Mutant p53 in Cancer Progression and Personalized Therapeutic Treatments PDF Download

Author: Marco Cordani
Publisher: Frontiers Media SA
ISBN: 288971537X
Category : Medical
Languages : en
Pages : 174

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Author: Swati Palit Deb
Publisher: Springer
ISBN: 9401792119
Category : Medical
Languages : en
Pages : 376

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Book Description
This book provides the readers with an overview of research on p53, which has been shown to play a role in numerous crucial biological pathways in normal and cancer cells. Leading scientist in the field, who have all made direct contributions to the understanding of the molecular events underpinning p53 function, have been invited to contribute the various chapters, which discuss the current knowledge of the signaling cascades that are activated by mutations in p53 and overexpression of MDM2, frequently found in human cancer and are major causes of oncogenesis. This book features chapters on the molecular basis of oncogenesis induced by gain of function mutation of p53, signaling pathways induced by MDM2 overexpression, control of mutant or wild-type p53 function by MDM2 and MDMX, p53 mutation in hereditary cancer and structural aspects that activate mutant p53 which can be targeted by drug therapy. This book should be useful for scientists at all levels.

Author: Reshma Shakya
Publisher:
ISBN:
Category : Cancer
Languages : en
Pages : 478

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Book Description
Among several genetic alterations in human cancer, mutations in the TP53 tumour suppressor gene represent the most common, occurring in approximately 50% of all human cancers. The majority of these mutations in p53 are missense mutations, resulting in cancer cells expressing stable, full-length mutated p53 proteins. Missense mutant p53's exhibit loss of tumour suppressive property of wild-type p53, dominant negative effects that can inactivate any wild-type p53 protein, and gain-of-function (GOF) properties that promote tumour progression and metastasis. Evidence suggests that cancer cells depend on the sustained expression of mutant p53 GOF. Thus, identifying the common downstream factor that drive mutant p53 GOF can provide an attractive approach to therapeutically target mutant p53 expressing tumours. This thesis presents the study of the characterization and functional analysis of mutant p53 secreted factors called "the mutant p53 secretome". In particular, the thesis aims at identifying the critical secreted effector of mutant p53 GOF that can serve as a potential therapeutic target for treatment of mutant p53 expressing tumours. Furthermore, the thesis investigates the association of the identified factor within the secretome with clinical parameters such as patient's survival. This thesis makes several original contributions to the field of cancer research, which are briefed below. Firstly, the mutant p53 induced secretome was characterized using quantitative proteomics of conditioned medium from mutant p53 expressing inducible H1299 human lung cancer cells. The majority of the identified secreted proteins were the transcriptional targets influenced by mutant p53. Alpha-1 antitrypsin (A1AT) was selected for further investigation, as it was the protein showing the highest expression in the mutant p53 secretome. The role of A1AT in driving the oncogenic activity of mutant p53 in human lung cancer cells was explored. A1AT was shown to drive mutant p53 induced invasion in lung cancer cell lines. Ablation of A1AT using antibodies and gene knockdown approaches inhibited the mutant p53 driven invasion, providing a rational to investigate the development of antibody-based cancer therapies that target A1AT. The clinical association of A1AT was further investigated in tissue microarray (TMA) samples of lung adenocarcinoma (ADC) patients. Mutant p53 expression was shown to correlate with A1AT, which validates in vivo that A1AT is a bonafide target of mutant p53. Furthermore, elevated expression of A1AT was demonstrated to correlate with increased local invasion and poor prognosis of lung ADC patients. Mutant p53 is reported to function as an aberrant transcription factor that can interact with other transcription factors to reprogram the cellular transcriptome of cancer cells. The mechanism of regulation of A1AT by mutant p53 was confirmed to involve p63. The role of A1AT in driving the mutant p53 induced invasive behavior of breast cancer cells was also explored, and a relationship of A1AT with p53 status and with different subtypes of breast cancer was established. In p53 mutant basal-like subtypes, A1AT expression was shown to drive invasion and treatment with anti-A1AT antibodies inhibited invasion. This suggests that the A1AT-targeted are potential therapies in various cancer types and its regulation in breast cancer may also extend beyond p53. Collectively, these studies provide new insights into the invasive behavior of mutant p53 that are manifested through aberrant secretion of extracellular proteins. The identification of A1AT as a critical and indispensable effector of mutant p53 gain-of-function offers a new therapeutic options for treatment of p53 mutant tumours. The findings in this thesis involve significant elements of novelty describing how mutant p53 influences the cellular secretome.

