Download or read book Mechanisms of Resistence of New Target Drugs in Acute Myeloid Leukemia written by Debora Capelli and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: New drugs targeting single mutations have been recently approved for Acute Myeloid Leukemia (AML) treatment, but allogeneic transplant still remains the only curative option in intermediate and unfavorable risk settings, because of the high incidence of relapse. Molecular analysis repertoire permits the identification of the target mutations and drives the choice of target drugs, but the etherogeneity of the disease reduces the curative potential of these agents. Primary and secondary AML resistance to new target agents is actually an intriguing issue and some of these mechanisms have already been explored and identified. Changes in mutations, release of microenvironment factors competing for the same therapeutic target or promoting the survival of blasts or of the leukemic stem cell, the upregulation of the target-downstream pathways and of proteins inhibiting the apoptosis, the inhibition of the cytochrome drug metabolism by other concomitant treatments are some of the recognized patterns of tumor escape. The knowledge of these topics might implement the model of the ,ÄòAML umbrella trial,Äô study through the combinations or sequences of new target drugs, preemptively targeting known mechanisms of resistance, with the aim to improve the potential curative rates, expecially in elderly patients not eligible to transplant.

Download or read book Drug Resistance in Leukemia and Lymphoma III written by G.J.L. Kaspers and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 613 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cellular drug resistance is a major limitation to the success of chemotherapy of leu kemia and lymphoma. The importance of this has now been recognized by both clinicians and scientists. It is of utmost importance to bridge the gap between laboratory and clinic in this field of research. This is the main purpose of the series of International Symposia on Drug Resistance in Leukemia and Lymphoma. These are held every three years in Am sterdam, The Netherlands, since 1992. This book contains the proceedings of the third of these meetings, organised in 1998. The book covers all important aspects of drug resistance in leukemia and lymphoma, both in the form of extensive reviews as in manuscripts describing original data. General mechanisms of resistance are discussed, including the drug resistance related proteins p glycoprotein, MRP (multi-drug resistance protein) and LRP (lung resistance protein), and the role of glutathione and glutathione-S-transferases. Moreover, more drug type-specific mechanisms of resistance are a topic, such as for glucocorticoids and antifolates. Much in formation is provided on apoptosis and its regulators, and on the results of cell culture drug resistance assays. Several papers focus on the modulation or circumvention of drug resistance.

Download or read book Mechanism of Drug Tolerance in FLT3 Mutant Acute Myeloid Leukemia written by Melat Gebru and published by . This book was released on 2020 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: AML is a heterogeneous disease caused by several mutations and cytogenetic abnormalities affecting differentiation and proliferation of myeloid lineage cells. FLT3 is a receptor tyrosine kinase frequently overexpressed or mutated, and its mutations are associated with poor prognosis in AML. Although aggressive chemotherapy followed by hematopoietic stem cell transplant is the current standard of care, the recent approval of targeted therapies, such as FLT3 targeted drugs, is revolutionizing AML treatment that had remained unchanged since the 1970s. As more targeted therapies become available, a personalized treatment approach where therapies are tailored to patients' mutation profiles will likely replace aggressive chemotherapies that are often associated with treatment-related mortality, especially in older patients. However, despite the dramatic clinical response to targeted agents, such as FLT3 inhibitors, remission is almost invariably short-lived and ensued by relapse and drug resistance. Hence, there is an urgent need to understand the molecular mechanisms underlying drug resistance in order to prevent relapse. The overarching aim of this dissertation was to understand the mechanisms by which FLT3 inhibitor-induced molecular alterations promote cell survival, and to identify drugs that can target those pro-survival changes. Recent accumulating evidence points to the presence of a transitional population of cells between the start of treatment and acquisition of mutational resistance, called drug-tolerant 'persisters' (DTPs). DTPs can tolerate an otherwise cytotoxic dose of targeted drug treatment by re-wiring their signaling pathways in response to therapy. The central hypothesis of this dissertation is that DTPs undergo transcriptomic alterations immediately after FLT3 inhibition which not only allow them to survive treatment, but also cause them to be uniquely vulnerable to new drugs as compared to treatment-naïve cells. In Chapter 2 of this dissertation, we sought to delineate the dynamic transcriptomic state associated with DTPs that survive lethal FLT3 inhibition. Our findings suggested that FLT3 targeted drug treatment induces differential expression of approximately 2000 genes in the remaining DTPs. Genes involved in inflammatory pathways were the most significantly up-regulated in DTPs. While this transcriptomic change likely promotes their survival, it also confers on them susceptibility to anti-inflammatory drugs. Indeed, our drug screen revealed that DTPs are particularly sensitive to glucocorticoids. We used different FLT3 mutant AML cell lines, patient cells as well as mouse models to validate that the combination of FLT3 inhibitors and glucocorticoids induces a synergistic cell death. In-silico prediction of upstream regulators of the up-regulated genes revealed that inflammatory transcription factors, including NF-[kappa]B, STAT3 and CIITA are activated. We confirmed that DTPs have an increased activation of NF-[kappa]B as compared to treatment naïve cells. In Chapter 3 of this dissertation, we dissect the mechanism by which glucocorticoids and FLT3 inhibitors synergize. We found that FLT3 inhibition causes the up-regulation of glucocorticoid receptor making DTPs susceptible to glucocorticoids. Furthermore, we demonstrated that glucocorticoids act through glucocorticoid receptor to increase the expression of the pro-apoptotic protein Bim and up-regulate the degradation of the anti-apoptotic protein Mcl-1. Together, our data demonstrate that disequilibrium between Bim and Mcl-1 is the key mechanism by which the combination of FLT3 inhibitors and glucocorticoids synergize to augment cell death. In summary, in this dissertation, we have uncovered that the combination of FLT3 inhibitors and glucocorticoids is a novel potential treatment strategy that can eliminate or minimize minimal residual disease and thereby prevent relapse in FLT3 mutant AML patients. This has a significant clinical implication because glucocorticoids have been in clinical use for decades, and hence, the proposed combination therapy can be explored and translated rapidly to improve patient outcome.

