered. This report will focus on the most relevant advancements in the pharmacotherapy of breast cancer. The selected presentations have been grouped together in separate sections, including the fields of prevention, early disease and advanced disease. The most promising data from translational research have also been included, with particular regard to those who will most likely influence the management of breast cancer patients in the future.     

Selected highlights from the 26th San Antonio Breast Cancer Symposium. December 3-6, 2003, San Antonio, TX, USA

The San Antonio Breast Cancer Symposium is one of the largest international meetings devoted solely to breast cancer research. Basic scientists, translational researchers, clinical investigators and physicians share state-of-the-art information on breast cancer covering almost all the aspects of breast cancer, including prevention, aetiology, diagnosis, molecular biology and treatment. The current report describes relevant therapeutic findings that were presented at the 26 th San Antonio Breast Cancer Conference, held in San Antonio, Texas, USA, in December 2003.     

Selected Highlights from the 26th San Antonio Breast Cancer Symposium

The San Antonio Breast Cancer Symposium is one of the largest international meetings devoted solely to breast cancer research. Basic scientists, translational researchers, clinical investigators and physicians share state-of-the-art information on breast cancer covering almost all the aspects of breast cancer, including prevention, aetiology, diagnosis, molecular biology and treatment. The current report describes relevant therapeutic findings that were presented at the 26^th San Antonio Breast Cancer Conference, held in San Antonio, Texas, USA, in December 2003.     

Collaborative approaches to anticancer drug discovery and development: a Cancer Research UK perspective

The pharmaceutical industry is under huge pressure to overhaul what is currently viewed as a highly inefficient operating model. Unacceptable levels of late-stage failure in clinical development remain a fundamental problem for the sector. Lack of efficacy is a major reason for candidate failure and a lack of understanding of disease biology is considered to be a key issue underpinning this problem. There has been a recent upsurge in interest from pharmaceutical and biotechnology companies to collaborate with academic institutions, with the latter viewed as being home to research teams with in-depth biological knowledge and translational research expertise. This article outlines models for collaboration in drug discovery and development being pursued by the research-based charity Cancer Research UK (CR-UK).     

Recent advances in the medical management of breast cancer: highlights from the 29th San Antonio Breast Cancer Conference

The 29th edition of the San Antonio Breast Cancer Symposium was attended by a total of > 8000 basic scientists, translational researchers, clinical investigators and physicians gathering from ~ 80 countries worldwide. This is the largest meeting focusing on breast cancer, encompassing a wide array of topics from prevention, aetiology and diagnosis to molecular biology and treatment. From the main presentations at the meeting, it seems clear that combined efforts at prevention and treatment of this disease have translated into small, but significant, achievements. Much of the research in the area is focused on improving the therapeutic ratio of available treatments by better selection of patients.     

Update in the treatment of locally advanced breast cancer: a multidisciplinary approach

Locally advanced breast cancer represents a wide variety of neoplasms and constitutes approximately 10%-20% of the newly diagnosed breast cancers. These cancers may have widely different clinical and biological characteristics. According to the American Joint Committee on Cancer (AJCC) staging system, all of stage III disease is considered locally advanced. The clinical treatment of locally advanced breast cancer is complex and should be tailored to the individual patient. In this paper we discuss the options of management of locally advanced breast cancer, focusing on a multidisciplinary approach through a combined-modality care involving surgery, radiotherapy and systemic therapy.     

Novel therapeutic strategy for breast cancer: mammalian target of rapamycin inhibition

Background: Mammalian target of rapamycin (mTOR) plays a central role in regulating cellular protein synthesis. Dysregulation of mTOR signaling pathway is strongly associated with tumorigenesis, angiogenesis, tumor progression and drug resistance. Inhibition of mTOR might not only promote cell cycle arrest, but also sensitize resistant cancer cells to chemotherapeutic and other targeted agents. Objective: To review and summarize the mechanism of mTOR on regulation of protein synthesis and latest clinical data, and to discuss the novel therapeutic strategy for the use of mTOR inhibitors in the treatment of breast cancer. Methods: A review of published literatures and conference abstracts obtained from MEDLINE, American Society of Clinical Oncology Meeting and San Antonio Breast Cancer Symposia proceedings for results of previous preclinical and latest clinical studies of mTOR inhibition in breast cancer was performed. Conclusions: mTOR inhibitors seemed to be potentially useful for the treatment of breast cancer with acceptable safety profile. The challenge remains the identification of suitable candidates with different phenotypes. More structured studies incorporating molecular, clinical and translational research need to be initiated. Future research on mTOR inhibitors for breast cancer should focus on the evaluation of optimal schedule, patient selection and combination strategies to maximize the use of this new class of targeted agents.     

La investigación traslacional en la oncología clínica: retos y oportunidades

The principal objective of the translational research in Oncology is to translate the knowledge derived from the basic research to the clinical practice as soon as possible. The goal is to develop and maximize the concepts of oncopharmacogenomic and oncopharmacogenetic. In this context it will be absolutely necessary that hospitals integrate the basic and clinical research in translational research units with the appropriate resources.     

