Robert rie Comprehensive Cancer Center

Chicago, IL, United States

Robert rie Comprehensive Cancer Center

Chicago, IL, United States
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Damiano M.G.,Northwestern University | Mutharasan R.K.,Feinberg Cardiovascular Research Institute | Tripathy S.,Northwestern University | McMahon K.M.,Northwestern University | And 3 more authors.
Advanced Drug Delivery Reviews | Year: 2013

High density lipoproteins (HDLs) are dynamic natural nanoparticles best known for their role in cholesterol transport and the inverse correlation that exists between blood HDL levels and the risk of developing coronary heart disease. In addition, enhanced HDL-cholesterol uptake has been demonstrated in several human cancers. As such, the use of HDL as a therapeutic and as a vehicle for systemic delivery of drugs and as imaging agents is increasingly important. HDLs exist on a continuum from the secreted HDL-scaffolding protein, apolipoprotein A-1 (Apo A1), to complex, spherical "mature" HDLs. Aspects of HDL particles including their size, shape, and surface chemical composition are being recognized as critical to their diverse biological functions. Here we review HDL biology; strategies for synthesizing HDLs; data supporting the clinical use and benefit of directly administered HDL; a rationale for developing synthetic methods for spherical, mature HDLs; and, the potential to employ HDLs as therapies, imaging agents, and drug delivery vehicles. Importantly, methods that utilize nanoparticle templates to control synthetic HDL size, shape, and surface chemistry are highlighted. © 2012 Elsevier B.V.

McMahon K.M.,Northwestern University | Thaxton C.S.,Northwestern University | Thaxton C.S.,Institute for Bionanotechnology and Medicine IBNAM | Thaxton C.S.,Robert rie Comprehensive Cancer Center
Expert Opinion on Drug Delivery | Year: 2014

Introduction: RNA interference (RNAi) is a powerful mechanism for gene silencing with the potential to greatly impact the development of new therapies for many human diseases. Short interfering RNAs (siRNAs) may be the ideal molecules for therapeutic RNAi. However, therapeutic siRNAs face significant challenges that must be overcome prior to widespread clinical use. Many efforts have been made to overcome the hurdles associated with systemic administration of siRNA; however, current approaches are still limited. As such, there is an urgent need to develop new strategies for siRNA delivery that have the potential to impact a broad spectrum of systemic diseases. Areas covered: This review focuses on the promise of siRNA therapies and highlights current siRNA delivery methods. With an eye toward new strategies, this review first introduces high-density lipoprotein (HDL) and describes its natural biological functions, and then transitions into how HDLs may provide significant opportunities as next-generation siRNA delivery vehicles. Importantly, this review describes how synthetic HDLs leverage the natural ability of HDL to stabilize and deliver siRNAs. Expert opinion: HDLs are natural nanoparticles that are critical to understanding the systemic delivery of therapeutic nucleic acids, like siRNA. Methods to synthesize biomimetic HDLs are being explored, and data demonstrate that this type of delivery vehicle may be highly beneficial for targeted and efficacious systemic delivery of siRNAs. © 2014 Informa UK, Ltd.

Zhang X.-Q.,Northwestern University | Lam R.,Northwestern University | Xu X.,Northwestern University | Chow E.K.,University of California at San Francisco | And 3 more authors.
Advanced Materials | Year: 2011

Multimodal nanodiamonds (NDs) were prepared by attaching fluorescently labeled drug-oligonucleotide conjugates and monoclonal antibodies onto the ND surface. Fluorescently labeled oligonucleotide linkers enabled the intracellular observation and quantification of resultant ND conjugates. The covalent attachment of the chemotherapeutic and targeting moiety to the ND surface significantly enhanced cellular internalization and therapeutic activity © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Savaryn J.P.,Chemistry of Life Processes Institute | Catherman A.D.,Chemistry of Life Processes Institute | Thomas P.M.,Chemistry of Life Processes Institute | Abecassis M.M.,Comprehensive Transplant Center | And 2 more authors.
Genome Medicine | Year: 2013