Download or read book Drug Resistance in Leukemia written by Gert-Jan L. Kaspers and published by CRC Press. This book was released on 1993-01-01 with total page 458 pages. Available in PDF, EPUB and Kindle. Book excerpt: The last ten years have seen the publication of a vast amount of data regarding cellular resistance to drugs in cancer cells. Recent studies have demonstrated that drug resistance assays appear to be predictive of clinical response and suggest that clinicians should now be considering the potential applications of these assays in the treatment of patients with hematological neoplasms. This collection of papers from the International Symposium on the Clinical Value of Drug Resistance Assays in Leukemia and Lymphoma, Amsterdam, 1992, provides a state-of-the-art discussion on drug resistance assays and their role in the design and individualization of treatment protocols.

Download or read book Acute Leukemias written by Pier Paolo Piccaluga and published by . This book was released on 2021 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Mechanism of Drug Action of the Specific CK2 Inhibitor CX 4945 in Acute Myeloid Leukemia written by Sadie Steffens and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Acute myeloid leukemia (AML) is a malignant disease of the myeloid line of blood cells and is characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. Cytarabine and other currently available treatments for acute myeloid leukemia are highly toxic and insufficient, as more than half of all AML patients develop resistance to chemotherapeutic agents. Since AML often affects older people who are less tolerant of chemotherapy, there is need for novel, targeted, less toxic drugs in order to improve survival for this disease. Casein Kinase II (CK2) is a pro-oncogenic serine/threonine kinase that is essential for cellular proliferation. Overexpression or increased CK2 activity is associated with various types of human malignancies. In hematopoietic cells, increased CK2 expression is associated with malignant transformation and development of leukemia. Increased CK2 activity is associated with a poor prognosis in AML. Targeted inhibition of CK2 with a novel, specific inhibitor produced a strong anti-leukemia effect in vitro and in pre-clinical models. However, the mechanism through which CK2 inhibitors exert an anti-leukemia effect is unknown. The goal of our project is to identify the mechanism of the therapeutic activity of CK2 inhibition using CX-4945 in AML. Ikaros is a zinc finger, DNA-binding protein that is encoded by the IKZF1 gene and acts as a tumor suppressor in hematopoietic malignancies. Deletion or functional inactivation of Ikaros is associated with development of high-risk acute lymphoblastic leukemia (ALL) as well as AML. Previously published data showed that CK2 directly phosphorylates Ikaros at multiple evolutionarily-conserved sites. The CK2-mediated phosphorylation of Ikaros results in reduced DNA-binding affinity and loss of Ikaros function as a transcriptional regulator of gene expression. Inhibition of CK2 restores Ikaros function as a tumor suppressor and produces an anti-leukemia effect in ALL. Based on these data, we hypothesized that one of the mechanisms of therapeutic action of CK2 inhibitors in AML involves restoration of Ikaros function as a transcriptional regulator of genes involved in malignant transformation. Genome-wide binding studies using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-Seq) demonstrated that inhibition of CK2 via CX-4945 in U937 and primary AML cells enhances Ikaros binding affinity at the promoter regions of its target genes. We used gain-of-function and loss-of-function experiments to determine how Ikaros regulates several novel target genes involved in malignant transformation and drug resistance. Results demonstrated that Ikaros directly represses transcription of the BCL2A1 gene, which promotes leukemogenesis and has an anti-apoptotic function. We show that the ability of Ikaros to repress transcription of BCL2A1 is impaired in AML, overexpression of BCL2A1 is a negative prognostic marker, and anti-apoptotic mechanisms contribute to resistance to chemotherapy. Repression of BCL2A1 results in increased apoptosis. The ability of Ikaros to repress BCL2A1 transcription is impaired by CK2. Inhibition of CK2 via CX-4945 increases Ikaros binding at the BCL2A1 promoter, resulting in transcriptional repression of BCL2A1. Increased Ikaros binding to the BCL2A1 promoter is associated with formation of repressive chromatin that is characterized by the loss of the positive marker H3K4me2 and increase in the negative marks H3K9me3 and H3K27me3. Since BCL2A1 has an anti-apoptotic function, we tested whether CK2 inhibition increases susceptibility of AML cells