News Article | April 18, 2017
Cancer Research UK and the Cancer Research Technology Pioneer Fund (CPF)* have committed £2.5 million in collaboration with the National Cancer Institute (NCI) in the US to tackle one of the toughest challenges in cancer that has thwarted researchers for more than 30 years. Scientists will develop and test promising new molecules for targeting RAS, one of the most common driving mutations in aggressive, hard to treat cancers including pancreatic and lung cancer. Scientists at the NCI in Frederick, Maryland, USA will work with the Drug Discovery Unit at the Cancer Research UK Beatson Institute** in Glasgow, Scotland to develop gold standard tests to analyse these novel RAS inhibitors. This new collaboration links up with the NCI's RAS Initiative*** which brings scientists together from around the globe to help develop drugs targeting the faulty protein. Launched in 2013, the initiative has established a hub of expertise that supports the international community in developments that could have huge clinical benefit. The CRT Pioneer Fund, managed by Sixth Element Capital, will be responsible for the commercial exploitation of compounds that arise from the collaboration. For decades, scientists have been attempting to target RAS,**** but with little success. This is because RAS lacks an obvious site on its surface for potential drug molecules to fit into and inhibit its signalling. Dr Martin Drysdale, head of the Drug Discovery Unit at the Cancer Research UK Beatson Institute, said: "Our team is determined to challenge the dogma that RAS is 'undruggable.' This collaboration is our biggest yet and will double our resource targeting RAS. We are excited to be joining forces with the NCI in their pioneering RAS Initiative." "Instead of scientists working and thinking in isolation, the NCI has created a research hub to pull together all the best science and expertise. My team is looking forward to contributing and working with Dr Frank McCormick, who leads the RAS Initiative and who has been at the forefront of cancer science for many years." Dr Frank McCormick, who directs the research efforts of the RAS Initiative at the Frederick National Laboratory for Cancer Research, sponsored by the NCI, said: "We're making progress in our understanding of how RAS proteins function at the molecular level and how they form signalling complexes in membranes. New technologies and tools mean we can now analyse these proteins in ways that were not possible a few years ago, and can now test new ways of blocking RAS function." Dr Iain Foulkes, chief executive officer of Cancer Research Technology and executive director of research and innovation at Cancer Research UK, said: "It's crucial that we unite the brightest minds across the globe. This international collaboration and investment could herald a new era in targeting RAS. "We hope to develop these small molecules to pave the way for potential drugs in the future. Our aim is to work alongside industry to ensure any progress makes its way into clinical trials." Dr Robert James, Managing Partner at Sixth Element Capital, said: "The CRT Pioneer Fund was established to invest in outstanding science that has the potential to benefit patients on a global scale. We are delighted to have catalysed this relationship which has created an opportunity to make real progress in discovering drugs against RAS, one of the most important oncogenes in cancer." For media enquiries contact Stephanie McClellan in the Cancer Research Technology press office on 020 3469 5314 or, out of hours, on 07050 264 059.
McCormick F.,Frederick National Laboratory for Cancer Research |
McCormick F.,University of California at San Francisco
Clinical Cancer Research | Year: 2015
KRAS proteins play a major role in human cancer, but have not yielded to therapeutic attack. New technologies in drug discovery and insights into signaling pathways that KRAS controls have promoted renewed efforts to develop therapies through direct targeting of KRAS itself, new ways of blocking KRAS processing, or by identifying targets that KRAS cancers depend on for survival. Although drugs that block the wellestablished downstream pathways, RAF-MAPK and PI3K, are being tested in the clinic, new efforts are under way to exploit previously unrecognized vulnerabilities, such as altered metabolic networks, or novel pathways identified through synthetic lethal screens. Furthermore, new ways of suppressing KRAS gene expression and of harnessing the immune system offer further hope that new ways of treating KRAS are finally coming into view. These issues are discussed in this edition of CCR Focus. ©2015 AACR.
Stephen A.G.,Frederick National Laboratory for Cancer Research |
Esposito D.,Frederick National Laboratory for Cancer Research |
Bagni R.G.,Frederick National Laboratory for Cancer Research |
McCormick F.,Frederick National Laboratory for Cancer Research |
McCormick F.,University of California at San Francisco
Cancer Cell | Year: 2014
Ras proteins play a major role in human cancers but have not yielded to therapeutic attack. Ras-driven cancers are among the most difficult to treat and often excluded from therapies. The Ras proteins have been termed "undruggable," based on failures from an era in which understanding of signaling transduction, feedback loops, redundancy, tumor heterogeneity, and Ras' oncogenic role was poor. Structures of Ras oncoproteins bound to their effectors or regulators are unsolved, and it is unknown precisely how Ras proteins activate their downstream targets. These knowledge gaps have impaired development of therapeutic strategies. A better understanding of Ras biology and biochemistry, coupled with new ways of targeting undruggable proteins, is likely to lead to new ways of defeating Ras-driven cancers. © 2014 Elsevier Inc.
