The Experts below are selected from a list of 267 Experts worldwide ranked by ideXlab platform
Kenneth C. Anderson - One of the best experts on this subject based on the ideXlab platform.
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Preclinical studies of novel targeted Therapies.
Hematology oncology clinics of North America, 2007Co-Authors: Teru Hideshima, Kenneth C. AndersonAbstract:The bone marrow (BM) milieu confers drug resistance in multiple myeloma (MM) cells to conventional Therapies. Novel Biologically Based Therapies are therefore needed. Preclinical studies have identified and validated molecular targeted therapeutics in MM. In particular, recognition of the biologic significance of the BM microenvironment in MM pathogenesis and as a potential target for novel therapeutics has already derived several promising approaches. Thalidomide, lenalidomide (Revlimid), and bortezomib (Velcade) are directed not only at MM cells but also at the BM milieu and have moved rapidly from the bench to the bedside and United States Food and Drug Administration approval to treat MM.
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Novel Biologically Based Therapies for Waldenstrom's macroglobulinemia.
Seminars in oncology, 2003Co-Authors: Constantine S. Mitsiades, Paul G. Richardson, Nicholas Mitsiades, Steven P. Treon, Kenneth C. AndersonAbstract:Abstract Waldenstrom's macroglobulinemia (WM) remains an incurable B-cell malignancy, necessitating urgent development of novel treatment strategies. Building on our experience on bed-to-bedside translational studies for multiple myeloma (mm), we identified a constellation of novel classes of anti-WM agents, including the proteasome inhibitor PS-341; the ansamycin family of inhibitors (eg, geldanamycin and its analogues) of the heat-shock protein 90 (hsp90) molecular chaperone; histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA); and the thiazolidinedione group of peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists (eg, ciglitazone or rosiglitazone). Our preclinical data show that these classes of agents induce growth arrest and apoptosis of WM cells, at concentrations relevant to those achieved in previous clinical uses of these drugs, and suggest that novel therapeutic strategies for WM can be designed to include combinations of these agents, to simultaneously target multiple levels of diverse pathways important for tumor cell growth and survival, and thus maximize the pro-apoptotic activities of these agents and/or neutralize protective responses of WM against their effects. These molecular studies provide a framework for rational design of the next generation of combination Therapies for WM. Semin Oncol 30:309-312. © 2003 Elsevier Inc. All rights reserved.
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Moving disease biology from the laboratory to the clinic
Seminars in Oncology, 2002Co-Authors: Kenneth C. AndersonAbstract:To address the urgent need for novel Therapies for multiple myeloma (MM), long-term research efforts have characterized the mechanisms whereby MM cells home to the bone marrow and adhere to bone marrow stromal cells and extracellular matrix proteins. Research also characterizes the functional sequelae of this binding to identify targets for novel Therapies. This article describes the mechanisms by which MM cells home to bone marrow and adhere to bone marrow stromal cells and extracellular matrix proteins, and describes the functional sequelae of this binding. Adhesion molecules that mediate MM cell binding to bone marrow stromal cells are identified, and the growth and survival advantage conferred by this binding is discussed. The biologic significance of cytokines in MM pathogenesis and the signaling cascades mediating their effects are delineated. Apoptotic and targeted therapeutic strategies to overcome drug resistance Based on interrupting growth or triggering apoptotic-signaling cascades also are identified, providing the basis for novel Biologically Based Therapies, such as thalidomide/immunomodulatory drugs and proteasome inhibitor PS-341.
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Novel Biologically Based Therapies for Multiple Myeloma
International Journal of Hematology, 2002Co-Authors: Nikhil C. Munshi, Teru Hideshima, Dharminder Chauhan, Paul G. Richardson, Kenneth C. AndersonAbstract:Despite improvements in complete responses and prolongation of overall and event-free survival with highdose therapy, multiple myeloma (MM) remains an incurable disease in the majority of patients [I]. Thus, in order to overcome resistance to standard dose and highdose Therapies and to improve patient outcome, approaches specifically targeting the mechanisms whereby MM cells grow and survive in the bone marrow (BM) are needed. We are attempting to derive novel Biologically Based Therapies focused upon targeting the MM cell as well as its BM microenvironment [2]. Improved understanding of myeloma cell survival in its microenvironment has provided such new targets. Myeloma cells adhere to the extracellular matrix and to bone marrow stromal cells (BMSC), allowing myeloma cells to proliferate, survive and have anti apoptotic effects against conventional chemoTherapies. These effects are partially mediated through various cytokine release, including IL-6, VEGF, TNF-a, and IGF-1. The molecular signals mediating these effects include the Ras/Raf MAPK cascade for proliferation and the PI3-K1Akt pathway which provides drug resistance signals. This understanding has now allowed us to evaluate novel Therapies that not only directly target myeloma cells but also act on the bone marrow microenvironment, specifically, the molecular and cytokine targets, to overcome drug resistance. In the past three years, we have used the in vitro and in vivo animal model systems to define novel therapeutic agents directed at targets specific to both the MM cell and its microenvironment, and have then translated these studies from bench to bedside in the related clinical trials. Thalidomide and its analogous immunomodulatory agents (lMiDs), proteasome inhibitor PS341,
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Novel Biologically Based therapeutic strategies in myeloma.