to apoptosis. Results showed that CK2 inhibition increases apoptosis of AML cells and that the CK2 inhibitor CX-4945 has synergistic therapeutic effects in combination with a standard drug for AML, Doxorubicin. These data indicate a new Ikaros target gene, one mechanism for the therapeutic activity of CK2 inhibition, and a novel combination treatment for AML.Similar functional experiments were performed on four additional Ikaros target genes that were identified by ChIP-Seq (MTHFR, CDA, DLX1, and DLX2). Results demonstrated that CK2 impairs transcriptional regulation of these genes by Ikaros in AML. Treatment with CK2 inhibitor restores Ikaros-mediated regulation of these genes. Since two of the newly-identified Ikaros target genes are known to be involved in drug resistance, the therapeutic effect of the CK2 inhibitor CX-4945 has been tested in combination with additional chemotherapeutic agents, and results showed a synergistic effect of these combination treatments in AML cells.Finally, a systems biology approach was used to determine the effect of CK2 inhibition on the epigenome and transcriptome of AML cells. The analysis revealed that CK2 inhibition results in alterations in the epigenomic signature of AML cells. The prominent changes involved alteration of enhancer and super-enhancer landscapes, which were associated with transcriptional regulation of many genes that are critical for cellular proliferation.In summary, our results demonstrate that the therapeutic effect of CK2 inhibition in AML cells involves restoration of Ikaros function as a tumor suppressor and transcriptional regulator. Our results have identified novel pathways that are regulated by Ikaros as well as an epigenomic landscape that is regulated by CK2. These data led to the development of novel combination treatments for AML which showed synergy when tested on AML cells. Our results provide a mechanistic rationale for development of novel, targeted treatments for AML.

Download or read book Cancer Drug Resistance written by Beverly A. Teicher and published by Springer Science & Business Media. This book was released on 2007-11-09 with total page 611 pages. Available in PDF, EPUB and Kindle. Book excerpt: Leading experts summarize and synthesize the latest discoveries concerning the changes that occur in tumor cells as they develop resistance to anticancer drugs, and suggest new approaches to preventing and overcoming it. The authors review physiological resistance based upon tumor architecture, cellular resistance based on drug transport, epigenetic changes that neutralize or bypass drug cytotoxicity, and genetic changes that alter drug target molecules by decreasing or eliminating drug binding and efficacy. Highlights include new insights into resistance to antiangiogenic therapies, oncogenes and tumor suppressor genes in therapeutic resistance, cancer stem cells, and the development of more effective therapies. There are also new findings on tumor immune escape mechanisms, gene amplification in drug resistance, the molecular determinants of multidrug resistance, and resistance to taxanes and Herceptin.

Download or read book Pathology and Epidemiology of Cancer written by Massimo Loda and published by Springer. This book was released on 2016-09-01 with total page 664 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book integrates the disciplines of cancer pathology and epidemiology to provide a synergistic and complementary approach to understanding the molecular mechanisms of cancer. This book provides relevant information on the diagnostic, prognostic and predictive molecular pathology of cancer. Epidemiological studies, including descriptive epidemiology, risk factors and molecular mechanisms of disease inform on the etiology and progression of cancer. The text concentrates on major cancers that are currently prevalent and those for which substantial molecular, pathological and epidemiological data is available. Each section is designed to provide an overview of that cancer type in terms of basic biology, review the current epidemiological data surrounding that cancer type and provide information on common practices and challenges related to the molecular pathology of that cancer type. Several relevant techniques in molecular pathology, which facilitate diagnosis and treatment are also explored. Pathology and Epidemiology of Cancer provides a succinct and comprehensive overview of multiple cancer types to guide clinicians during patient care and to guide scientists for innovations in research. It represents an integral resource for pathologists, epidemiologists, medical students as well as translational, basic and clinical science researchers who are all working to progress the field of cancer in terms of diagnosis, treatment and prevention.