Non-small cell lung cancer: from cytotoxic systemic chemotherapy to molecularly targeted therapy

Surgery is the only method of cure in lung cancer. Seldom its application with radical intent is possible. Despite the efforts aimed at integrating all the therapeutic strategies, the overall outcome of the management of this disease remains disappointing. For this reason, in the last three decades, thousands of preclinical and clinical attempts have been realised in order to investigate any possible way to cure this disease and significant steps forward have been made on the basis of the increasing "molecular knowledge" in the so called "post-genomic era". Particularly the impressive step forward in the biological characterization of cancer as a result of genetic/epigenetic multistep process has brought in a multitude of variables with staggering classification potentialities. "Benchside" and "bedside" scientists have assembled in functional teams to move the common efforts "translationally" to bridge basic and clinical research for a mutual synergistic enhancement. This paper represents the effort of a lung cancer focused translational research team made up of molecular biologists, medical oncologists and thoracic surgeons to achieve a comprehensive, but simple, review of the current status of the shift from cytotoxic to molecularly targeted therapy in lung cancer treatment potentially useful in the planning of translational research trials.     

The potential of translational bioinformatics approaches for pharmacology research

The field of bioinformatics has allowed the interpretation of massive amounts of biological data, ushering in the era of ‘omics’ to biomedical research. Its potential impact on pharmacology research is enormous and it has shown some emerging successes. A full realization of this potential, however, requires standardized data annotation for large health record databases and molecular data resources. Improved standardization will further stimulate the development of system pharmacology models, using translational bioinformatics methods. This new translational bioinformatics paradigm is highly complementary to current pharmacological research fields, such as personalized medicine, pharmacoepidemiology and drug discovery. In this review, I illustrate the application of transformational bioinformatics to research in numerous pharmacology subdisciplines.     

Mapping translational research in personalized therapeutics: from molecular markers to health policy

Translational research is frequently used in the bioscience literature to refer to the translation of basic science into practical applications at the point of patient care. With the introduction of theragnostics, a new medical subspecialty that fuses therapeutics and diagnostic medicine with the goal of providing individualized pharmacotherapy, we suggest that the focus of translational research is shifting. We identify two bottlenecks or gaps in translational research for theragnostics: GAP1 translation from basic science to first-in-human proof-of-concept; and GAP2 translation from clinical proof-of-concept to development of evidence-based personalized treatment guidelines. GAP1 translational research in theragnostics is usually performed in traditional craft-based studies with small sample sizes and led by independent academic or industry researchers. In contrast, GAP2 translational investigations typically rely on large research consortiums and population-based biobanks that couple biomarker information with longitudinal 'real-life' observational data on a broad range of pharmacological phenotypes. Despite an abundance of research on the use of biobanks in disease gene discovery, there has been little conceptual work on whether and to what extent population biobanks can be utilized for translating genomics discoveries to practical treatment guidelines for theragnostic tests.     

Molecular toxicology of corals: a review

Coral reefs worldwide have become increasingly affected by a phenomenon known as "coral bleaching," the loss of the symbiotic algae from the host corals. The underlying causes and mechanism(s) of coral bleaching are not well known, although several have been hypothesized. While coral bleaching has been a primary focus in recent years, corals respond differentially to numerous environmental stresses. The impacts of heat, hydrocarbons, salinity, sewage effluents, biocides, heavy metals, and ultraviolet light have been investigated in both laboratory experiments and field surveys among multiple coral species. Herein what is known regarding the biological impacts of such stresses on corals at the molecular level of organization is summarized. The objective is to focus attention at the early stages of biological effects in order to encourage and facilitate research that provide ways to understand how changes at the molecular level might elucidate processes likely occurring at the population level. This, in turn, should accelerate studies that may elucidate the cellular and physiological changes contributing to coral decline, rather than just document the continued global loss of coral diversity and abundance.     

Prediction of exposure-response relationships to support first-in-human study design

In drug development, phase 1 first-in-human studies represent a major milestone as the drug moves from preclinical discovery to clinical development activities. The safety of human subjects is paramount to the conduct of these studies and regulatory considerations guide activities. Forces of evolution on the pharmaceutical industry are re-shaping the first-in-human dose selection strategy. Namely, high attrition rates in part due to lack of efficacy have led to the re-organization of research and development organizations around the umbrella of translational research. Translational research strives to bring basic research advances into the clinic and support the reverse transfer of information to enhance compound selection strategies. Pharmacokinetic/pharmacodynamic (PK/PD) modeling holds a unique position in translational research by attempting to integrate diverse sets of information. PK/PD modeling has demonstrated utility in dose selection and trial design for later stages of drug development and is now being employed with greater prevalence in the translational research setting to manage risk (i.e., oncology and inflammation/immunology). Moving from empirical E (max) models to more mechanistic representations of the biological system, a higher fidelity of human predictions is expected. Strategies that have proven useful for PK predictions are being applied to PK/PD predictions. This review article examines examples of the application of PK/PD modeling in establishing target concentrations for supporting first-in-human study design.     

