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A panel of leading academic and pharmaceutical investigators takes stock of the remarkable work that has been accomplished to date with proteasome inhibitors in cancer, and examines emerging therapeutic possibilities. The topics range from a discussion of the chemistry and cell biology of the proteasome and the rationale for proteasome inhibitors in cancer to a review of current clinical trials underway. The discussion of rationales for testing proteasome inhibitors in cancer models covers the role of the proteasome in NF-kB activation, the combining of conventional chemotherapy and radiation with proteasome inhibition, notably PS-341, new proteasome methods of inhibiting viral maturation, and the role of protesome inhibition in the treatment of AIDS. The authors also document the development of bortezomib (VelcadeTM) in Phase I clinical trials and in a multicentered Phase II clinical trials in patients with relapsed and refractory myeloma.
Tyrosine Kinase Inhibitors as Sensitizing Agents for Chemotherapy, the fourth volume in the Cancer Sensitizing Agents for Chemotherapy Series, focuses on strategic combination therapies that involve a variety of tyrosine kinase inhibitors working together to overcome multi-drug resistance in cancer cells. The book discusses several tyrosine kinase inhibitors that have been used as sensitizing agents, such as EGFR, BCR-ABL, ALK and BRAF. In each chapter, readers will find comprehensive knowledge on the inhibitor and its action, including its biochemical, genetic, and molecular mechanisms' emphases. This book is a valuable source for oncologists, cancer researchers and those interested in applying new sensitizing agents to their research in clinical practice and in trials. - Summarizes the sensitizing role of some tyrosine kinase inhibitors in existing research - Brings recent findings in several cancer types, both experimental and clinically, with a particular emphases on underlying biochemical, genetic, and molecular mechanisms - Provides an updated and comprehensive knowledge regarding the field of combinational cancer treatment
This volume gives an overview of pro tea some-mediated protein degradation and the regulatory role of the ubiquitin system in cellular proteolysis. The first chapter describes the molecular evolution of the proteasome and its associated activators, i. e. , the 20S core, the base and the lid of the 19S cap, and the 11 S regulator. The ensuing chapter gives an overview of the structure and assembly of the 20S proteasome and the regulation of the archaeal proteasome by PAN. The third contribution summarizes our knowledge on the eukaryotic 26S proteasome and its regulation by the 19S regu lator, followed by a chapter devoted to the llS regulator, which elucidates the structural basis for the 11 S-mediated activation of the 20S proteasome. The fifth chapter reviews in detail the role of the proteasome in the immune response. The subsequent chapter of the natural substrates of the gives a comprehensive description proteasome and their recognition by the enzymes of the ubiqui tination machinery. The penultimate chapter rounds up the in formation on intracellular distribution of proteasomes in yeast and mammalian cells, while the last contribution highlights proteasome inhibitors, tools which proved to be very valuable for dissecting the cellular roles of the proteasome and which might turn out to be of pharmacological importance.
Multiple Myeloma (MM) is the second most common type of blood cancer, resulting from an overproduction of cancerous infection-fighting white blood cells, known as plasma cells. Plasma cells are a crucial part of the immune system responsible for the production of antibodies. Bortezomib is a promising anticancer drug targeting the proteasome. This proteasome inhibitor induces cell stress and apoptosis in the cancer cells. While multiple mechanisms are likely to be involved, proteasome inhibition may prevent the degradation of pro-apoptotic factors, permitting activation of programmed cell death in neoplastic cells dependent upon the suppression of proapoptotic pathways. This monograph on bortezomib is a valuable source of information for researchers and clinicians from the fields of oncology and pharmacology, working either in academia or the pharmaceutical industry.
Protein homeostasis, or “Proteostasis”, lies at the heart of human health and disease. From the folding of single polypeptide chains into functional proteins, to the regulation of intracellular signaling pathways, to the secreted signals that coordinate cells in tissues and throughout the body, the proteostasis network operates to support cell health and physiological fitness. However, cancer cells also hijack the proteostasis network and many of these same processes to sustain the growth and spread of tumors. The chapters in this book are written by world experts in the many facets of the proteostasis network. They describe cutting-edge insights into the structure and function of the major chaperone and degradation systems in healthy cells and how these systems are co-opted in cancer cells and the cells of the tumor microenvironment. The chapters also cover therapeutic interventions such as the FDA-approved proteasome inhibitors Velcade and Krypolis as well as other therapies currently under clinical investigation to disarm the ability of the proteostasis network to support malignancy. This compendium is the first of its kind and aims to serve as a reference manual for active investigators and a primer for newcomers to the field. This book is dedicated to the memory of Susan Lindquist, a pioneer of the proteostasis field and a champion of the power of basic scientific inquiry to unlock the mechanisms of human disease. The chapter “Reflections and Outlook on Targeting HSP90, HSP70 and HSF1 in Cancer: A Personal Perspective” is available open access under a Creative Commons Attribution 4.0 International License via link.springer.com.
