R&D最新情報：既存の血管新生阻害剤の改良

Abstract

Introduction

Antiangiogenic drugs represent a new class of antitumor therapeutics that will be used along with cytotoxic agents, targeted agents, and immunomodulatory agents to fi ght cancer. The fi rst antiangiogenic compound on the market, Genentech' s Avastin (bevacizumab), has become one of the top-selling anticancer drugs worldwide. In November 2007, another antiangiogenic agent, Onyx/Bayer' s Nexavar, became the fi rst agent approved to treat hepatocellular carcinoma. Based on Avastin' s success, pharmaceutical and biotechnology companies are developing a rich pipeline of antiangiogenic agents, including multitargeted kinase inhibitors, other smallmolecule compounds, and large-molecule biological agents.

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• The vascular endothelial growth factor (VEGF) pathway is the most well understood of the angiogenic pathways and all approved antiangiogenic drugs--Avastin, Onyx/Bayer' s Nexavar (sorafenib), and Pfi zer' s Sutent (sunitinib)- primarily target this pathway and its receptors. What other pathways are associated with angiogenesis? What are the disadvantages of targeting the VEGF pathway? What pathways do emerging antiangiogenic drugs target?
• Current antiangiogenic agents offer only limited benefi t to patients in terms of improved survival and quality of life. How have emerging antiangiogenic compounds fared in clinical trials? What strategies are drug developers exploring to improve the effi cacy of antiangiogenic drugs?
• Resistance to anti-VEGF agents remains a challenge to the long-term effi cacy of existing anti-angiogenic agents. What approaches are pharmaceutical companies taking to address VEGF resistance? Does the targeting of HIF (hypoxia-inducible factor) or mTOR (mammalian target of rapamycin) represent a viable strategy to overcoming VEGF resistance?

Scope

• Tumor angiogenesis: the systems that contribute to its growth and those that inhibit its growth.
• Marketed antiangiogenic agents: Genentech' s Avastin (bevacizumab), Onyx/Bayer' s Nexavar (sorafenib), and Pfi zer' s Sutent (sunitinib).
• Emerging antiangiogenic agents: Adnexus' s Angiocept, Amgen' s AMG-386, AstraZeneca' s cediranib, AstraZeneca' s Zactima, Celgene' s thalidomide derivatives, GlaxoSmithKline' s pazopanib, MedImmune' s abegrin, Merck KGaA' s cilengitide, Novartis' s vatalanib, PDL BioPharma/Biogen Idec' s volociximab, Pfi zer' s axitinib, Regeneron/Sanofi -Aventis' s afl ibercept, UCB/ImClone' s CDP-791.
• Strategies to improve antiangiogenic agents: maximizing the effi cacy of antiangiogenic compounds and preventing development of resistance to the compounds.

Table of Contents

• Executive Summary
  • Strategic Implications
  • Stakeholder Implications
• Introduction
• Biology of Tumor Angiogenesis
  • VEGF Pathway
  • Integrin Signaling
  • PDGFR
  • Cell Hypoxia
• Antiangiogenic Agents Approved to Treat Cancer
  • Genentech' s Avastin
  • Bayer' s Nexavar
  • Pfizer' s Sutent
• Emerging Antiangiogenesis Agents to Treat Cancer
  • Emerging Small-Molecule Antiangiogenic Drugs
    • Celgene' s Thalidomide Derivatives
    • Merck' s Cilengitide
    • GlaxoSmithKline' s Pazopanib
    • AstraZeneca' s Zactima
    • AstraZeneca' s Cediranib
  • Emerging Large-Molecule Antiangiogenic Drugs
    • Regeneron/Sanofi -Aventis' s Afl ibercept
    • PDL BioPharma/Biogen Idec' s Volociximab
    • UCB/ImClone' s CDP-791
    • Amgen' s AMG-386
• Improving on Antiangiogenesis Agents
  • Improving the Effi cacy of Antitumor Agents
  • Preventing Resistance to Antiangiogenic Drugs
• Outlook

Tables:

• 1. Major Angiogenic Growth Factors
• 2. Key Angiogenesis Inhibitors
• 3. Antiangiogenic Agents Approved for the Treatment of Cancer
• 4. Emerging Small-Molecule Antiangiogenic Agents
• 5. Emerging Large-Molecule Antiangiogenic Agents

Figures:

• 1. The Angiogenic Process
• 2. The Role of mTor in the Regulation of HIF-1α and Angiogenesis