Download or read book Multi Drug Resistance in Cancer written by Jun Zhou and published by Humana Press. This book was released on 2012-08-09 with total page 492 pages. Available in PDF, EPUB and Kindle. Book excerpt: Chemotherapy is one of the major treatment options for cancer patients; however, the efficacy of chemotherapeutic management of cancer is severely limited by multidrug resistance, in that cancer cells become simultaneously resistant to many structurally and mechanistically unrelated drugs. In the past three decades, a number of mechanisms by which cancer cells acquire multidrug resistance have been discovered. In addition, the development of agents or strategies to overcome resistance has been the subject of intense study. This book contains comprehensive and up-to-date reviews of multidrug resistance mechanisms, from over-expression of ATP-binding cassette drug transporters such as P-glycoprotein, multidrug resistance-associated proteins, and breast cancer resistance p- tein to the drug ratio-dependent antagonism and the paradigm of cancer stem cells. The book also includes strategies to overcome multidrug resistance, from the development of compounds that inhibit drug transporter function to the modulation of transporter expression. In addition, this book contains techniques for the detection and imaging of drug transporters, methods for the investigation of drug resistance in animal models, and strategies to evaluate the efficacy of resistance reversal agents. The book intends to provide a state-of-the-art collection of reviews and methods for both basic and clinician investigators who are interested in cancer multidrug resistance mechanisms and reversal strategies. Tianjin, China Jun Zhou v Contents Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix 1 Multidrug Resistance in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Bruce C. Baguley 2 Multidrug Resistance in Oncology and Beyond: From Imaging of Drug Efflux Pumps to Cellular Drug Targets . . . . . . . . . . . . . . . . . . . . . . . . . .

Download or read book Identifying Mechanisms of Resistance and Potential Therapeutic Targets for Pediatric Acute Myeloid Leukemia written by John Timothy Caldwell and published by . This book was released on 2014 with total page 153 pages. Available in PDF, EPUB and Kindle. Book excerpt: In the second half of this work, we investigated the response of 2 DS AML cell lines, CMK and CMY, to the combination of araC and one of either the aurora A kinase inhibitor MLN8237, the aurora B kinase inhibitor AZD1152-HQPA, the Plk1 inhibitor BI6237, or the wee1 inhibitor MK-1775. It was found that MK-1775, in contrast to the other three agents, synergized with araC in antiproliferative MTT assays in both cell lines as well as in ex vivo DS-AML primary patient samples. MK-1775 was able to decrease inhibitory CDK1(Y15) phosphorylation after only 4 hours, and was able to enhance araC-induced DNA damage in S-phase and partially abrogate araC-induced cell cycle arrest. The work presented in this dissertation describes preclinical efforts at improving outcomes for pediatric AML patients in both the DS and the non-DS populations. The findings presented demonstrate a potential for using novel therapies, like HDAC or Bcl-2 family inhibitors to treat AMKL, as well as offering insight into the mechanisms of resistance in a difficult to treat disease. Furthermore, these findings lay the foundation for the use of MK-1775 to enhance the effects of araC in DS-AML. Though there is always more to be elucidated, the studies described herein set the stage for such further work, with the eventual goal of improving outcomes for pediatric AML.

Download or read book Novel Aspects in Acute Lymphoblastic Leukemia written by Stefan Faderl and published by IntechOpen. This book was released on 2011-11-16 with total page 272 pages. Available in PDF, EPUB and Kindle. Book excerpt: Acute lymphoblastic leukemia (ALL) has turned from a universally fatal to a highly curable disease in little more than four decades. Even though differences in outcome continue to exist between children and adults, intense efforts are under way to overcome this discrepancy and improve the prognosis of adult patients as well. This exemplary progress in ALL therapy has been possible by the combination of an increasingly better understanding of the biology of the disease, availability of a range of effective drugs, and astute designs and relentless executions of many clinical trials. ALL is a complex disease requiring complex therapy. Whereas this book cannot provide a comprehensive review of every one of its many facets, the chapters from many investigators from around the world nevertheless cover a number of relevant topics: aspects of the epidemiology of ALL in Hispanics, ophthalmologic manifestations of ALL, overviews of current therapy and drug-resistance mechanisms, novel biological pathways and targets, new drugs in development, and long-term consequences of CNS prophylaxis and therapy. The publishers and editor therefore hope that the prospective readers will find enough insight and information for their own endeavors.

