Therapeutic Targeting of Cancer Cells
Era of Molecularly Targeted Agents
Summary of Key Points
• Molecularly targeted anticancer agents (MTAs) are those that selectively target specific molecular features of cancer cells such as aberrations in genes, proteins, or pathways that regulate tumor growth, progression, and survival.
• Molecular targets include the following: products of activating mutations and translocations, growth factors and receptors, aberrant signal transduction and apoptotic pathways, factors that control tumor angiogenesis and microenvironment, dysregulated proteins, DNA repair machinery, and aberrant epigenetic mechanisms.
• The development of MTAs requires innovative strategies that differ from those traditionally applied to nontargeted conventional chemotherapy.
• Successful development of an MTA depends largely on the importance of the target in controlling tumor cell proliferation and survival and effective modulation of the target in the tumor at clinically achievable concentrations.
• Primary objectives of clinical trials of MTAs differ from those used in trials of conventional chemotherapy. An important objective in phase 1 trials of MTAs should be to determine a phase 2 dose based on optimal target modulation (i.e., a biologically effective dose) rather than on maximum tolerated dose. In addition, objective tumor response may not be an adequate end point for efficacy evaluations of MTAs that have a primarily cytostatic effect. Alternate end points, such as progression-free survival, may be more appropriate.
• Functional and molecular imaging plays an increasingly important role in the development of MTAs.
1. What is meant by “pharmacodynamics”?
A Plasma exposures for the agent and its metabolites
2. Properties of molecularly targeted agents differ from those of cytotoxic chemotherapies in which of the following ways?
3. Optimal development of molecularly targeted agents should include:
A Assessment of target modulation in tumor
B Determining the “biologically effective dose”
4. When should pharmacodynamic assay validation be performed in the context of clinical development?
A Before the initiation of first-in-human clinical trials