Proteomic technology has advanced steadily since the development of 'soft-ionization' techniques for mass-spectrometry-based molecular identification more than two decades ago. Now, the large-scale analysis of proteins (proteomics) is a mainstay of biological research and clinical translation, with researchers seeking molecular diagnostics, as well as protein-based markers for personalized medicine. Proteomic strategies using the protease trypsin (known as bottom-up proteomics) were the first to be developed and optimized and form the dominant approach at present. However, researchers are now beginning to understand the limitations of bottom-up techniques, namely the inability to characterize and quantify intact protein molecules from a complex mixture of digested peptides. To overcome these limitations, several laboratories are taking a whole-protein-based approach, in which intact protein molecules are the analytical targets for characterization and quantification. We discuss these top-down techniques and how they have been applied to clinical research and are likely to be applied in the near future. Given the recent improvements in mass-spectrometry-based proteomics and stronger cooperation between researchers, clinicians and statisticians, both peptide-based (bottom-up) strategies and whole-protein-based (top-down) strategies are set to complement each other and help researchers and clinicians better understand and detect complex disease phenotypes. © 2013 BioMed Central Ltd.

Cooley A.,Northwestern University | Zelivianski S.,Northwestern University | Jeruss J.S.,Northwestern University | Jeruss J.S.,Robert rie Comprehensive Cancer Center
Cell Cycle | Year: 2010

Smad3, a component of the TGFβ signaling pathway, contributes to G1 arrest in breast cancer cells. Overexpression of the cell cycle mitogen, cyclin E, is associated with poor prognosis in breast cancer, and cyclin E/CDK2 mediated phosphorylation of Smad3 has been linked with inhibition of Smad3 activity. We hypothesized that the biological aggressiveness of cyclin E overexpressing breast cancer cells would be associated with CDK2 phosphorylation and inhibition of the tumor suppressant action of Smad3. Expression constructs containing empty vector, wild type (WT) Smad3 or Smad3 with CDK phosphorylation site mutations were co-transfected with a Smad3-responsive reporter construct into parental, vector control (A1) or cyclin E overexpressing (EL1) MCF7 cells. Smad3 function was evaluated by luciferase reporter assay and mRNA analysis. The impact of a Cdk2 inhibitor and cdk2 siRNA on Smad3 activity was also assessed. Cells expressing Smad3 containing mutations of the CDK phosphorylation sites had higher p15 and p21 and lower c-myc mRNA levels, as well as higher Smad3-responsive reporter activity, compared with controls or cells expressing WT Smad3. Transfection of cdk2 siRNA resulted in a significant increase in Smad3-responsive reporter activity compared with control siRNA; reporter activity was also increased after the treatment with a Cdk2 inhibitor. Thus, cyclin E-mediated inhibition of Smad3 is regulated by CDK2 phosphorylation of the Smad3 protein in MCF7 cells. Inhibition of CDK2 may lead to restoration of Smad3 tumor suppressor activity in breast cancer cells, and may represent a potential treatment approach for cyclin E overexpressing breast cancers. © 2010 Landes Bioscience.

Bryan L.J.,Northwestern University | Gordon L.I.,Robert rie Comprehensive Cancer Center
Blood Reviews | Year: 2015

Immunotherapy remains an important tool for treatment of hematologic malignancies. The Programmed Death-1 (PD-1) immune checkpoint pathway has emerged as a mechanism of tumor evasion from the anti-tumor immune response. The recent development of anti-PD-1 monoclonal antibodies has offered a targeted approach to cancer therapy. Several agents are in various stages of development and have shown clinical responses across a broad spectrum of both solid and hematologic malignancies. The use of anti-PD-1 therapy in hematologic malignancies is limited but has demonstrated clinical responses in relapsed/refractory disease following multiple lines of therapy. PD-1 blockade may reduce relapse rates for patients who fail to obtain a complete remission prior to autologous hematopoietic cell transplant. The role of the PD-1 pathway for tumor escape is reviewed. We explore the use of anti-PD-1 therapy in hematologic malignancies. The proposed mechanism of PD-1 blockade as a modulator of the innate and acquired immune response is considered. Finally, the challenges of anti-PD-1 therapy and the future direction of investigation in this area are reviewed. © 2014 Elsevier Ltd.

