Current Cancer Research – serie

Cancer is fundamentally a disease of abnormal cell proliferation: Cancer cells multiply when and where they should not. This proliferation entails escape from normal bounds imposed by the tissue environment, the internal biology of the cell (DNA damage, chromosomal imbalances, disorganized mitotic spindles), and the proliferative history of the cell (normal generational times). Some of the key oncogenic events in cancer directly perturb proteins that regulate progression through the cell division cycle, others alter cell cycle progression indirectly, through effects on signaling pathway that impinge on the cell cycle. This biology is fundamentally important in cancer therapy. Many of the workhorse treatments for cancer rely on killing proliferating cells. Furthermore, there is growing recognition that stem cell-transit amplifying cell hierarchies may persist or be generated during tumorigenesis, generating important functional heterogeneity in cell cycle control among tumor cells, with far-reaching scientific and clinical implications. This volume outlines major cell cycle perturbations that drive tumorigenesis and considers the prospects for using such knowledge in cancer therapy.

Cancer gene therapy is a novel therapy that targets the underlying genetic defects in the cancer cell. Progress in this field has been rapid and gene therapy promises to further extend personalized cancer treatment. In this volume leading experts have contributed their experience in developing gene therapies for a variety of cancers. Translational gene therapy approaches are emphasized. Chapters include discussions of specific gene delivery technologies as well as their application to various cancers with extensive discussions of ongoing clinical trials. This information should be useful to both students, fellows, and experienced scientists with an interest in this rapidly developing area.

Molecular Determinants of Radiation Response includes chapters by expert authors who detail the present understanding of key DNA damage response pathways and proteins. The chapters include comprehensive discussions on where and how specific alterations in function of these pathways and proteins result in substantive modifications of cellular response to DNA injury. Given the importance of therapies that induce DNA injury in the management of human disease, this book is timely and relevant for basic and translational researchers, as well as clinicians alike.

The acknowledgment that viruses are potent biological factors in driving many cancers have seen a dramatic upsurge in recent years in large part to the success of the human papilloma virus vaccine against invasive cervical carcinomas and followed by the awarding of the noble prize in medicine in 2008 to Dr. Harald zurHausen who identified the link between papilloma virus and cervical cancers. Over the last few years there have been some volumes addressing different aspects of viruses and cancers and to some extent focusing on the DNA viruses, more specifically the human DNA viruses. This proposed volume will attempt to review and address the major gaps in current knowledge in DNA viruses as well as RNA viruses bringing a historical perspective of where studies began to a more recent molecular approach and vaccine successes in tumor viruses. We will also cover other known oncogenic viruses associated cancers in other mammals in addition to humans.

Caveolins are important structural proteins of Caveolae, small invaginations of the membrane. They have been shown to play an important role in the pathogenesis of multiple cancers. In this volume, we will mainly focus on the importance of Caveolin-1 in breast, prostate, lung, skin, colon, pancreatic and brain cancers with also a mention of the novel role of Caveolin-3 in breast cancer.

Cancer is fundamentally a disease of abnormal cell proliferation: Cancer cells multiply when and where they should not. This proliferation entails escape from normal bounds imposed by the tissue environment, the internal biology of the cell (DNA damage, chromosomal imbalances, disorganized mitotic spindles), and the proliferative history of the cell (normal generational times). Some of the key oncogenic events in cancer directly perturb proteins that regulate progression through the cell division cycle, others alter cell cycle progression indirectly, through effects on signaling pathway that impinge on the cell cycle. This biology is fundamentally important in cancer therapy. Many of the workhorse treatments for cancer rely on killing proliferating cells. Furthermore, there is growing recognition that stem cell-transit amplifying cell hierarchies may persist or be generated during tumorigenesis, generating important functional heterogeneity in cell cycle control among tumor cells, with far-reaching scientific and clinical implications. This volume outlines major cell cycle perturbations that drive tumorigenesis and considers the prospects for using such knowledge in cancer therapy.

Cancer gene therapy is a novel therapy that targets the underlying genetic defects in the cancer cell. Progress in this field has been rapid and gene therapy promises to further extend personalized cancer treatment. In this volume leading experts have contributed their experience in developing gene therapies for a variety of cancers. Translational gene therapy approaches are emphasized. Chapters include discussions of specific gene delivery technologies as well as their application to various cancers with extensive discussions of ongoing clinical trials. This information should be useful to both students, fellows, and experienced scientists with an interest in this rapidly developing area.