Download or read book Childhood Acute Lymphoblastic Leukemia written by Ajay Vora and published by Springer. This book was released on 2017-04-21 with total page 345 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides a comprehensive and up-to-date review of all aspects of childhood Acute Lymphoblastic Leukemia, from basic biology to supportive care. It offers new insights into the genetic pre-disposition to the condition and discusses how response to early therapy and its basic biology are utilized to develop new prognostic stratification systems and target therapy. Readers will learn about current treatment and outcomes, such as immunotherapy and targeted therapy approaches. Supportive care and management of the condition in resource poor countries are also discussed in detail. This is an indispensable guide for research and laboratory scientists, pediatric hematologists as well as specialist nurses involved in the care of childhood leukemia.

Download or read book New insights into the mechanisms of resistance to anti cancer drugs written by Simona Rapposelli and published by Frontiers Media SA. This book was released on 2023-03-17 with total page 116 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Allogeneic Stem Cell Transplantation written by Hillard M. Lazarus and published by Springer Science & Business Media. This book was released on 2010-03-02 with total page 885 pages. Available in PDF, EPUB and Kindle. Book excerpt: Since the original publication of Allogeneic Stem Cell Transplantation: Clinical Research and Practice, Allogeneic hematopoietic stem cell transplantation (HSC) has undergone several fast-paced changes. In this second edition, the editors have focused on topics relevant to evolving knowledge in the field in order to better guide clinicians in decision-making and management of their patients, as well as help lead laboratory investigators in new directions emanating from clinical observations. Some of the most respected clinicians and scientists in this discipline have responded to the recent advances in the field by providing state-of-the-art discussions addressing these topics in the second edition. The text covers the scope of human genomic variation, the methods of HLA typing and interpretation of high-resolution HLA results. Comprehensive and up-to-date, Allogeneic Stem Cell Transplantation: Clinical Research and Practice, Second Edition offers concise advice on today's best clinical practice and will be of significant benefit to all clinicians and researchers in allogeneic HSC transplantation.

Download or read book Acute Leukemias written by Pier Paolo Piccaluga and published by BoD – Books on Demand. This book was released on 2021-03-24 with total page 324 pages. Available in PDF, EPUB and Kindle. Book excerpt: Written by expert research teams, this book describes different aspects of both acute myeloid and acute lymphocytic leukemia, specifically their pathobiology, classification/diagnosis, and treatment. Chapters highlight current research as well as the gold standards for diagnosis and treatment of these diseases, examining recent advances in personalized approaches to acute leukemia.

Download or read book New Mechanisms for Anti Cancer Drugs written by Ayaz Shahid and published by Frontiers Media SA. This book was released on 2024-04-15 with total page 353 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer is the second leading cause of death. Every year, many anticancer drug candidates are discovered and synthesized, but the major challenge lies in identifying, characterizing and evaluating their efficacy. The aim of this Research Topic, "New Mechanisms for Anti-Cancer Drugs" is to collect a group of publications focused on novel chemical compounds exhibiting new modes of actions and/or new target proteins to fulfill their cytotoxic activity on cancer cells. In this context, we will also be pleased to consider studies on drug repurposing, including approved, discontinued, and shelved drugs, when anti-cancer activity results from an unexpected mode of action.

Download or read book Network Pharmacology written by Shao Li and published by Springer Nature. This book was released on 2021-09-29 with total page 480 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book introduces “network pharmacology” as an emerging frontier subject of systematic drug research in the era of artificial intelligence and big data. Network Pharmacology is an original subject of fusion system biology, bioinformatics, network science and other related disciplines. It emphasizes on starting from the overall perspective of the system level and biological networks, the analysis of the laws of molecular association between drugs and their treatment objects, reveals the systematic pharmacological mechanisms of drugs, and guides the research and development of new drugs and clinical diagnosis and treatment. After it was proposed, network pharmacology has been paid attention by researchers, and it has been rapidly developed and widely used. In order to systematically reveal the biological basis of diagnosis and treatment in traditional Chinese medicine and modern medicine, we proposed a new concept of "network target" for the first time, which has become the core theory of "network pharmacology". The core principle of a network target is to construct a biological network that can be used to decipher complex diseases. The network is then used as the therapeutic target, to which multicomponent remedies are applied. This book mainly includes four parts: 1) The concept and theory of network pharmacology; 2) Common analysis methods, databases and software in network pharmacological research; 3) Typical cases of traditional Chinese medicine modernization and modern drug research based on network pharmacology; 4) Network pharmacology practice process based on drugs and diseases.