McLaren P.J.,Ecole Polytechnique Federale de Lausanne |
Carrington M.,Frederick National Laboratory for Cancer Research |
Carrington M.,Massachusetts Institute of Technology
Nature Immunology | Year: 2015
The outcome after infection with the human immunodeficiency virus type 1 (HIV-1) is a complex phenotype determined by interactions among the pathogen, the human host and the surrounding environment. An impact of host genetic variation on HIV-1 susceptibility was identified early in the pandemic, with a major role attributed to the genes encoding class I human leukocyte antigens (HLA) and the chemokine receptor CCR5. Studies using genome-wide data sets have underscored the strength of these associations relative to variants located throughout the rest of the genome. However, the extent to which additional polymorphisms influence HIV-1 disease progression, and how much of the variability in outcome can be attributed to host genetics, remain largely unclear. Here we discuss findings concerning the functional impact of associated variants, outline methods for quantifying the host genetic component and examine how available genome-wide data sets may be leveraged to discover gene variants that affect the outcome of HIV-1 infection.
Nussinov R.,Frederick National Laboratory for Cancer Research |
Nussinov R.,Tel Aviv University |
Tsai C.-J.,Frederick National Laboratory for Cancer Research
Cell | Year: 2013
Allostery is largely associated with conformational and functional transitions in individual proteins. This concept can be extended to consider the impact of conformational perturbations on cellular function and disease states. Here, we clarify the concept of allostery and how it controls physiological activities. We focus on the challenging questions of how allostery can both cause disease and contribute to development of new therapeutics. We aim to increase the awareness of the linkage between disease symptoms on the cellular level and specific aberrant allosteric actions on the molecular level and to emphasize the potential of allosteric drugs in innovative therapies. © 2013 Elsevier Inc.
Rapisarda A.,Frederick National Laboratory for Cancer Research |
Melillo G.,Bristol Myers Squibb
Nature Reviews Clinical Oncology | Year: 2012
Cancer cells rely on angiogenesis to fulfil their need for oxygen and nutrients; hence, agents targeting angiogenic pathways and mediators have been investigated as potential cancer drugs. Although this strategy has demonstrated delayed tumour progression-leading to progression-free survival and overall survival benefits compared with standard therapy-in some patients, the results are more modest than predicted. A significant number of patients either do not respond to antiangiogenic agents or fairly rapidly develop resistance to them, which raises questions about how resistance develops and how it can be overcome. Furthermore, whether cancers, once they develop resistance, become more invasive or lead to metastatic disease remains unclear. Several mechanisms of resistance have been recently proposed and emerging evidence indicates that, under certain experimental conditions, antiangiogenic agents increase intratumour hypoxia by promoting vessel pruning and inhibiting neoangiogenesis. Indeed, several studies have highlighted the possibility that inhibitors of VEGF (and its receptors) can promote an invasive metastatic switch, in part by creating an increasingly hypoxic tumour microenvironment. As a potential remedy, a number of therapeutic approaches have been investigated that target the hypoxic tumour compartment to improve the clinical outcome of antiangiogenic therapy. © 2012 Macmillan Publishers Limited. All rights reserved.
O'Carroll I.P.,Frederick National Laboratory for Cancer Research
Virus research | Year: 2013
The Gag polyprotein is the building block of retroviral particles and its expression is sufficient for assembly in cells. In HIV-1, nucleic acid (NA) is required for recombinant Gag molecules to assemble in a defined system in vitro. Experiments performed by Barklis and co-workers suggested that NA contributes to assembly by promoting Gag oligomerization. Gag is composed of four main domains: the matrix (MA), capsid (CA), nucleocapsid (NC), and p6 domains. We have recently shown that the SP1 linker, which lies between the CA and NC domains, assumes a helical structure at high, but not low, concentrations. We suggested that Gag oligomerization mediates assembly via an SP1-dependent conformational switch that exposes new interfaces for assembly. Although NA is required for assembly in vitro, deletion of NC, the main RNA-binding domain, does not eliminate particle formation in vivo; these particles lack NA. We hypothesized that alternative pathways that lead to Gag oligomerization or an increase in local Gag concentration, namely Gag-membrane or inter-protein interactions, rescue assembly in the absence of NC-RNA binding. We constructed mutants in which either Gag-membrane binding, the Gag dimer interface, or NC-RNA binding are disrupted. None of these mutants disables assembly. However, combined mutations in any two of these three classes render Gag completely unable to form virus-like particles. Thus, it seems, Gag utilizes at least three types of interactions to form oligomers and any two out of the three are sufficient for assembly. Published by Elsevier B.V.
