Cancer Research UK

About: Cancer Research UK is a nonprofit organization based out in London, United Kingdom. It is known for research contribution in the topics: Cancer & Gene. The organization has 1025 authors who have published 777 publications receiving 148154 citations. The organization is also known as: CRUK.

Biomarker-Driven Early Clinical Trials in Oncology A Paradigm Shift in Drug Development

Abstract: Early clinical trials represent a crucial bridge between preclinical drug discovery and the especially resource-intense randomized phase III trial-the definitive regulatory hurdle for drug approval. High attrition rates and rising costs, when Coupled with the extraordinary opportunities opened up by cancer genomics and the promise of personalized medicine call for new approaches in the conduct and design of phase I/II trials. The key challenge lies in increasing the odds for successful and efficient transition of a compound through the drug development pipeline. The incorporation of scientifically and analytically validated biomarkers into rationally designed hypothesis-testing clinical trials offers a promising way forward to achieving this objective. In this article, we provide an overview of biomarkers in early clinical trials, including examples where they have been particularly successful, and the caveats and pitfalls associated with indiscriminate application. We describe the use of pharmacodynamic end points to demonstrate the proof of modulation of target, pathway, and biologic effect, as well as predictive biomarkers for patient selection and trial enrichment. Establishing the pharmacologic audit trail provides a means to assess and manage risk in a drug development program and thus increases the rationality of the decision-making process. Accurate preclinical models are important for pharmacokinetic-pharmacodynamic-efficacy modeling and biomarker validation. The degree of scientific and analytical validation should ensure that biomarkers are fit-for purpose, according to the stage of development and the impact on the trial; specifically they are either exploratory or used to make decisions within the trial. To be maximally useful at an early stage, these must be in place before the commencement of phase I trials. Validation and qualification of biomarkers then continues through clinical development. We highlight the impact of modem technology platforms, such as genomics, proteomics, circulating tumor cells, and minimally invasive functional and molecular imaging, with respect to their potential role in improving the success rate and speed of drug development and in interrogating the consequences of therapeutic intervention and providing a unique insight into human disease biology. With these technologies already having an impact in the clinic today, we predict that further future advances will come from the application of network analysis to clinical trials, leading to individualized systems-based medicine for cancer.

Role of Discoidin Domain Receptors 1 and 2 in Human Smooth Muscle Cell-Mediated Collagen Remodeling: Potential Implications in Atherosclerosis and Lymphangioleiomyomatosis

Abstract: Obstructive diseases of blood vessels and the lung are characterized by degradation and synthesis of new extracellular matrix (ECM) components Regulated remodeling of the ECM in diseases such as atherosclerosis and lymphangioleiomyomatosis (LAM), both characterized by excessive accumulation of smooth muscle cells (SMCs), is thought to be controlled in part by cell surface receptors for specific ECM components Discoidin domain receptors (DDR) 1 and 2 represent a family of tyrosine kinase collagen receptors that are activated by fibrillar collagens To test the hypothesis that DDR may be involved in ECM remodeling by SMCs in vivo, we analyzed DDR expression by reverse transcriptase-polymerase chain reaction and immunohistochemistry and demonstrate that both DDR1 and DDR2 are up-regulated in nodules of LAM as compared to normal controls, and are expressed in lesions of atherosclerosis In vitro, retroviral overexpression of DDR1 or DDR2 in human SMCs cultured on polymerized collagen gels leads to a reduction of collagen expression and induces matrix metalloproteinase (MMP) 1 at both mRNA and protein levels, but only DDR2 enhances MMP2 activation Moreover, DDR2 overexpression increases SMC-mediated collagen and elastin degradation in vitro Using laser microdissection, we extend our studies to the analysis of SMCs from LAM nodules where we observe higher MMP1 expression and MMP2 activation Taken together, these data provide evidence for the potential roles of DDR1 and DDR2 in the regulation of collagen turnover mediated by SMCs in obstructive diseases of blood vessels and the lung

Role of pericytes in vascular morphogenesis.

Abstract: Pericytes are solitary, smooth muscle-like mural cells that invest the wall of microvessels For a long time, the functional significance of the presence and distribution of pericytes in the microvasculature was unclear However, in recent years, the application of experimental genetics to the PDGF-B/PDGFRbeta signaling pathway in mice has provided a range of mutants with primary defects in pericytes, allowing for studies of the physiological consequences of pericyte deficiency in developmental angiogenesis and adult physiology Interestingly, some of the phenotypic consequences of these mutations resemble human diseases, such as diabetic retinopathy The studies have also led to the discovery of critical mechanisms involved in pericyte recruitment and differentiation The present review focuses on genetic data suggesting that pericytes take active part in developmental angiogenic processes

Prognostic and predictive biomarkers in resected colon cancer: Current status and future perspectives for integrating genomics into biomarker discovery

Abstract: The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era.

Distinct roles for Sld3 and GINS during establishment and progression of eukaryotic DNA replication forks

Abstract: The Cdc45 protein is crucial for the initiation of chromosome replication in eukaryotic cells, as it allows the activation of prereplication complexes (pre-RCs) that contain the MCM helicase. This causes the unwinding of origins and the establishment of DNA replication forks. The incorporation of Cdc45 at nascent forks is a highly regulated and poorly understood process that requires, in budding yeast, the Sld3 protein and the GINS complex. Previous studies suggested that Sld3 is also important for the progression of DNA replication forks after the initiation step, as are Cdc45 and GINS. In contrast, we show here that Sld3 does not move with DNA replication forks and only associates with MCM in an unstable manner before initiation. After the establishment of DNA replication forks from early origins, Sld3 is no longer essential for the completion of chromosome replication. Unlike Sld3, GINS is not required for the initial recruitment of Cdc45 to origins and instead is necessary for stable engagement of Cdc45 with the nascent replisome. Like Cdc45, GINS then associates stably with MCM during S-phase.