Reviews in clinical and experimental hematology, 2002Co-Authors: Deepak K. Gupta, Teru Hideshima, Kenneth C. AndersonAbstract:Multiple myeloma remains incurable despite advances in conventional chemotherapy and wider applicability of high dose chemotherapy with single and/or tandem autologous peripheral blood stem cell transplantation. Although a complete remission rate of 41% and an event-free survival of 43 months have been reported after tandem transplantation, it is highly unlikely that further improvements in the outcome of multiple myeloma will be achieved by escalating cytotoxic chemotherapy alone. Novel Biologically Based Therapies are therefore urgently required. Targeted therapeutic approaches Based on: identification of genetic abnormalities in malignant plasma cells; interrupting growth of myeloma cells; triggering apoptotic signaling cascades in tumor cells; modulating growth and survival of multiple myeloma cells in the bone marrow microenvironment, i.e. angiogenesis and cytokine networks; enhancing allogeneic and autologous antimyeloma immunity; and characterizing newer myeloma antigens for serotherapy are under development. These Therapies offer great promise, used alone/or in combination with conventional treatment approaches, to improve the outcome in this disease in newly diagnosed/refractory or relapsed patients with multiple myeloma.
David H. Gutmann - One of the best experts on this subject based on the ideXlab platform.
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Eliminating barriers to personalized medicine Learning from neurofibromatosis type 1
Neurology, 2014Co-Authors: David H. GutmannAbstract:With the emergence of high-throughput discovery platforms, robust preclinical small-animal models, and efficient clinical trial pipelines, it is becoming possible to envision a time when the treatment of human neurologic diseases will become personalized. The emergence of precision medicine will require the identification of subgroups of patients most likely to respond to specific Biologically Based Therapies. This stratification only becomes possible when the determinants that contribute to disease heterogeneity become more fully elucidated. This review discusses the defining factors that underlie disease heterogeneity relevant to the potential for individualized brain tumor (optic pathway glioma) treatments arising in the common single-gene cancer predisposition syndrome, neurofibromatosis type 1 (NF1). In this regard, NF1 is posited as a model genetic condition to establish a workable paradigm for actualizing precision therapeutics for other neurologic disorders.
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Using Neurofibromatosis-1 to Better Understand and Treat Pediatric Low-Grade Glioma:
Journal of child neurology, 2008Co-Authors: David H. GutmannAbstract:Relatively little is known about the seminal genetic events that trigger the development of low-grade gliomas in children. Genetically engineered mouse models of the neurofibromatosis-1-inherited tumor predisposition syndrome have identified key intracellular growth control pathways, defined the contribution of the tumor microenvironment to glioma growth, and helped researchers understand the genetic basis for glioma susceptibility. In addition, genetically engineered mouse low-grade glioma models have recently been used in preclinical therapeutic studies to evaluate the efficacy of particular Biologically Based Therapies and to define outcome measures.
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Mammalian target of rapamycin: master regulator of cell growth in the nervous system.
Histology and histopathology, 2007Co-Authors: Danielle K. Sandsmark, Corey L. Pelletier, Jason D. Weber, David H. GutmannAbstract:The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase that regulates a number of diverse biologic processes important for cell growth and proliferation, including ribosomal biogenesis and protein translation. In this regard, hyperactivation of the mTOR signaling pathway has been demonstrated in numerous human cancers, including a number of inherited cancer syndromes in which individuals have an increased risk of developing benign and malignant tumors. Three of these inherited cancer syndromes (Lhermitte-Duclos disease, neurofibromatosis type 1, and tuberous sclerosis complex) are characterized by significant central nervous system dysfunction and brain tumor formation. Each of these disorders is caused by a genetic mutation that disrupts the expression of proteins which negatively regulate mTOR signaling, indicating that the mTOR signaling pathway is critical for appropriate brain development and function. In this review, we discuss our current understanding of the mTOR signaling pathway and its role in promoting ribosome biogenesis and cell growth. We suggest that studies of this pathway may prove useful in identifying molecular targets for Biologically-Based Therapies of brain tumors associated with these inherited cancer syndromes as well as sporadic central nervous system tumors.