Cragg G.M.,Frederick National Laboratory for Cancer Research |
Newman D.J.,Frederick National Laboratory for Cancer Research
Biochimica et Biophysica Acta - General Subjects | Year: 2013
Background Nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. Following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. Combinatorial chemistry (late 1980s), shifted the focus of drug discovery efforts from Nature to the laboratory bench. Scope of Review This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases. It is clear Nature will continue to be a major source of new structural leads, and effective drug development depends on multidisciplinary collaborations. Major Conclusions The explosion of genetic information led not only to novel screens, but the genetic techniques permitted the implementation of combinatorial biosynthetic technology and genome mining. The knowledge gained has allowed unknown molecules to be identified. These novel bioactive structures can be optimized by using combinatorial chemistry generating new drug candidates for many diseases. General Significance The advent of genetic techniques that permitted the isolation / expression of biosynthetic cassettes from microbes may well be the new frontier for natural products lead discovery. It is now apparent that biodiversity may be much greater in those organisms. The numbers of potential species involved in the microbial world are many orders of magnitude greater than those of plants and multi-celled animals. Coupling these numbers to the number of currently unexpressed biosynthetic clusters now identified (> 10 per species) the potential of microbial diversity remains essentially untapped.
Dimitrov D.S.,Frederick National Laboratory for Cancer Research
Methods in Molecular Biology | Year: 2012
Protein-based therapeutics are highly successful in clinic and currently enjoy unprecedented recognition of their potential. More than 100 genuine and similar number of modified therapeutic proteins are approved for clinical use in the European Union and the USA with 2010 sales of US$108 bln; monoclonal antibodies (mAbs) accounted for almost half (48%) of the sales. Based on their pharmacological activity, they can be divided into five groups: (a) replacing a protein that is deficient or abnormal; (b) augmenting an existing pathway; (c) providing a novel function or activity; (d) interfering with a molecule or organism; and (e) delivering other compounds or proteins, such as a radionuclide, cytotoxic drug, or effector proteins. Therapeutic proteins can also be grouped based on their molecular types that include antibody-based drugs, Fc fusion proteins, anticoagulants, blood factors, bone morphogenetic proteins, engineered protein scaffolds, enzymes, growth factors, hormones, interferons, interleukins, and thrombolytics. They can also be classified based on their molecular mechanism of activity as (a) binding non-covalently to target, e.g., mAbs; (b) affecting covalent bonds, e.g., enzymes; and (c) exerting activity without specific interactions, e.g., serum albumin. Most protein therapeutics currently on the market are recombinant and hundreds of them are in clinical trials for therapy of cancers, immune disorders, infections, and other diseases. New engineered proteins, including bispecific mAbs and multispecific fusion proteins, mAbs conjugated with small molecule drugs, and proteins with optimized pharmacokinetics, are currently under development. However, in the last several decades, there are no conceptually new methodological developments comparable, e.g., to genetic engineering leading to the development of recombinant therapeutic proteins. It appears that a paradigm change in methodologies and understanding of mechanisms is needed to overcome major challenges, including resistance to therapy, access to targets, complexity of biological systems, and individual variations. © 2012 Springer Science+Business Media, LLC.
Estes J.D.,Frederick National Laboratory for Cancer Research
Immunological Reviews | Year: 2013
Acquired immunodeficiency syndrome (AIDS) is principally a disease of lymphoid tissues (LTs), due to the fact that the main target cell of human immunodeficiency virus (HIV) is the CD4+ T lymphocyte that primarily resides within organs of the immune system. The impact of HIV infection on secondary LTs, in particular lymph nodes, is critical to delineate, as these immune organs are the principal sites for initiating and facilitating immune responses and are critical for lymphocyte homeostatic maintenance and survival. The underlying structural elements of LTs, fibroblastic reticular cell (FRC) network, not only form the architectural framework for these organs, but also play in integral role in the production and storage of cytokines needed for T-cell survival. There is an interdependent relationship between the FRC stromal network and CD4+ T lymphocytes for their survival and maintenance that is progressively disrupted during HIV disease. HIV infection results in profound pathological changes to LTs induced by persistent chronic immune activation and inflammation that leads to progressive collagen deposition and fibrosis disrupting and damaging the important FRC network. In this review, I focus on the process, mechanisms, and the implications of pathological damage to important secondary LTs, combining what we have learned from HIV-infected individuals as well as the invaluable knowledge gained from studies in non-human primate simian immunodeficiency virus infection models. © 2013 John Wiley & Sons A/S 254 1 July 2013 10.1111/imr.12070 Invited Review Invited Reviews Published 2013. This article is a U.S. Government work and is in the public domain in the USA.