靶向药物及中药抗血管治疗乳腺癌研究进展

目的叙述靶向药物及抑制血管生成中药治疗乳腺癌的近年研究进展。方法通过收集大量关于靶向药物治疗乳腺癌及抑制血管生成中药治疗乳腺癌相关文献。结果大量实验研究表明肿瘤血管生成和乳腺癌演进密切相关。抗血管生成药物对乳腺癌的治疗有广阔的应用前景。与其他新疗法类似,抗血管生成靶向药物的疗效的评价尚需设计严谨的前瞻性临床随机试验来加以证实。结论抗血管生成治疗肿瘤和转移已成为肿瘤生物靶向治疗研究的主要方向。中药抗血管生成药物在乳腺癌治疗也取得一定的进展及成果,但仍需要进一步研究,发挥其优势为预防及治疗肿瘤提供新的途径。     

Exosomes: Breast cancer-derived extracellular vesicles; recent key findings and technologies in disease progression,diagnostics, and cancer targeting

Breast cancer is one of the most frequently diagnosed types of cancer in women. Metastasis, particularly to the lungs and brain, increases mortality in breast cancer patients. Recently, breast cancer-related exosomes have received significant attention because of their key role in breast cancer progression. As a result, numerous exosome-based therapeutic tools for diagnosis and treatment have been developed, and their biological and chemical mechanisms have been explored. This review summarizes up-to-date advanced key findings and technologies in breast cancer progression, diagnostics, and targeting. We focused on recent research on the basic biology of exosomes and disease-related exosomal genes and proteins, as well as their signal transduction in cell-to-cell communications, diagnostic markers, and exosome-based antibreast cancer technologies. We also paid special attention to technologies employing exosomes modified with functional peptides for the targeted delivery of therapeutic and diagnostic agents.     

Proteomic profiling from human samples: the body fluid alternative

Proteomics is one of the technologies rapidly changing our approach to drug development. The applications of proteomics, particularly with reference to analysis of body fluid samples, will be described. Proteomic analysis involves the systematic separation, identification and characterisation of proteins present in a biological sample. By comparing the proteins present in diseased samples with those present in normal samples, it is possible to identify changes in expression of proteins that potentially may be related to organ toxicity. Proteomics is regarded as a sister technology to genomics. Although the pattern of gene activity will be abnormal in a tissue with a pathological lesion, there can be a poor correlation between the level of activity of different genes and the relative abundance within the tissue of the corresponding proteins. This is especially true where the mode of action of the test material interferes with protein synthesis and/or post translational modification. Consequently, the information about a pathological process that can be derived at the level of gene activity is incomplete. Proteomics has now made it possible to analyse proteins using high throughput, automated techniques. Although both mRNA and proteomic profiling can be applied to tissue samples, analysis of body fluids (e.g. serum, urine, CSF, synovial fluid) is restricted to proteomics. In these cases the protein composition is derived from many tissues and processes. Proteomic analysis can yield information on disease processes and potential response to treatment. Examples will be presented of the identification of surrogate markers for hepatocellular carcinoma, breast cancer, from cerebrospinal fluid in humans and gentamicin toxicity in the rat.     

Insights into the pharmacological relevance of lysophospholipid receptors

The discovery of lysophospholipid (LP) 7-transmembrane, G protein-coupled receptors (GPCRs) that began in the 1990s, together with research into the functional roles of the major LPs known as lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), have opened new research avenues into their biological processes and mechanisms. Major examples of LP signalling effects include embryogenesis, nervous system development, vascular development, uterine implantation, immune cell trafficking, and inflammatory reactions. LP signalling also influences the pathophysiology of many diseases including cancer, autoimmune and inflammatory diseases, which indicate that LP receptors may be attractive targets for pharmacological therapies. A key example of such a therapeutic agent is the S1P receptor modulator FTY720, which upon phosphorylation and continued drug exposure, acts as an S1P receptor functional antagonist. This compound (also known as fingolimod or Gilenya) has recently been approved by the FDA for the treatment of relapsing forms of multiple sclerosis. Continued basic and translational research on LP signalling should provide novel insights into both basic biological mechanisms, as well as novel therapeutic approaches to combat a range of human diseases.     

Bacterial ribosomal subunit synthesis: a novel antibiotic target

The continuing increase in antibiotic-resistant pathogenic bacterial has stimulated research on the development of new antimicrobial agents and the identification of new cellular targets. One such target is the sequence of assembly steps required for the formation of bacterial ribosomal subunits. A large number of different protein synthesis inhibitors which affect large subunit function also prevent the 50S particle from being formed in growing cells. These compounds include the macrolide and ketolide antibiotics as well as certain lincosamides, B-type streptogramins and several other structurally unrelated translational inhibitors. This review describes the activities of these compounds as inhibitors of 50S subunit formation. For most of these drugs, their inhibitory effect on particle synthesis is equivalent to their effect on translation. This new target is thus of equal importance to translational inhibition as a mechanism of action of these compounds. Features of the 50S subunit precursor particle as a target for these drugs are described. Finally a model is presented which accounts for this activity and predicts certain features of the substrate for erythromycin methylase activity in inducible cells. Antibiotics which target subunit formation preferentially are predicted to be important bactericidal agents.