化学抗癌剤開発における課題と機会

Abstract

Introduction:

During the past 30 years, researchers' understanding of cancer progression has increased tremendously. This critical development has allowed for the possibility of developing cancer chemopreventive agents. Among potential chemopreventive agents, modalities that are already approved for cancer treatment present the greatest potential for success, as these agents' safety and efficacy have already been proved in cancer treatment. However, combination therapies are now being touted as demonstrating synergistic increases in efficacy as well as improvements in safety profiles. Although oncology drugs are lucrative for pharmaceutical companies, the industry is hesitant to enter the chemoprevention field because of various challenges, including intellectual property and reimbursement issues. The development of safe, innovative, effective drugs for cancer chemotherapy is at risk for stagnancy if such barriers are not overcome.

Get the Answers You Need to Shape Your Strategy:

• The possible causal relationship between inflammation and cancer has been observed in numerous malignancies. Agents that interfere with the inflammatory process have therefore become attractive candidates upon which to base chemopreventive strategies. Which anti-inflammatory agents are undergoing active chemoprevention trials?
• Because many signal transduction pathways that lead to tumor growth are also active in precancerous lesions, they, too, have become promising targets for chemoprevention. Which of these pathway signals are already targeted by several cancer treatments, and which treatment is currently undergoing clinical trials specifically for cancer prevention?
• On September 13, 2007, the FDA approved Eli Lilly' s Evista for chemoprevention of breast cancer in high-risk women. Why does Evista represent a major advancement in the design of chemopreventive drugs?
• Clinical studies in breast and prostate cancers have yielded important lessons in understanding the characteristics of chemopreventive agents and in successfully designing chemopreventive trials. What lessons can be learned from the earlier studies?
• Owing to challenges associated with transitioning cancer chemopreventive agents to clinical use, cancer chemoprevention has received limited investment for discovering and developing candidate agents. What challenges does chemoprevention face? What solutions have been proposed to overcome these challenges?
• In contrast to measuring the efficacy of well-established cardiovascular chemopreventive agents, measuring the efficacy of an oncology chemopreventive is extremely challenging. How can stakeholders most effectively overcome this hurdle?

Scope:

Classes of chemopreventive agents: anti-inflammatory agents, modulators of cancer-associated pathways, modulators of epidermal growth factor receptor signaling pathways, modulators of TGF-beta/Smad signaling pathway, modulators of nuclear-receptor superfamily, bioactive food components (BFCs).

Preclinical animal models: criteria for choosing an ideal animal model; current animal models in use for evaluating cancer chemopreventive agents; models with genetically engineered mice.

Lessons from earlier cancer chemoprevention trials: critical lessons and guidelines to keep in mind from past breast cancer and prostate cancer trials.

Current chemopreventive agents in development for breast cancer: selective estrogen receptor modulators (SERMs); aromatase inhibitors; retinoids and rexionoids; COX-2 inhibitors; combination therapy; dietary agents.

Current chemopreventive agents in development for prostate cancer: 5-alpha-reductase inhibitors; anti-androgens; dietary agents; NSAIDs; polyamine synthesis inhibitors; SERMs.

Challenges in chemopreventive agent development: patient-perception barriers affecting clinical trials; reimbursement issues; intellectual property barriers.

Opportunities: FDA-approved agents for cancer treatment; combination therapies; strategic alliances with nutraceutical companies; biomarker development; veterinary oncology.

Future perspectives: factors driving the development of innovative modalities; gauging long-term safety risks; why a combination of strategies will likely be needed to address each type of cancer malignancy; the importance of strategic alliances.

Table of Contents

• Executive Summary
  • Strategic Considerations
  • Stakeholder Implications
• Overview of the Chemoprevention Strategy
• Classes of Chemopreventive Agents
  • Anti-Infl ammatory Agents
    • Nonspecifi c Nonsteroidal Anti-Infl ammatory Drugs
    • Cyclooxygenase-2 Inhibitors
    • Lipoxygenase Inhibitors
  • Antimutagens
    • Dithiolethiones
    • Isothiocyanates
  • Modulators of Cancer-Associated Pathways
    • Epidermal Growth Factor Receptor
    • TGFβ/Smad
  • Modulators of Nuclear-Receptor Superfamily
  • Bioactive Food Components
    • Tea Polyphenols
    • Vitamin E
    • Lycopene
    • Curcuminoids
• Preclinical Animal Models
• Chemoprevention Trials: Lessons from the Past
  • Breast Cancer
  • Prostate Cancer
• Chemopreventive Agents in Development for Breast Cancer
  • Selective Estrogen Receptor Modulators
  • Aromatase Inhibitors
  • Retinoids
• Chemopreventive Agents in Development for Prostate Cancer
  • 5-α-Reductase Inhibitors
  • Selenium
• Challenges in Chemopreventive Agent Development
  • Patient Perception Barriers Affecting Clinical Trial Participation
  • Insurance Policy Affecting Reimbursement of Chemopreventive Agents
  • Intellectual Property Barriers Affecting R&D and Investment Recovery
• Opportunities in Chemopreventive Agent Development
  • FDA-Approved Agents
    • EGFR Inhibitors
    • HMG-CoA Reductase Inhibitors
    • Angiogenesis Inhibitors
    • Matrix Metalloproteinases
  • Combination Therapies
  • Strategic Alliances with Nutraceutical Companies
  • Biomarker Development
  • Veterinary Oncology
• Future Perspectives

Tables

• 1. Classes of Potential Chemopreventive Agents
• 2. Potential Chemopreventive Bioactive Food Components
• 3. Animal Models for the Screening and Development of Chemopreventive Agents
• 4. Chemopreventive Agents and Related Clinical Trials for Breast Cancer
• 5. Chemopreventive Agents and Related Clinical Trials for Prostate Cancer
• 6. Key Challenges and Proposed Solutions for Chemopreventive Agent Development
• 7. Potential Chemopreventive Molecular Targets and Agents

Figures

• 1. Carcinogenesis and Chemoprevention