The treatment of patients with advanced malignancies has undergone remarkable change in the last few years. While in the past decisions about systemic therapy were largely based on the performance status of a patient, oncologists today also take into account the pathological and molecular characteristics of the patient’s tumor. Targeting specific molecular pathways important for tumorigenesis has become the preferred way of treatment for many types of malignancies. With these advances come new challenges including the optimization of therapy, recognizing and dealing with side effects and, importantly, the development of resistance. This book provides an up-to-date overview of the advances and limitations of targeted therapy for several tumor entities including breast cancer, colon cancer, gastrointestinal stromal tumors, lung cancer, melanoma, ovarian cancer and renal cell carcinoma. Written by over a dozen internationally renowned scientists, the book is suitable for advanced students, postdoctoral researchers, scientists and clinicians who wish to update their knowledge of the latest approaches to targeted cancer therapies.
This book, written by members of the European network PROTEOSTASIS, provides an up-to-date review of the research regarding protein homeostasis in health and disease. With new discoveries contributing to the increasing complexity of this topic, the book offers a detailed overview of the pathways regulating protein homeostasis, including autophagy and the ubiquitin protein family. Following a basic introduction, it explains how defects in protein homeostasis contribute to numerous pathologies, including cancer, neurodegeneration, inflammation and a number of rare diseases. In addition, it discusses, the role of protein homeostasis in cellular development and physiology. Highlighting the latest research in the field of protein homeostasis and its implications for various clinically relevant diseases, the book appeals to researchers and clinicians, while also offering a reference guide for scholars who are new to the field.
This volume will review different classes of "target" drugs that have been developed, approved, or are under investigation in the field of lymphoma therapy. The discussion will not only be on the understanding of the mechanisms of action or clinical response of those agents, but also help the reader to understand the nature of lymphoma biology in patients who relapse or are refractor after exposure to those drugs. Contributors will discuss what is currently known about mechanisms of tumor-related or host-related resistance, and how to overcome this resistance. This understanding is crucial given the dismal outcomes of patients with relapsed or refractory lymphomas. The book provides a unique opportunity to review and reflect on the recent successes and pitfalls of the modern lymphoma therapy era.
Heat shock proteins are emerging as important molecules in the development of cancer and as key targets in cancer therapy. These proteins enhance the growth of cancer cells and protect tumors from treatments such as drugs or surgery. However, new drugs have recently been developed particularly those targeting heat shock protein 90. As heat shock protein 90 functions to stabilize many of the oncogenes and growth promoting proteins in cancer cells, such drugs have broad specificity in many types of cancer cell and offer the possibility of evading the development of resistance through point mutation or use of compensatory pathways. Heat shock proteins have a further property that makes them tempting targets in cancer immunotherapy. These proteins have the ability to induce an inflammatory response when released in tumors and to carry tumor antigens to antigen presenting cells. They have thus become important components of anticancer vaccines. Overall, heat shock proteins are important new targets in molecular cancer therapy and can be approached in a number of contrasting approaches to therapy.
The first book focusing specifically on frequent and frequently disabling side effects involving the skin, hair and nails in cancer patients According to the World Health Organization, there are approximately thirty million people living with a diagnosis of cancer – the majority of whom will receive surgery, systemic therapy, and/or radiation, and who will suffer from dermatologic adverse events. Dermatologists and oncologists are only beginning to grapple with these events, which pose serious quality-of-life issues with so many patients, and will become more prevalent as survival rates improve, thanks in part to new cancer treatments and drug regimens. Concentrating on a topic that has only been briefly touched upon by other texts, this book offers a focused perspective on the clinical presentation, underlying pathophysiologic mechanisms, and management of skin, hair, and nail conditions for oncologists, dermatologists, and allied practitioners. Dermatologic Principles and Practice in Oncology: Conditions of the Skin, Hair, and Nails in Cancer Patients: • Covers in detail the dermatologic adverse events of oncologic therapies, clinical presentations, and treatment recommendations • Enables dermatologists and other practitioners to significantly improve the care of patients with cancer • Addresses the dermatologic adverse events of cancer therapies used globally, of which a large number are found in developing countries • Emphasizes prophylactic measures – based on treatments used and type of cancer – to prevent the appearance of adverse events • Provides built-in discussions on patient education for practical counseling during therapies • Offers rapid-reference sections on topical dermatology drugs The first book to present dermatologic conditions in cancer patients and survivors in a uniform and in-depth manner, Dermatologic Principles and Practice in Oncology is ideal for oncologists, oncology nurses, and dermatologists who wish to take better care of those with adverse skin, hair, and nail conditions.