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Tissue-based approaches to study pharmacodynamic endpoints in early phase oncology clinical trials

Joo Ern Ang1, Stan Kaye, Udai Banerji

  • 1The Institute of Cancer Research, Sutton, UK.

Current Drug Targets
|September 15, 2012
PubMed

Insights

Integrating pharmacodynamic biomarkers into early phase clinical trials can accelerate anti-cancer drug development. This review explores tissue-based approaches for pharmacodynamic studies of molecularly targeted agents.

Area of Science:

  • Oncology
  • Pharmacology
  • Biomarker Discovery

Background:

  • Anti-cancer drug development is expensive, slow, and has a high failure rate.
  • There is a critical need for improved methods in early-phase clinical trials.
  • The pharmacologic audit trail framework highlights the importance of pharmacodynamic biomarkers.

Purpose of the Study:

  • To review the rationale, benefits, drawbacks, and practicalities of tissue-based pharmacodynamic studies.
  • To examine the application of these methods in early phase oncology clinical trials.
  • To discuss the development of molecularly targeted anti-cancer agents.

Main Methods:

  • Review of case histories involving molecular targeting agents (PI3K, m-TOR, HSP90, HDAC, PARP inhibitors).
  • Exploration of normal surrogate tissues: peripheral blood mononuclear cells, platelet-rich plasma, hair follicles, skin biopsies, plasma assays, proteomics, metabolomics, circulating endothelial cells.
  • Discussion of neoplastic tissues: tumor biopsies, circulating tumor DNA, circulating tumor cells, metabolomics.

Main Results:

  • Various tissue-based approaches can be employed for pharmacodynamic assessments.
  • Both normal surrogate tissues and tumor-derived materials offer valuable insights.
  • Proteomics, metabolomics, and circulating biomarkers represent key technology platforms.

Conclusions:

  • Utilizing diverse tissues and technology platforms for biomarker studies is crucial.
  • These approaches can significantly accelerate the development of molecularly targeted cancer therapies.
  • Integration of pharmacodynamic biomarkers enhances the efficiency of oncology drug development.

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