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proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1 associated human and mouse brain tumors
Cancer Research, 2005Co-Authors: Biplab Dasgupta, Jason D. Weber, David Y Chen, David H. GutmannAbstract:Individuals with the tumor predisposition syndrome, neurofibromatosis 1 (NF1), are prone to development of nervous system tumors, including neurofibromas and pilocytic astrocytomas. Based on the ability of the NF1 gene product (neurofibromin) to function as a GTPase activating protein for RAS, initial Biologically Based Therapies for NF1-associated tumors focused on the use of RAS inhibitors, but with limited clinical success. In an effort to identify additional targets for therapeutic drug design in NF1, we used an unbiased proteomic approach to uncover unanticipated intracellular signaling pathways dysregulated in Nf1-deficient astrocytes. We found that the expression of proteins involved in promoting ribosome biogenesis was increased in the absence of neurofibromin. In addition, Nf1-deficient astrocytes exhibit high levels of mammalian target of rapamycin (mTOR) pathway activation, which was inhibited by blocking K-RAS or phosphatidylinositol 3-kinase activation. This mTOR pathway hyperactivation was reflected by high levels of ribosomal S6 activation in both Nf1 mutant mouse optic nerve gliomas and in human NF1-associated pilocytic astrocytoma tumors. Moreover, inhibition of mTOR signaling in Nf1−/− astrocytes abrogated their growth advantage in culture, restoring normal proliferative rates. These results suggest that mTOR pathway inhibition may represent a logical and tractable Biologically Based therapy for brain tumors in NF1.
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Neurofibromatosis 1 and 2
Principles of Molecular Medicine, 1Co-Authors: Gregory J. Esper, David H. GutmannAbstract:Neurofibromatosis (NF) 1 and 2 are genetically and phenotyp-ically distinct genetic disorders characterized by the development of benign and malignant tumors. Advances in molecular genetics have resulted in the identification of the NF1 and NF2 genes and their encoded proteins, neurofibromin, and merlin/schwannomin. Identification of these causative genes has led to an improved understanding of the molecular pathogenesis of NF1 and NF2, and has recently resulted in the development of targeted Biologically Based Therapies for tumors in NF1. In this chapter, the epidemiology, clinical features, molecular pathogenesis, animal models, and therapeutic strategies for NF1 and NF2 will be discussed.
Teru Hideshima - One of the best experts on this subject based on the ideXlab platform.
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Preclinical studies of novel targeted Therapies.
Hematology oncology clinics of North America, 2007Co-Authors: Teru Hideshima, Kenneth C. AndersonAbstract:The bone marrow (BM) milieu confers drug resistance in multiple myeloma (MM) cells to conventional Therapies. Novel Biologically Based Therapies are therefore needed. Preclinical studies have identified and validated molecular targeted therapeutics in MM. In particular, recognition of the biologic significance of the BM microenvironment in MM pathogenesis and as a potential target for novel therapeutics has already derived several promising approaches. Thalidomide, lenalidomide (Revlimid), and bortezomib (Velcade) are directed not only at MM cells but also at the BM milieu and have moved rapidly from the bench to the bedside and United States Food and Drug Administration approval to treat MM.
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Novel Biologically Based Therapies for Multiple Myeloma
International Journal of Hematology, 2002Co-Authors: Nikhil C. Munshi, Teru Hideshima, Dharminder Chauhan, Paul G. Richardson, Kenneth C. AndersonAbstract:Despite improvements in complete responses and prolongation of overall and event-free survival with highdose therapy, multiple myeloma (MM) remains an incurable disease in the majority of patients [I]. Thus, in order to overcome resistance to standard dose and highdose Therapies and to improve patient outcome, approaches specifically targeting the mechanisms whereby MM cells grow and survive in the bone marrow (BM) are needed. We are attempting to derive novel Biologically Based Therapies focused upon targeting the MM cell as well as its BM microenvironment [2]. Improved understanding of myeloma cell survival in its microenvironment has provided such new targets. Myeloma cells adhere to the extracellular matrix and to bone marrow stromal cells (BMSC), allowing myeloma cells to proliferate, survive and have anti apoptotic effects against conventional chemoTherapies. These effects are partially mediated through various cytokine release, including IL-6, VEGF, TNF-a, and IGF-1. The molecular signals mediating these effects include the Ras/Raf MAPK cascade for proliferation and the PI3-K1Akt pathway which provides drug resistance signals. This understanding has now allowed us to evaluate novel Therapies that not only directly target myeloma cells but also act on the bone marrow microenvironment, specifically, the molecular and cytokine targets, to overcome drug resistance. In the past three years, we have used the in vitro and in vivo animal model systems to define novel therapeutic agents directed at targets specific to both the MM cell and its microenvironment, and have then translated these studies from bench to bedside in the related clinical trials. Thalidomide and its analogous immunomodulatory agents (lMiDs), proteasome inhibitor PS341,
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Novel Biologically Based therapeutic strategies in myeloma.