Siu K.T.,Northwestern University | Rosner M.R.,University of Chicago | Minella A.C.,Northwestern University | Minella A.C.,Robert rie Comprehensive Cancer Center
Cell Cycle | Year: 2012

Cancers of diverse cell lineages express high levels of cyclin E, and in various studies, cyclin E overexpression correlates with increased tumor aggression. One way that normal control of cyclin E expression is disabled in cancer cells is via loss-of-function mutations sustained by FBXW7. This gene encodes the Fbw7 tumor suppressor protein that provides substrate specificity for a ubiquitin ligase complex that targets multiple oncoproteins for degradation. Numerous other mechanisms besides Fbw7 mutations can deregulate cyclin E expression and activity in cancer cells. Recent reports demonstrate that inappropriate cyclin E expression may have far-reaching biological consequences for cell physiology, including altering gene expression programs governing proliferation, differentiation, survival and senescence. In this review, we discuss the function of mammalian cyclin E in the context of these new data as well as the complex network that connects cyclin E functions to the cellular controls regulating its expression and activity. © 2012 Landes Bioscience.

Kelleher N.L.,Northwestern University | Kelleher N.L.,Robert rie Comprehensive Cancer Center
Journal of the American Society for Mass Spectrometry | Year: 2012

The general scope of a project to determine the protein molecules that comprise the cells within the human body is framed. By focusing on protein primary structure as expressed in specific cell types, this concept for a cell-based version of the Human Proteome Project (CB-HPP) is crafted in a manner analogous to the Human Genome Project while recognizing that cells provide a primary context in which to define a proteome. Several activities flow from this articulation of the HPP, which enables the definition of clear milestones and deliverables. The CB-HPP highlights major gaps in our knowledge regarding cell heterogeneity and protein isoforms, and calls for development of technology that is capable of defining all human cell types and their proteomes. The main activities will involve mapping and sorting cell types combined with the application of beyond the state-of-the art in protein mass spectrometry. © The Author(s), 2012.

Tarasewicz E.,Northwestern University | Tarasewicz E.,Robert rie Comprehensive Cancer Center | Jeruss J.S.,Northwestern University | Jeruss J.S.,Robert rie Comprehensive Cancer Center
Cell Cycle | Year: 2012

Members of the TGFβ superfamily are known to exert a myriad of physiologic and pathologic growth controlling influences on mammary development and oncogenesis. In epithelial cells, TGFβ signaling inhibits cell growth through cytostatic and pro-apoptotic activities but can also induce cancer cell EMT and, thus, has a dichotomous role in breast cancer biology. Mechanisms governing this switch are the subject of active investigation. Smad3 is a critical intracellular mediator of TGFβsignaling regulated through phosphorylation by the TGFβreceptor complex at the C terminus. Smad3 is also a substrate for several other kinases that phosphorylate additional sites within the Smad protein. This discovery has expanded the understanding of the significance and complexity of TGFβsignaling through Smads. This review highlights recent advances revealing the critical role of phospho-specific Smad3 in malignancy and illustrates the potential prognostic and therapeutic impact of Smad3 phospho-isoforms in breast cancer. © 2012 Landes Bioscience.

Stegh A.H.,Robert rie Comprehensive Cancer Center
Expert Opinion on Therapeutic Targets | Year: 2012

Introduction: Research over the past three decades has identified p53 as a multi-functional transcription factor. p53 influences myriad, highly diverse cellular processes, and represents one of the most important and extensively studied tumor suppressors. Activated by various stresses, p53 blocks cancer progression by provoking transient or permanent growth arrest, by enabling DNA repair, or by advancing cellular death programs. This anti-cancer activity profile, together with genomic and mutational analyses documenting inactivation of p53 in more than 50% of human cancers, motivated drug development efforts to (re-) activate p53 in established tumors. Areas covered: The complexities of p53 signaling in cancer are summarized, including current strategies and challenges to restore p53's tumor suppressive function in established tumors, to inactivate p53 inhibitors, and to restore wild type function of p53 mutant proteins. Expert opinion: p53 represents an attractive target for the development of anti-cancer therapies. Whether p53 is 'druggable', however, remains an area of active research and discussion, as p53 has pro-survival functions and chronic p53 activation accelerates aging, which may compromise the long-term homeostasis of an organism. The complex biology and dual functions of p53 in cancer prevention and age-related cellular responses pose significant challenges to the development of p53-targeting cancer therapies. © 2012 Informa UK, Ltd.

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