Author: Damian Jerome Junk
Publisher:
ISBN:
Category :
Languages : en
Pages : 372

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Breast cancer is the most frequently diagnosed form of cancer in women and the second leading cause of cancer-related deaths. Breast cancer is a heterogeneous disease consisting of many types of tissue neoplasia, and there appears to be no model of how a particular lesion develops into an aggressive, malignant, invasive carcinoma. Genetic mutation and aberrant epigenetic regulation are among the most common events that lead to neoplasia. In breast cancer, p53 mutation is the most common genetic defect related to a single gene. Therefore, this dissertation focuses on the mechanisms and consequences of p53 mutation during breast tumorigenesis. Genome-wide analysis of gene expression and epigenetic modifications in a panel of breast cancer cell lines suggested that p53 mutation and aberrant epigenetic silencing were cooperating mechanisms in the silencing of wild-type p53 target genes during cancer progression. Therefore, models of p53 inactivation were created in non-malignant human mammary epithelial cells to determine the role of p53 mutation on the epigenetic status of its target genes and the acquisition of malignant phenotypes. Comparisons of each model demonstrated that differing modes of p53 inactivation produced different functional consequences. Loss of wild-type p53 function alone ablated the normal cellular response to external stress stimuli, but had no affect on the expressionof genes or epigenetic status in untreated cells. Introduction of missense mutant p53 protein caused very few changes when the protein was expressed at low levels. However, accumulation of mutant p53 caused a variety of gene expression changes and interfered with endogenous wild-type p53. The accumulation of mutant p53 also caused an increase in migration and invasion of the cells that expressed it. Interestingly, epigenetic aberrations were not detected in response to any of the p53 manipulations. These data suggest that accumulation of missense mutation is particularly dangerous to normal cells. They also suggest that p53 mutation and epigenetic aberration are two distinct mechanisms, which overlap and cooperate during tumorigenesis. These data suggest that treatment strategies for human breast cancer should include modalities to target both defects for increased efficacy.

Author: Karol Sikora
Publisher: Wiley
ISBN: 9780471925835
Category : Medical
Languages : en
Pages : 364

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Book Description
This work serves as an introduction to the applications of molecular biology in the field of oncology. It provides a basic understanding of the genetic events involved in fully developed human cancer, including research into inherited and acquired gene defects initiating new neoplasms and the subsequent genetic alterations involved in tumor progression. Some of the specific topics explored include gene control, molecular therapy and antibodies, drug resistance, growth factors and receptors, and tumor biology. While intended primarily as an advanced text for oncologists, postgraduate molecular geneticists and molecular biologists, the book will certainly be of interest to other researchers who frequently encounter cancer in their practice.

Author: Shay Soker
Publisher: Humana Press
ISBN: 3319605119
Category : Medical
Languages : en
Pages : 225