Molecular Determinants of Radiation Response includes chapters by expert authors who detail the present understanding of key DNA damage response pathways and proteins. The chapters include comprehensive discussions on where and how specific alterations in function of these pathways and proteins result in substantive modifications of cellular response to DNA injury. Given the importance of therapies that induce DNA injury in the management of human disease, this book is timely and relevant for basic and translational researchers, as well as clinicians alike.

The study of Burkitt’s lymphoma is now in its 6 decade beginning with its discovery by Dr. Dennis Burkitt in equatorial Africa in the mid to late 1950’s. A large body of information is available which provides a current understanding of the underlying molecular changes that are linked to the initiation and development of Burkitt’s lymphoma. This proposed volume will provide a comprehensive view of Burkitt’s Lymphoma from the diagnosis to potential animal models for this disease and include a view from physicians who have a up close view of the patients in populations where the disease is rampant. We expect that this will be an excellent resource for Medical students and faculty as well as educated laypersons who have a person interest in the disease.

With the explosion of information on autophagy in cancer, this is an opportune time to speed the efforts to translate our current knowledge about autophagy regulation into better understanding of its role in cancer. This book will cover the latest advances in this area from the basics, such as the molecular machinery for autophagy induction and regulation, up to the current areas of interest such as modulation of autophagy and drug discovery for cancer prevention and treatment. The text will include an explanation on how autophagy can function in both oncogenesis and tumor suppression and a description of its function in tumor development and tumor suppression through its roles in cell survival, cell death, cell growth as well as its influences on inflammation, immunity, DNA damage, oxidative stress, tumor microenvironment, etc. The remaining chapters will cover topics on autophagy and cancer therapy. These pages will serve as a description on how the pro-survival function of autophagy may help cancer cells resist chemotherapy and radiation treatment as well as how the pro-death functions of autophagy may enhance cell death in response to cancer therapy, and how to target autophagy for cancer prevention and therapy − what to target and how to target it. ​

Recent advances in understanding of fundamental immunology have created new insights into the dynamic interactions between tumors and the immune system. This includes new understanding of T- and B-cell interaction, immune inhibitory mechanisms including the biology of T regulatory cells, myeloid suppressor cells, and dendritic cell subsets. Enhanced understanding of mechanisms underlying T-cell anergy such as arginine deprivation, immunosuppressive cytokines, defective innate and interferon response pathways, and NKG2D downregulation have all provided new insight into suppression of anti-tumor immunity and tumor evasion. In addition to emerging understanding of tumor evasion, new immune targets such as CTLA4 blockade, NK stimulatory receptors, manipulation of the antigen processing and presentation, cytokine and costimulatory responses all provide new possibilities for enhancing anti-tumor immunity even in tumors previously felt to be resistant to immune attack. Several of these strategies have already been realized in the clinic. The volume will explore evolving paradigms in antigen presentation, dendritic cell biology, the innate response and immunosuppressive mechanisms, and emerging strategies for manipulation of the immune system for therapeutic benefit that have realized success in neuroblastoma, leukemia, melanoma, lung cancer, and allogeneic transplantation. Early successes as well as failures will be highlighted to provide a snapshot of the state of clinical immunotherapy with an eye to future possibilities such as combination therapies, adoptive T-cell transfer, and the retargeting of immune cells via T-cell receptor engineering.

The study of Burkitt’s lymphoma is now in its 6 decade beginning with its discovery by Dr. Dennis Burkitt in equatorial Africa in the mid to late 1950’s. A large body of information is available which provides a current understanding of the underlying molecular changes that are linked to the initiation and development of Burkitt’s lymphoma. This proposed volume will provide a comprehensive view of Burkitt’s Lymphoma from the diagnosis to potential animal models for this disease and include a view from physicians who have a up close view of the patients in populations where the disease is rampant. We expect that this will be an excellent resource for Medical students and faculty as well as educated laypersons who have a person interest in the disease.

