Third Generation EGFR Inhibitors: Overcoming EGFR Resistance and Toxicity Problems reviews current issues relating to the design of reversible and irreversible third generation EGFR inhibitors, highlighting the types of mutation responsible for resistance, and providing different chemical starting points for researchers to optimize and develop in designing the next generation of drugs. Beginning with an introduction to EGFR inhibitors and a review of inhibitors currently approved or in clinical trials, the book goes on to discuss current approaches in the development of both covalent irreversible and covalent reversible EGFR Inhibitors. In addition, mechanisms of resistance to third generation inhibitors, and discovery of fourth generation allosteric C797S inhibitors are explored before a discussion of potential future trends. This comprehensive coverage of the design and development of improved analogues to overcome the problems of resistance and toxicity associated with third generation EGFR inhibitors makes Third Generation EGFR Inhibitors a crucial resource for medicinal chemists, drug developers, and researchers investigating cancer therapeutics. Includes full synthetic schemes of all approved and in-trial third generation inhibitors Highlights the emergence of fourth generation EGFR inhibitors and the possibilities of them overcoming constraints of third generation compounds Provides a structural correlation of third and fourth generation EGFR inhibitors, reviewing both their design strategies and typical anticancer activity
|Author||: Umberto Malapelle,Pierlorenzo Pallante|
|Publisher||: Frontiers Media SA|
|Release Date||: 2017-08-29|
|ISBN 10||: 2889452638|
|Pages||: 329 pages|
Lung cancer still remains a challenging disease with a higher mortality rate in comparison to other cancers. The discovery of oncogene addicted tumours and targeted therapies responsive to these targets lead to a meaningful change in the prognosis of these diseases. Unfortunately, these newer therapeutic options are reserved to a minor part of lung cancer patients harbouring specific mutations. In the so called wild type population, the first line options bring the median overall survival to go beyond 1 year, and in the population receiving the maintenance therapy over 16 months. Given these results, more than 60% of patients may receive a second line therapy with further opportunities to improve the length and quality of life. For patients not harbouring targetable DNA mutations newer options will be available for second line therapeutic schemes and two major assets seem to be promising: immune modulation and anti-angiogenetic agents. In particular, anti PD1/PDL1 antibodies, VEGFR antibodies and TKIs, these latter combined with standard chemotherapy docetaxel advance the median overall survival of 12 months. These drugs have a different mechanism of action, various adverse events and their activity is different depending on the types of population. However, the biomarkers’ activity and efficacy prediction are not fully or totally understood. In addition, also for patients with DNA targetable mutations new drugs seems to be promising for the use in the second line therapeutic protocols. In particular, drugs selectively directed against ALK translocation and mutational events and EGFR T790M secondary mutations seems to be very promising. In this Research Topic we critically discuss the older therapies and the historical development of second line, putting in to perspective the new agents available in clinical practice. We discuss their importance from a clinical point of view, but also consider and exploit the complex molecular mechanisms responsible of their efficacy or of the subsequently observed resistance phenomena. In this perspective, the undercovering and characterization of novel predictive biomarkers by NGS technology, the characterization of novel actors in the signal transduction pathway modulating the response of the cells, the optimization of new diagnostic tool as the evaluation of liquid biopsy and the implementation of more suitable pre-clinical models are crucial aspects dissected too. Nivolumab, nintedanib and ramucirumab probably will give the opportunity to improve the efficacy outcomes for the treatment of wild type tumours in second line therapeutic schemes, but many aspects should be debated in order that these agents are made available to patients, planning ahead a therapeutic strategy, beginning from the first line therapy, to the subsequent ones in a logical and affordable manner. As well, for treatment of mutated tumours, mutated EGFR irreversible inhibitors such as rociletinib and AZD9291, and ALK targeting drugs ceritinib and alectinib will also play an important role in the immediate future. Probably the right way is to give all the available opportunities to patients, but challenges and pitfalls should be carefully debated, and by launching this Research Topic we tried to give some practical insights in this changing landscape.
|Release Date||: 2018|
|Pages||: 329 pages|
Abstract Lung cancer represents the leading cause of cancer-related deaths worldwide. Despite great advances in its management with the recent emergence of molecular targeted therapies for non-small-cell lung cancer (NSCLC), relapse of the metastatic disease always occurs within approximately one year. Epidermal growth factor receptor (EGFR) mutant tumours are the prime example of oncogene addiction and clonal evolution in oncology, regarding the emergence of resistance to first- and second-generation EGFR inhibitors. Multiple studies have revealed that the EGFR-T790M gatekeeper mutation is the main cause of tumour escape. Recently, irreversible pyrimidine-based EGFR inhibitors especially designed for this particular setting have shown robust clinical activity. However, similar to first- and second-generation inhibitors, the development of a diversified set of resistance mechanisms in response to these new compounds is an emerging issue. To date, clinical management of this growing number of patients has not been clearly established, even if anecdotal responses to subsequent molecularly guided therapies have been observed. By exhaustively reviewing and classifying all the preclinical and clinical data published on resistance to third-generation EGFR inhibitors in NSCLC, this work reveals the heterogeneity of the mechanisms that a tumour can develop to evade therapeutic pressure. Strategies currently being tested in clinical trials are discussed in light of these findings.
