Oncogenomics

From Basic Research to Precision Medicine

Franco Dammacco, Franco Silvestris

• Publisher: Academic Press
• Year: 2018
• ISBN:
  9780128117866
• Topic: Biological Sciences
• Subtopic: Genetics & Genomics
• Index: Biological Sciences

Oncogenomics: From Basic Research to Precision Medicine offers a thorough survey of precision medicine and its diagnostic and therapeutic applications in oncology. Gathering contributions from leading international researchers in the field, chapters examine recent translational advances in oncogenomic methods and technologies, detailing novel molecular classifications of tumors as well as diagnostic and prognostic biomarkers for various types of cancers including pancreatic, gastrointestinal, breast, hematological, lung, osteotropic, genitourinary, and skin cancers. This book provides a foundation for clinical oncologists, human geneticists, and physicians to develop new targeted cancer treatments and incorporate genomic medicine into clinical practice, with particular attention paid to noninvasive diagnostic techniques such as the liquid biopsy and molecular characterization of solid malignancies.

• Provides clinical oncologists, human geneticists, physicians, and students with a thorough understanding of current diagnostic and prognostic applications of genomic methods and technologies to a variety of solid malignancies
• Employs current knowledge in oncogenomics towards developing therapeutic interventions for various cancer types
• Features a team of internationally recognized researchers and physicians in clinical oncology, oncogenomics and precision medicine

Part I

Molecular Medicine: A Novel Approach to Cancer Investigation

Outline

• Chapter 1 From the Double Helix to Oncogenomics and Precision Cancer Medicine
• Chapter 2 Intratumor Heterogeneity
• Chapter 3 The Role of Proteomics in Cancer Research
• Chapter 4 Next-Generation Sequencing in Clinical Practice
• Chapter 5 Cancer Epigenetics
• Chapter 6 Cancer Stem Cells
• Chapter 7 Cancer Stem Cells, Apoptosis Pathways and Mechanisms of Death Resistance
• Chapter 8 Targeting the Hedgehog and Notch Signaling Pathways in Cancer Stem Cells
• Chapter 9 Cancer Stem Cells in Multiple Myeloma and the Development of Novel Therapeutic Strategies

Chapter 1

From the Double Helix to Oncogenomics and Precision Cancer Medicine

An Evolving Story

Franco Dammacco and Franco Silvestris, Department of Biomedical Sciences & Human Oncology, University of Bari “Aldo Moro”, Bari, Italy

Abstract

With the completion of the Human Genome Project in June 2000 and in step with the development of next generation -omics, a new era of medicine has started. In particular, the application and expansion of the molecular profiling of tumors have ushered in the development of personalized treatments, collectively referred to as precision cancer medicine (PCM), a field that is steadily growing. An increasing number of targetable molecules are being produced by the pharmaceutical industry, and their efficacy is strictly related to their specificity for reliable and well-characterized oncogenic pathways. The US Food and Drug Administration has therefore recommended that the development of these agents should be accompanied by companion diagnostics. The genomic revolution is also changing the way clinical trials of targeted drugs for cancer patients are being planned and conducted. The most common master protocols include basket trials, umbrella trials, and platform trials. Due to their flexibility and characteristics across molecularly defined tumor subtypes, novel drugs are included or excluded depending on their efficacy. Two examples on the use of precision diagnosis and treatment are described. The first one concerns patients with advanced non-small cell lung carcinoma, characterized by actionable or “druggable” oncogenic alterations and the sometimes remarkable improvement in objective response rates, progression-free survival, and overall survival compared with platinum-based chemotherapy. The second successful example of PCM is malignant melanoma. In parallel with a better understanding of the molecular mechanisms driving melanoma progression and drug resistance, the standard of care for this tumor has shifted from poorly effective chemotherapy to more optimistic targeted approaches. However, despite these encouraging results, a wider clinical application of PCM is still hampered by several drawbacks that will require major efforts before they can be overcome. It is hoped that, through the continuous and progressive refinement of its applications, PCM will eventually result in significant progress in the prevention, diagnosis, and treatment of tumors.

Keywords

Human genome; master protocols; oncogenomics; precision medicine; targeted drug

Abbreviations

ALK anaplastic lymphoma kinase

CDx companion diagnostics

EGFR epidermal growth factor receptor

FDA Food and Drug Administration

MoAb monoclonal antibody

NSCLC non-small cell lung cancer

ORR objective response rate

OS overall survival

PCM precision cancer medicine

PD-1 programmed death 1

PD-L1 programmed death ligand 1

PFS progression-free survival

PMI precision medicine initiative

ROS1 rat osteosarcoma

TKI tyrosine kinase inhibitor

VEGF vascular endothelial growth factor

***

“Bethink you of the seed

whence you have sprung; for you were not created

to lead the life of brutes,

but virtue and knowledge to pursue”

(The “Divine Comedy” by Dante Alighieri [1265-1321], Hell, XXVI canto)

An irrepressible impulse to pursue knowledge is innate to humankind and was emphatically expressed by Dante Alighieri in his imagining of Ulysses urging his traveling companions to follow his lead in steering his ship beyond the Pillars of Hercules, where they would face the unknown. Approximately 700 years later, the same strong curiosity drives the worldwide scientific community.