With the explosion of information on autophagy in cancer, this is an opportune time to speed the efforts to translate our current knowledge about autophagy regulation into better understanding of its role in cancer. This book will cover the latest advances in this area from the basics, such as the molecular machinery for autophagy induction and regulation, up to the current areas of interest such as modulation of autophagy and drug discovery for cancer prevention and treatment. The text will include an explanation on how autophagy can function in both oncogenesis and tumor suppression and a description of its function in tumor development and tumor suppression through its roles in cell survival, cell death, cell growth as well as its influences on inflammation, immunity, DNA damage, oxidative stress, tumor microenvironment, etc. The remaining chapters will cover topics on autophagy and cancer therapy. These pages will serve as a description on how the pro-survival function of autophagy may help cancer cells resist chemotherapy and radiation treatment as well as how the pro-death functions of autophagy may enhance cell death in response to cancer therapy, and how to target autophagy for cancer prevention and therapy − what to target and how to target it. ​

Caveolins are important structural proteins of Caveolae, small invaginations of the membrane. They have been shown to play an important role in the pathogenesis of multiple cancers. In this volume, we will mainly focus on the importance of Caveolin-1 in breast, prostate, lung, skin, colon, pancreatic and brain cancers with also a mention of the novel role of Caveolin-3 in breast cancer.

This book provides an unprecedented overview of "Targeted Therapies" for acute myeloid leukemias. It aims at an almost comprehensive coverage of the diverse therapeutic strategies that have been developed during the last decade and are now being evaluated in early clinical trials. Paired and authoritative chapters by leading research scientists and clinicians explain basic concepts and clinical translation of topics that include the underlying genetic and proteomic abnormalities of AML, the development of novel nucleoside analogues, the roles of microRNAs, apoptosis regulators Bcl-2 and p53 and of critical cell signaling proteins such as PIM, FLT3, Raf/MEK, PI3K/AKT/mTOR and aurora kinases. Chapters on epigenetic mechanisms, nuclear receptors, cell surface antigens, the hypoxic leukemia microenvironment, stem cells and leukemia metabolism provide insights into leukemia cell vulnerabilities. Cell therapies utilizing T-, NK- and mesenchymal stem cells and progress in hematopoietic transplantation strategies round up this overview of the multi-dimensional therapeutic landscape in which leukemia specialists develop treatment strategies that are expected to make "leukemia history" in the near future.

This book provides an unprecedented overview of "Targeted Therapies" for acute myeloid leukemias. It aims at an almost comprehensive coverage of the diverse therapeutic strategies that have been developed during the last decade and are now being evaluated in early clinical trials. Paired and authoritative chapters by leading research scientists and clinicians explain basic concepts and clinical translation of topics that include the underlying genetic and proteomic abnormalities of AML, the development of novel nucleoside analogues, the roles of microRNAs, apoptosis regulators Bcl-2 and p53 and of critical cell signaling proteins such as PIM, FLT3, Raf/MEK, PI3K/AKT/mTOR and aurora kinases. Chapters on epigenetic mechanisms, nuclear receptors, cell surface antigens, the hypoxic leukemia microenvironment, stem cells and leukemia metabolism provide insights into leukemia cell vulnerabilities. Cell therapies utilizing T-, NK- and mesenchymal stem cells and progress in hematopoietic transplantation strategies round up this overview of the multi-dimensional therapeutic landscape in which leukemia specialists develop treatment strategies that are expected to make "leukemia history" in the near future.

The acknowledgment that viruses are potent biological factors in driving many cancers have seen a dramatic upsurge in recent years in large part to the success of the human papilloma virus vaccine against invasive cervical carcinomas and followed by the awarding of the noble prize in medicine in 2008 to Dr. Harald zurHausen who identified the link between papilloma virus and cervical cancers. Over the last few years there have been some volumes addressing different aspects of viruses and cancers and to some extent focusing on the DNA viruses, more specifically the human DNA viruses. This proposed volume will attempt to review and address the major gaps in current knowledge in DNA viruses as well as RNA viruses bringing a historical perspective of where studies began to a more recent molecular approach and vaccine successes in tumor viruses. We will also cover other known oncogenic viruses associated cancers in other mammals in addition to humans.