|Release Date||: 2018|
|Pages||: 329 pages|
Abstract Osimertinib was the first third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) to receive FDA and EMA approval for metastatic EGFR-mutant non-small-cell lung cancer (NSCLC) patients that have acquired the EGFR T790M resistance mutation. Clinical trials have demonstrated the efficacy of osimertinib in this patient population and clinical trials of other third-generation EGFR TKI are currently under way. Additional challenges in this patient population, such as the upfront efficacy of osimertinib, validation of T790M in liquid biopsies as a dynamic predictive marker of efficacy, along with combination with immune checkpoint inhibitors are being explored, representing an extraordinary time of development for EGFR-mutant NSCLC.
|Author||: Marianne Davies,Beth Eaby-Sandy|
|Release Date||: 2019-07-16|
|ISBN 10||: 3030165507|
|Pages||: 120 pages|
This book aims to educate nurses and advanced practice providers (APP’s) about known mutations, availability of targeted therapy and the management of patients with non-small cell lung cancer (NSCLC). It will educate nurses and practitioners about the scope of therapy to assure safe and effective lung cancer treatment. In this era of personalized medicine, nurses and APP’s are responsible for guiding patients from diagnosis through treatment. This starts with the identification of patients that can benefit from these therapies, the key role of biopsy acquisition (ie. what to test, when and how often) and treatment selection based on the mutation identified. Readers will learn about the mechanisms of action, administration, potential adverse side effects and unique management strategies for these targeted agents. Lung cancer continues to be the leading cause of cancer death in the United States and worldwide. Recent advances in the identification of specific oncogenic mutations that drive cancer development, growth and metastasis have led to major paradigm shifts in lung cancer treatment. Sophisticated methods are required to identify specific mutations at the time of diagnosis. This book explains how molecularly targeted therapies have been developed that target these drivers. To date, several tyrosine kinase inhibitors have been approved to target the epidermal growth factor receptor (EGFR), EML4-ALK ,ROS1 and BRAF. Most recently, immune checkpoint inhibitors have been approved with some indication that efficacy may be enhanced for patients who overexpress PD-L1. While some driver mutations have been identified, there is ongoing investigation into additional mutations. In the case of driver mutations, lung cancers will develop resistance to therapy. This book provides nurses and APP’s with the mechanisms of resistance that have been identified such as T790 mutation and many others in the EGFR mutation, and shows how the next level of drug development is focused on identifying mechanisms of resistance and development of new agents that overcome these mutations. With this book in hand, nurses and practitioners will be able to navigate patients through this ever expanding field of lung cancer treatment.
With international experts sharing their experience and knowledge on these different aspects in the management of colorectal cancer, this book has this opportunity to offer all physicians treating colorectal cancer, as well as researchers, updated information concerning the biology, diagnosis, screening, and treatment of colorectal carcinoma. This book provides a detailed evaluation of diagnostic modalities, in-depth analysis of screening for colorectal cancer, recent advances in treatment, and principles and trends in the management of colorectal cancer. This updated knowledge will be an interesting and informative read for any clinician involved in the management of patients with colorectal cancer. In addition, readers such as related physicians, researchers, and colorectal cancer patients are potential beneficiaries of this book.
Tumor progression is driven by mutations that confer growth advantages to different subpopulations of cancer cells. As a tumor grows, these subpopulations expand, accumulate new mutations, and are subjected to selective pressures from the environment, including anticancer interventions. This process, termed clonal evolution, can lead to the emergence of therapy-resistant tumors and poses a major challenge for cancer eradication efforts. Written and edited by experts in the field, this collection from Cold Spring Harbor Perspectives in Medicine examines cancer progression as an evolutionary process and explores how this way of looking at cancer may lead to more effective strategies for managing and treating it. The contributors review efforts to characterize the subclonal architecture and dynamics of tumors, understand the roles of chromosomal instability, driver mutations, and mutation order, and determine how cancer cells respond to selective pressures imposed by anticancer agents, immune cells, and other components of the tumor microenvironment. They compare cancer evolution to organismal evolution and describe how ecological theories and mathematical models are being used to understand the complex dynamics between a tumor and its microenvironment during cancer progression. The authors also discuss improved methods to monitor tumor evolution (e.g., liquid biopsies) and the development of more effective strategies for managing and treating cancers (e.g., immunotherapies). This volume will therefore serve as a vital reference for all cancer biologists as well as anyone seeking to improve clinical outcomes for patients with cancer.
