癌基因体：癌症治疗的未来

Abstract

Oncogenomics: The Future of Cancer Care analyzes the key advances and challenges associated with translating research efforts into successful, clinically meaningful therapeutic products. The emergence of oncogenomics promises a new era of cancer care. Over the next decade or so, biomedical researchers hope to have fully catalogued all genetic alterations associated with cancer, greatly expanding the number of "druggable" anticancer molecular targets.

Oncogenomics has already seen clinical and market success with a handful of "first-generation" oncogenomic therapeutics such as Herceptin, raising hope and expectations that safer and more effective patient-selected targeted therapeutics will revolutionize cancer therapy and transform cancer into a manageable chronic disease. While patient-selected genomic-based therapy has only recently emerged as a viable clinical practice, many experts argue that it will become crucial not just in clinical practice but as an integral component of targeted drug development.

However, despite the early success stories of Herceptin and Gleevec, many leaders in the field are cautious about the extent to which genomics will truly impact cancer care over the next 10 to 15 years. Employing the right tools, technologies, and strategies will be crucial to realizing the clinical and marketplace opportunities stemming from the burgeoning growth of oncogenomics. Oncogenomics: The Future of Cancer Care offers insightful evaluation of the following key challenges to achieving this goal and examines current approaches to addressing these issues:

• Preclinical drug candidate screening needs to be more predictive in order to increase the chance that a targeted drug entering clinical trials will succeed.
• Patient selection needs to be integrated into targeted drug development and clinical practice.
• Many pharmaceutical companies remain resistant to the patient-selected targeted drug model.
• Not all of the targets yielded by the Human Genome Project are "druggable" and it is extremely difficult to determine which genes associated with cancer are consequences, not causes, of cancer.
• Most tumors involve multiple mutations, which could translate into multiple pathways.

This report also:

• Evaluates important questions about the potential medical and revenue benefits of targeted cancer drugs that are not being realized.
• Provides an overview of the early success stories of patient-selected targeted therapeutics and highlights promising targeted therapeutics in development.
• Explores the scientific arguments for patient-selected clinical development, discusses the disincentives and challenges to patient-selected therapy, and examines the economics of patient-selected trials.
• Highlights key technologies used to discover cancer-associated genetic variation and gene expression patterns, and discusses the way in which the tools and technologies advanced by the HGP have improved this discovery process. Some of the key in vitro and animal model technologies being used to functionally test and "validate" (i.e., preclinically) these discoveries are summarized.

Table of Contents

Chapter 1. Cancer as a Genetic Disease

• 1.1. The Genetic Basis of Cancer
  • Cancer Epigenetics
• 1.2. Cancer Statistics: Mortality Has Decreased, but the Number of New Cases Is Increasing Cancer Survivor Care
• 1.3. What Are Molecularly Targeted Drugs?
• 1.4. Target Selection versus Patient Selection
• 1.5. The Future of Cancer Care
  • Parallels between Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome and Cancer Care
• 1.6. The Diagnostic Potential of Druggable Targets

Chapter 2. Targeted Therapies: Early Success Stories and Promising Candidates

• 2.1. Small Molecule Drugs
  • Gleevec (Imatinib): Approved 2001
  • Iressa (Gefitinib): Approved May 2003
  • Tarceva (Erlotinib): Approved November 2004
  • Promising Small Molecule Drugs in Development
• 2.2. Hypomethylating Agents
  • Azacitidine
  • Decitabine and Zebularine
• 2.3. Immunotherapeutic Intervention: Antibodies and Vaccines
  • Therapeutic Monoclonal Antibodies
  • Rituxan (Rituximab)
  • Herceptin (Trastuzumab)
  • Immunoconjugates
  • Avastin (Bevacizumab)
  • Cancer Vaccines

Chapter 3. Toward Targeted Therapies: Preclinical Discovery Technology

• 3.1. Finding the Cancer Gene: Discovery Technology
  • Comparative Genomic Hybridization (CGH)
  • Array CGH
• 3.2. The Human Genome Project
  • Advances in Sequencing Technology: Digital Karyotyping as an Example
  • Accelerated Drug Discovery
• 3.3. Oncogenomic Diagnostic Testing: Gene Expression Technology
  • Transcription Profiling Technology
  • Oncogenomics Normal Tissue Database
• 3.4. Proteomics and Cancer Care
• 3.5. Preclinical Validation: Screening Cancer Genes

Chapter 4. Patient-Selected Targeted Drugs in the Clinic: Opportunities and Challenges

• 4.1. The Gleevec Paradigm: From Skepticism to Iressa
• 4.2. The Importance of Patient Selection: A Scientific Argument
• 4.3. The Small-Size Advantage of Patient-Selected Trials
• 4.4. How to Design Patient-Selected Clinical Trials
• 4.5. Sample Acquisition as a Major Barrier to Patient-Selected Research
• 4.6. Lessons about Sample Acquisition from Past Attempts to Individualize Cancer Chemotherapy
• 4.7. Patient Selection from the Patient, Physician, and Payer Perspective: Disincentives

Chapter 5. The Business of Oncogenomics: Challenges and Opportunities

• 5.1. Public and Academic Involvement in Translational Research
  • Drug Discovery
• 5.2. The Potential Financial Rewards of a Patient-Selected Tiered Market
  • Expanding Indications for Targeted Drugs
  • Drug Safety
  • The Scientific Counterargument
• 5.3. The Molecular Diagnostics Industry
  • Patient-Selected Molecular Diagnostics

Chapter 6. Expert Interviews

• Charles Brenner, PhD, Dartmouth Medical School; Coeditor (with David Duggan), Oncogenomics: Molecular Approaches to Cancer
• Walter P. Carney, PhD, Oncogene Science (part of Bayer HealthCare)
• Nicholas C. Dracopoli, PhD, Vice President of Clinical Discovery Technology, Pharmaceutical Research Institute, Bristol-Myers Squibb
• Geoffrey Duyk, MD, PhD, Managing Director, Texas Pacific Group Ventures
• Michael L. Salgaller, PhD, Toucan Capital Corporation
• Herman Spolders, PhD, Chief Executive Officer, OncoMethylome Sciences

Chapter 7. Company Profiles

• Abgenix, Inc.
• ArtisOptimus, Inc.
• Dendreon Corporation
• Genomic Health, Inc.
• ImClone Systems, Inc.
• Medarex, Inc.
• OncoMethylome Sciences, Inc.
• Onyx Pharmaceuticals, Inc.
• OSI Pharmaceuticals, Inc.
• Spectral Genomics, Inc.
• Vivo Biosciences, Inc.

Notes

Index