Squamous cell cancers of the head and neck (SCCHN), also known as head and neck cancers (HNC) encompass malignancies of the oral cavity, larynx, nasopharynx and pharynx, and are diagnosed in over 500,000 patients worldwide each year, accounting for 5% of all malignancies. In the past several years, there have been significant developments in understanding of HNC. It is now recognized that although alcohol and tobacco use has represented the likely predominant cause of SCCHN, the incidence of a second class of SCCHN related to oncogenic human papillomavirus (HPV) infection is increasing, with a four-fold increase in the past 2 decades, and now thought to represent up to 30% of cases. The first effective target for SCCHN, the EGFR-targeting antibody cetuximab, was approved as recently as in 2006; since then, a growing body of research has identified additional signaling pathways as important in disease pathogenesis, and in resistance to treatment. Proteins such as c-Met, Src, and HER2 are emerging as new therapeutic targets, with a considerable ferment in the clinical trial community. As a capstone of research progress, 2011 marked the first reports of high throughput sequencing of SCCHN tumors, with these efforts identifying unexpected players such as Notch as frequent subject of mutation, spawning new hypotheses for future research. This book will be of interest to researchers who are interested in better understanding the biology of head and neck cancers, with the goals of better designing therapies, identifying risk factors, or investigating the molecular basis of the disease.

Recent advances in understanding of fundamental immunology have created new insights into the dynamic interactions between tumors and the immune system. This includes new understanding of T- and B-cell interaction, immune inhibitory mechanisms including the biology of T regulatory cells, myeloid suppressor cells, and dendritic cell subsets. Enhanced understanding of mechanisms underlying T-cell anergy such as arginine deprivation, immunosuppressive cytokines, defective innate and interferon response pathways, and NKG2D downregulation have all provided new insight into suppression of anti-tumor immunity and tumor evasion. In addition to emerging understanding of tumor evasion, new immune targets such as CTLA4 blockade, NK stimulatory receptors, manipulation of the antigen processing and presentation, cytokine and costimulatory responses all provide new possibilities for enhancing anti-tumor immunity even in tumors previously felt to be resistant to immune attack. Several of these strategies have already been realized in the clinic. The volume will explore evolving paradigms in antigen presentation, dendritic cell biology, the innate response and immunosuppressive mechanisms, and emerging strategies for manipulation of the immune system for therapeutic benefit that have realized success in neuroblastoma, leukemia, melanoma, lung cancer, and allogeneic transplantation. Early successes as well as failures will be highlighted to provide a snapshot of the state of clinical immunotherapy with an eye to future possibilities such as combination therapies, adoptive T-cell transfer, and the retargeting of immune cells via T-cell receptor engineering.

This volume provides the latest research on circulating tumor cells aimed for cancer researchers, scientists, and molecular oncologists. It presents the basic concepts behind circulating tumor cells (CTCs), metastatic biology, and potential applications as to how CTCs can be used in diagnostic biomarkers.CTCs are cells that have detached from the primary tumor and circulate in the bloodstream. Such cells may become "seeds" for the growth of additional tumors. The field of analysis surrounding cancer metastasis has been steadily growing, and CTCs provide effective biomarkers that can be examined in peripheral blood through a minimally invasive “liquid biopsy” procedure. CTCs offer several exciting applications, not only as markers of disease progression but also as biomarkers of monitoring response to therapy and companion diagnostics for novel anticancer drug development. In recent years there has been rapid growth and worldwide developments on CTCs, which span both the basic sciences and biomedical engineering fields.

Protein kinase C (PKC), a family of serine-threonine kinases, rocketed to the forefront of the cancer research field in the early 1980’s with its identification as an effector of phorbol esters, natural products with tumor promoting activity. Phorbol esters had long been of interest to the cancer research field due to early studies in the mouse skin carcinogenesis model, which showed that prolonged topical application of phorbol esters promoted the formation of skin tumors on mice previously treated with mutagenic agents. Research in the last years has established key roles for PKC isozymes in the control of cell proliferation, migration, adhesion, and malignant transformation. In addition, there is a large body of evidence linking PKC to invasion and cancer cell metastasis. Moreover, it is now well established that the expression of PKC isozymes is altered in various types of cancers. More importantly, small molecule inhibitors have been developed with significant anti-cancer activity. The relevance of PKC isozymes in cancer signaling is therefore remarkable.This book will have 4 sections. There will be 23 chapters. Each section will have a brief introduction by an expert in the field (~ 1-2 pages).