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Book Description
Cancer cell biology research in general, and anti-cancer drug development specifically, still relies on standard cell culture techniques that place the cells in an unnatural environment. As a consequence, growing tumor cells in plastic dishes places a selective pressure that substantially alters their original molecular and phenotypic properties.The emerging field of regenerative medicine has developed bioengineered tissue platforms that can better mimic the structure and cellular heterogeneity of in vivo tissue, and are suitable for tumor bioengineering research. Microengineering technologies have resulted in advanced methods for creating and culturing 3-D human tissue. By encapsulating the respective cell type or combining several cell types to form tissues, these model organs can be viable for longer periods of time and are cultured to develop functional properties similar to native tissues. This approach recapitulates the dynamic role of cell–cell, cell–ECM, and mechanical interactions inside the tumor. Further incorporation of cells representative of the tumor stroma, such as endothelial cells (EC) and tumor fibroblasts, can mimic the in vivo tumor microenvironment. Collectively, bioengineered tumors create an important resource for the in vitro study of tumor growth in 3D including tumor biomechanics and the effects of anti-cancer drugs on 3D tumor tissue. These technologies have the potential to overcome current limitations to genetic and histological tumor classification and development of personalized therapies.

Author: Trygve Tollefsbol
Publisher: Academic Press
ISBN: 0128032405
Category : Science
Languages : en
Pages : 944

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Medical Epigenetics provides a comprehensive analysis of the importance of epigenetics to health management. The purpose of this book is to fill a current need for a comprehensive volume on the medical aspects of epigenetics with a focus on human systems, epigenetic diseases that affect these systems and modes of treating epigenetic-based disorders and diseases. The intent of this book is to provide a stand-alone comprehensive volume that will cover all human systems relevant to epigenetic maladies and all major aspects of medical epigenetics. The overall goal is to provide the leading book on medical epigenetics that will be useful not only to physicians, nurses, medical students and many others directly involved with health care, but also investigators in life sciences, biotech companies, graduate students and many others who are interested in more applied aspects of epigenetics. Research in the area of translational epigenetics is a cornerstone of this volume. Critical reviews dedicated to the burgeoning role of epigenetics in medical practice Coverage of emerging topics including twin epigenetics as well as epigenetics of gastrointestinal disease, muscle disorders, endocrine disorders, ocular medicine, pediatric diseases, sports medicine, noncoding RNA therapeutics, pain management and regenerative medicine Encompasses a disease-oriented perspective of medical epigenetics as well as diagnostic and prognostic epigenetic approaches to applied medicine

Author: Hong-Gang Wang
Publisher: Springer Science & Business Media
ISBN: 1461465613
Category : Medical
Languages : en
Pages : 267

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Book Description
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. ​

Author: Kelly K. Hunt
Publisher: Springer Science & Business Media
ISBN: 159745222X
Category : Medical
Languages : en
Pages : 469

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Book Description
The three sections of this volume present currently available cancer gene therapy techniques. Part I describes the various aspects of gene delivery. In Part II, the contributors discuss strategies and targets for the treatment of cancer. Finally, in Part III, experts discuss the difficulties inherent in bringing gene therapy treatment for cancer to the clinic. This book will prove valuable as the volume of preclinical and clinical data continues to increase.

Author: Kenneth K.W. To
Publisher: Academic Press
ISBN: 0128199032
Category : Science
Languages : en
Pages : 460

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Book Description
Drug Repurposing in Cancer Therapy: Approaches and Applications provides comprehensive and updated information from experts in basic science research and clinical practice on how existing drugs can be repurposed for cancer treatment. The book summarizes successful stories that may assist researchers in the field to better design their studies for new repurposing projects. Sections discuss specific topics such as in silico prediction and high throughput screening of repurposed drugs, drug repurposing for overcoming chemoresistance and eradicating cancer stem cells, and clinical investigation on combination of repurposed drug and anticancer therapy. Cancer researchers, oncologists, pharmacologists and several members of biomedical field who are interested in learning more about the use of existing drugs for different purposes in cancer therapy will find this to be a valuable resource. Presents a systematic and up-to-date collection of the research underpinning the various drug repurposing approaches for a quick, but in-depth understanding on current trends in drug repurposing research Brings better understanding of the drug repurposing process in a holistic way, combining both basic and clinical sciences Encompasses a collection of successful stories of drug repurposing for cancer therapy in different cancer types