Colorectal cancer (CRC) is a major health problem because it represents around 10% of all cancers and achieves a worldwide estimate of 1.4 million newly diagnosed cases annually, resulting in approximately 700,000 deaths. Approximately 19-31% of patients present liver metastases. At diagnosis, a further 23-38% will develop extra-hepatic disease. Over the past decade, the widespread use of modern chemotherapeutic and biological agents, combined with laparoscopic surgical techniques, has improved the prognosis of metastatic CRC. A better understanding of the biology of the tumor, along with high efficiency of diagnostic and therapeutic methods, as well as the spread of screening programs, will improve the survival of the CRC patients in the near future.
Extensive research into the molecular mechanisms of cancer disease has heralded a new age of targeted therapy. In malignant cells, key proteins that are crucial to tumor growth and survival are now being targeted directly with rationally designed inhibitors. Apart from monoclonal antibodies, small molecule therapeutics such as oncogenic protein kinase inhibitors are attracting a vast amount of investigational attention. This textbook, written by acknowledged experts, provides a broad overview of the small molecules currently used for the treatment of malignant diseases and discusses interesting novel compounds that are in the process of clinical development to combat cancer.
As with other books in the Molecular Pathology Library Series, Molecular Pathology of Lung Cancer bridges the gap between the molecular specialist and the clinical practitioner, including the surgical pathologist who now has a key role in decisions regarding molecular targeted therapy for lung cancer. Molecular Pathology of Lung Cancer provides the latest information and current insights into the molecular basis for lung cancer, including precursor and preinvasive lesions, molecular diagnosis, molecular targeted therapy, molecular prognosis, molecular radiology and related fields for lung cancer generally and for the specific cell types. As many fundamental concepts about lung cancer have undergone revision in only the past few years, this book will likely be the first to comprehensively cover the new molecular pathology of lung cancer. It provides a foundation in this field for pathologists, medical oncologists, radiation oncologists, thoracic surgeons, thoracic radiologists and their trainees, physician assistants, and nursing staff.
This, the first of two volumes on personalized medicine in lung cancer, touches on the core issues related to the understanding of lung cancer—statistics and epidemiology of lung cancer—along with the incidence of lung cancer in non-smokers. A major focus of this volume is the state of current therapies against lung cancer—immune, targeted therapies against EGFR TKIs, KRAS, ALK, angiogenesis; the associated challenges, especially resistance mechanisms; and recent progress in targeted drug development based on metal chemistry. Chapters are written by some of the leading experts in the field, who provide a better understanding of lung cancer, the factors that make it lethal, and current research focused on developing personalized treatment plans. With a unique mix of topics, this volume summarizes the current state-of-knowledge on lung cancer and the available therapies.
FDA's Drug Review Process and the Package Label provides guidance to pharmaceutical companies for writing FDA-submissions, such as the NDA, BLA, Clinical Study Reports, and Investigator's Brochures. The book provides guidance to medical writers for drafting FDA-submissions in a way more likely to persuade FDA reviewers to grant approval of the drug. In detail, the book reproduces data on efficacy and safety from one hundred different FDA-submissions (NDAs, BLAs). The book reproduces comments and complaints from FDA reviewers regarding data that are fragmentary, ambiguous, or that detract from the drug's approvability, and the book reveals how sponsors overcame FDA's concerns and how sponsors succeeded in persuading FDA to grant approval of the drug. The book uses the most reliable and comprehensive source of information available for writing FDA-submissions, namely text and data from NDAs and BLAs, as published on FDA's website. The source material for writing this book included about 80,000 pages from FDA's Medical Reviews, FDA's Clinical Pharmacology Reviews, and FDA's Pharmacology Reviews, from one hundred different NDAs or BLAs for one hundred different drugs. Each chapter focuses on a different section of the package label, e.g., the Dosage and Administration section or the Drug Interactions section, and demonstrates how the sponsor's data supported that section of the package label. Reveals strategies for winning FDA approval and for drafting the package label Examples are from one hundred FDA-submissions (NDAs, BLAs) for one hundred different drugs, e.g., for oncology, metabolic diseases, autoimmune diseases, and neurological diseases This book uses the most reliable and comprehensive source of information available for writing FDA-submissions, namely, the data from NDAs and BLAs as published on FDA's website at the time FDA grants approval to the drug