This volume will provide a contemporary account of advances in chemical carcinogenesis. It will promote the view that it is chemical alteration of the DNA that is a route cause of many cancers. The multi-stage model of chemical carcinogenesis, exposure to major classes of human carcinogens and their mode-of-action will be a focal point. The balance between metabolic activation to form biological reactive intermediates and their detoxification, ensuing DNA-lesions and their repair will be profiled. It will describe the chemical changes that occur in DNA that result from endogenous insults including epigenetic changes that lead to gene silencing. It will describe major mechanisms of mutagenesis, affects on tumor suppressor genes and proto-oncogenes, and how cell-cycle check points can be by-passed by the "stealth-like" properties of chemical carcinogens. Environmental agents that can promote tumor formation will be discussed. The monograph will have wide appeal as a knowledge base for graduate students, post-doctoral fellows and faculty interested in this aspect of cancer causation and research.

Protein kinase C (PKC), a family of serine-threonine kinases, rocketed to the forefront of the cancer research field in the early 1980’s with its identification as an effector of phorbol esters, natural products with tumor promoting activity. Phorbol esters had long been of interest to the cancer research field due to early studies in the mouse skin carcinogenesis model, which showed that prolonged topical application of phorbol esters promoted the formation of skin tumors on mice previously treated with mutagenic agents. Research in the last years has established key roles for PKC isozymes in the control of cell proliferation, migration, adhesion, and malignant transformation. In addition, there is a large body of evidence linking PKC to invasion and cancer cell metastasis. Moreover, it is now well established that the expression of PKC isozymes is altered in various types of cancers. More importantly, small molecule inhibitors have been developed with significant anti-cancer activity. The relevance of PKC isozymes in cancer signaling is therefore remarkable.This book will have 4 sections. There will be 23 chapters. Each section will have a brief introduction by an expert in the field (~ 1-2 pages).

This volume will provide a contemporary account of advances in chemical carcinogenesis. It will promote the view that it is chemical alteration of the DNA that is a route cause of many cancers. The multi-stage model of chemical carcinogenesis, exposure to major classes of human carcinogens and their mode-of-action will be a focal point. The balance between metabolic activation to form biological reactive intermediates and their detoxification, ensuing DNA-lesions and their repair will be profiled. It will describe the chemical changes that occur in DNA that result from endogenous insults including epigenetic changes that lead to gene silencing. It will describe major mechanisms of mutagenesis, affects on tumor suppressor genes and proto-oncogenes, and how cell-cycle check points can be by-passed by the "stealth-like" properties of chemical carcinogens. Environmental agents that can promote tumor formation will be discussed. The monograph will have wide appeal as a knowledge base for graduate students, post-doctoral fellows and faculty interested in this aspect of cancer causation and research.

This book ventures into a new and exciting area of discovery that directly ties our current knowledge of cancer to the discovery of microorganisms associated with different types of cancers. Recent studies demonstrate that microorganisms are directly linked to the establishment of cancers and that they can also contribute to the initiation, as well as persistence of, the cancers. Microbiome and Cancer covers the current knowledge of microbiome and its association with human cancers. It provides important reading for novices, senior undergraduates in cancer and microbiology, graduate students, junior investigators, residents, fellows and established investigators in the fields of cancer and microbiology. We cover areas related to known, broad concepts in microbiology and how they can relate to the ongoing discoveries of the micro-environment and the changes in the metabolic and physiologic states in that micro-environment, which are important for the ongoing nurturing and survival of the poly-microbial content that dictates activities in that micro-environment.We cover the interactions of microorganisms associated with gastric carcinomas, which are important for driving this particular cancer. Additional areas include oral cancers, skin cancers, ovarian cancers, breast cancers, nasopharyngeal cancers, lung cancers, mesotheliomas, Hodgkin’s and non-Hodgkin’s lymphomas, glioblastoma multiforme, hepatocellular carcinomas, as well as the inflammatory response related to the infectious agents in cancers. This book covers the metabolic changes that occur because of infection and their support for development of cancers, chronic infection and development of therapeutic strategies for detection and control of the infection. The field of microbiome research has exploded over the last five years, and we are now understanding more and more about the context in which microorganisms can contribute to the onset of cancers in humans. The field of microbiome research has demonstrated that the human body has specific biomes for tissues and that changes in these biomes at the specific organ sites can result in disease. These changes can result in dramatic differences in metabolic shifts that, together with genetic mutations, will produce the perfect niche for establishment of the particular infection programmes in that organ site. We are just beginning to understand what those changes are and how they influence the disease state. Overall, we hope to bring together the varying degrees of fluctuations in the microbiome at the major organ sites and how these changes affect the normal cellular processes because of dysregulation, leading to proliferation of the associated tissues.