Reviews in clinical and experimental hematology, 2002Co-Authors: Deepak K. Gupta, Teru Hideshima, Kenneth C. AndersonAbstract:Multiple myeloma remains incurable despite advances in conventional chemotherapy and wider applicability of high dose chemotherapy with single and/or tandem autologous peripheral blood stem cell transplantation. Although a complete remission rate of 41% and an event-free survival of 43 months have been reported after tandem transplantation, it is highly unlikely that further improvements in the outcome of multiple myeloma will be achieved by escalating cytotoxic chemotherapy alone. Novel Biologically Based Therapies are therefore urgently required. Targeted therapeutic approaches Based on: identification of genetic abnormalities in malignant plasma cells; interrupting growth of myeloma cells; triggering apoptotic signaling cascades in tumor cells; modulating growth and survival of multiple myeloma cells in the bone marrow microenvironment, i.e. angiogenesis and cytokine networks; enhancing allogeneic and autologous antimyeloma immunity; and characterizing newer myeloma antigens for serotherapy are under development. These Therapies offer great promise, used alone/or in combination with conventional treatment approaches, to improve the outcome in this disease in newly diagnosed/refractory or relapsed patients with multiple myeloma.
Ahmad Hussein Awada - One of the best experts on this subject based on the ideXlab platform.
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Review: Side Effects of Approved Molecular Targeted Therapies in Solid Cancers
The Oncologist, 2007Co-Authors: Christian Widakowich, P. Dinh, Evandro De Azambuja, G. Castro, Ahmad Hussein AwadaAbstract:Major advances have been achieved in the field of Biologically Based Therapies for cancer in the last few years, and some of the recently approved molecular-targeted Therapies are now being used in daily clinical practice. These molecular targets are also expressed in normal cells, which explains the different grades of toxicity, resulting from the disruption of normal cellular function. In general, targeted molecular Therapies have good toxicity profiles, but some patients are exquisitely sensitive to these drugs and can develop particular and severe toxicities. In this article, we review the toxicity and safety of various small molecules and monoclonal antibodies used in solid tumors, with discussion of the pathophysiology, correlation with response, and strategies for prevention and management.
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Side effects of anti-cancer molecular-targeted Therapies (not monoclonal antibodies)
Current Opinion in Oncology, 2006Co-Authors: G. Castro, Ahmad Hussein Awada, Ahmad AwadaAbstract:PURPOSE OF REVIEW: Major advances have been achieved in the field of Biologically Based Therapies for cancer in the last few years, and some of the recently approved 'molecular-targeted Therapies' are now being used in daily clinical practice. We aim to review some aspects of the toxicity and safety of small-molecule anti-cancer molecular-targeted Therapies, with some insights into the physiopathology and predictive factors of toxicity, its correlation with response, and how to prevent and overcome it. RECENT FINDINGS: As a whole, small-molecule molecular-targeted Therapies are well tolerated. Their toxic profile is favorable, but during the drug development process some severe (sometimes lethal) toxicities have been observed, such as interstitial lung disease in patients treated with drugs targeting the epidermal growth factor receptor. Pharmacogenomic studies can help us to identify those patients with well characterized polymorphisms, and to define the best-tolerated and most effective treatments. SUMMARY: Molecular-targeted Therapies have a good toxicity profile in general; however, some patients are exquisitely sensitive to developing particular and severe toxicities related to these drugs.
Anthony J. Smith - One of the best experts on this subject based on the ideXlab platform.
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Pulp Development, Repair, and Regeneration: Challenges of the Transition from Traditional Dentistry to Biologically Based Therapies
Journal of Endodontics, 2014Co-Authors: Gottfried Schmalz, Anthony J. SmithAbstract:Abstract The traditional concept of replacing diseased tooth/pulp tissues by inert materials (restoration) is being challenged by recent advances in pulp biology leading to regenerative strategies aiming at the generation of new vital tissue. New tissue formation in the pulp chamber can be observed after adequate infection control and the formation of a blood clot. However, differentiation of true odontoblasts is still more speculative, and the approach is largely limited to immature teeth with open apices. A more systematic approach may be provided by the adoption of the tissue engineering concepts of using matrices, suitable (stem) cells, and signaling molecules to direct tissue events. With these tools, pulplike constructs have already been generated in experimental animals. However, a number of challenges still remain for clinical translation of pulp regeneration (eg, the cell source [resident vs nonresident stem cells, the latter associated with cell-free approaches], mechanisms of odontoblast differentiation, the pulp environment, the role of infection and inflammation, dentin pretreatment to release fossilized signaling molecules from dentin, and the provision of suitable matrices). Transition as a process, defined by moving from one form of “normal” to another, is Based not only on the progress of science but also on achieving change to established treatment concepts in daily practice. However, it is clear that the significant recent achievements in pulp biology are providing an exciting platform from which clinical translation of dental pulp regeneration can advance.