The Double Helix and the Human Genome Project

In a one-page paper published in Nature on April 25, 1953, James D. Watson and Francis H. Crick first described the double helix, the twisted-ladder structure of DNA. This extraordinary discovery was a milestone in the history of science and laid the foundations of modern molecular biology. The authors were awarded the 1962 Nobel Prize in Physiology or Medicine.

Less than 50 years later, on June 26, 2000, during a press teleconference, US President Bill Clinton, Prime Minister Tony Blair of the United Kingdom (via satellite), Dr. Francis Collins, Director of the National Human Genome Research Institute, and Dr. Craig Venter, President and Chief Scientific Officer of Celera Genomics Corporation, jointly announced the completion of the first survey within the Human Genome Project. The final, high-quality, reference genome sequence was generated and then completed by the end of 2002, more than 2 years ahead of schedule (Collins, Morgan, & Patrinos, 2003; Venter et al., 2001).

Complete mapping of the human genome, the result of an immense research endeavor, was described by US President Clinton as “the most important, most wondrous map ever produced by humankind.” In fact it was a “genetic revolution,” marking a turning point in all fields of biology and the beginning of a new era in research. The significance of this work was already predicted in 1986 by the 1975 Nobel laureate Renato Dulbecco, who expressed the following, at the time visionary, idea of sequencing the human genome: “We are at a turning point in the study of tumor virology and cancer in general. If we wish to learn more about cancer, we must now concentrate on the cellular genome. We are back to where cancer research started, but the situation is drastically different because we have new knowledge and crucial tools, such as DNA cloning. We have two options: either to try to discover the genes important in malignancy by a piecemeal approach, or to sequence the whole genome of a selected animal species.… I think that it will be far more useful to begin by sequencing the cellular genome. The sequence will make it possible to prepare probes for all the genes and to classify them for their expression in various cell types at the level of individual cells by means of cytological hybridization. The classification of the genes will facilitate the identification of those involved in progression. In which species should this effort be made? If we wish to understand human cancer, it should be made in humans because the genetic control of cancer seems to be different in different species. Research on human cancer would receive a major boost from the detailed knowledge of DNA” (p. 1055).

The complete sequencing of the DNA blueprint of Homo sapiens (3 billion DNA letters) has been (rightly) acknowledged as one of the greatest scientific undertakings of all times. Its full achievement can be considered (albeit perhaps somewhat exaggeratedly) as the biological equivalent of the moon landing or the splitting of the atom. Although completion of the Human Genome Project has important therapeutic implications for all types of disease, the most obvious and immediate ones are in the field of oncology because of the increasing prevalence of malignant tumors in the world’s aging population, the general trend to greater longevity, the high lethality of most tumors, the limited success of chemotherapy for the majority of advanced neoplasias, and the strong demand for clinically applicable scientific advancements in this field. Complete sequencing of the genes of several cancers, as planned in the Cancer Genome Project, will improve our knowledge of the molecular mechanisms responsible for neoplastic transformation (Green, Watson, & Collins, 2015). Indeed, the expanded molecular profiling of the tumors so far studied has already revealed a large number of potentially actionable targets.

Precision Medicine Initiative and Precision Cancer Medicine

In parallel with the complete sequencing of the human genome, there has been a rapid development of related technologies, including the various -omics (genomics, proteomics, regulomics, transcriptomics, and metabolomics), for biomedical analysis (Fig. 1.1). This has been supported by new computational tools for collecting and analyzing large data sets, commonly known as “big data.” Together, they have allowed the design of molecularly targeted therapies that in later iterations are expected to revolutionize the treatment of cancer (Savage & Antman, 2002). The first convincing example of this innovative approach was the tyrosine kinase inhibitor (TKI) imatinib, first administered to patients with chronic myeloid leukemia and subsequently shown to be effective in gastrointestinal stromal tumors.

Figure 1.1 Omics sciences show new molecular landscapes in cancer research and treatment. CGH, comparative genomic hybridization; DNA, deoxyribonucleic acid; Methyl-DIP, methylated DNA immu...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedications
• List of Contributors
• Preface
• Part I: Molecular Medicine: A Novel Approach to Cancer Investigation
• Part II: Oncogenomics: Circulating Biomarkers in Clinical Oncology
• Part III: Gastrointestinal Tumors: Molecular Diagnosis and Treatment
• Part IV: Perspectives in Breast Cancer Genomics
• Part V: Lung Cancer: Role of Genomics in Clinical Practice
• Part VI: Genomics in Genitourinary Cancer
• Part VII: Genomics in Neuroendocrine Tumors, Melanoma, and Sarcoma
• Index