Squamous cell cancers of the head and neck (SCCHN), also known as head and neck cancers (HNC) encompass malignancies of the oral cavity, larynx, nasopharynx and pharynx, and are diagnosed in over 500,000 patients worldwide each year, accounting for 5% of all malignancies. It is estimated that approximately 50,000 patients develop head and neck cancer annually in the United States, of whom approximately 50% succumb to this cancer. For most cases of SCCHN, treatment is multimodal, often combining surgery or irradiation with chemotherapy; even successfully treated patients frequently experience durable and severe side effects.  Improving cure rates and reducing chronic morbidity are urgent clinical needs for head and neck cancer.  However, in contrast to cancer types such as breast or prostate that have been much studied and have well-defined biology, until recently, relatively few researchers investigated the molecular basis of HNC, making it difficult to design targeted treatments with better efficacy and less debilitating side effects.  This volume will provide an overview of the factors contributing to disease pathogenesis, including the recognition of discrete molecular subtypes with distinct etiology, prognosis, and treatment response.  This volume will familiarize the reader with the critical signaling pathways and oncogenic drivers for HNC. It will outline the differences between HPV-positive and HPV-negative disease, and how these differences affect treatment choice and outcome.  The book will emphasize developments in the past five years, including the growing understanding of the genomic and epigenomic features of the disease based on analysis of next generation sequencing (NGS) data, and timely topics such as the analysis of HNC stem cell populations, non-coding mRNAs, and inflammatory response.  It will address exciting new therapeutic approaches such as the use of immunotherapies to treat HNC patients.  Overall, the book will provide the reader with current understanding of the biology and treatment of the disease, and describe timely questions that will guide future research aimed at controlling and curing this disease.

This book contextualizes translational research and provides an up to date progress report on therapies that are currently being targeted in lung cancer. It is now well established that there is tremendous heterogeneity among cancer cells both at the inter- and intra-tumoral level. Further, a growing body of work highlights the importance of targeted therapies and personalized medicine in treating cancer patients. In contrast to conventional therapies that are typically administered to the average patient regardless of the patient’s genotype, targeted therapies are tailored to patients with specific traits. Nonetheless, such genetic changes can be disease-specific and/or target specific; thus, the book addresses these issues manifested in the somatically acquired genetic changes of the targeted gene. Each chapter is written by a leading medical oncologist who specializes in thoracic oncology and is devoted to a particular target in a specific indication. Contributors provide an in-depth review of the literature covering the mechanisms underlying signaling, potential cross talk between the target and downstream signaling, and potential emergence of drug resistance.

This book contextualizes translational research and provides an up to date progress report on therapies that are currently being targeted in lung cancer. It is now well established that there is tremendous heterogeneity among cancer cells both at the inter- and intra-tumoral level. Further, a growing body of work highlights the importance of targeted therapies and personalized medicine in treating cancer patients. In contrast to conventional therapies that are typically administered to the average patient regardless of the patient’s genotype, targeted therapies are tailored to patients with specific traits. Nonetheless, such genetic changes can be disease-specific and/or target specific; thus, the book addresses these issues manifested in the somatically acquired genetic changes of the targeted gene. Each chapter is written by a leading medical oncologist who specializes in thoracic oncology and is devoted to a particular target in a specific indication. Contributors provide an in-depth review of the literature covering the mechanisms underlying signaling, potential cross talk between the target and downstream signaling, and potential emergence of drug resistance.

Lung cancer has seen a paradigm shift in disease treatment over the past few years, with major changes in the therapeutic drugs now available as well as in the overall management approach.  For targeted and immunotherapeutic approaches, understanding the biology of acquired resistance is a key strategy that has yielded productive advances in the subsequent treatment.  Future advances also include incorporating biomarker data obtained from solid and liquid biopsies, as well as combination of immunotherapy with radiotherapy and in special populations such patients with CNS involvement.