Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation

Slide 1 of 8: Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation

James H. Doroshow, M.D.
Director, Division of Cancer Treatment and Diagnosis
National Cancer Institute
Bethesda, MD

July 21, 2009


Slide 2 of 8: Critical Requirements for the Development of Personalized Cancer Treatment: Phase I-III Transition

  • Timely prioritization & dedicated resources for essential biomarker validation studies, utilizing standardized laboratory practices
  • Accelerate prioritized translational research initiatives in the area of personalized therapy
  • Support for the coordination of hypothesis-driven biomarker studies across the entire clinical/translational science continuum

Focus: Improve the specificity of treatment while reducing the high rate of failure (and cost) during the Phase I to III transition.


Slide 3 of 8: Critical Issues in the Development of Personalized Therapies

  • How best to support academic investigators who wish to move from target or molecule discovery to clinical trials (preclinical testing, toxicology, GMP production, and regulatory support)
  • Addressing the “pharmacogenomics divide” (courtesy of Drs. Ames and Goetz, Mayo Clinic)
  • How to support the integration of pharmacogenomic studies into the NCI’s clinical trials system

Slide 4 of 8: Image showing metabolic pathway of tamoxifen in humans

[Image] showing metabolic pathway of tamoxifen in humans from Jin Y. et al. JNCI. 2005; 97(1): 30. Reprinted by permission of Oxford University Press.


Slide 5 of 8: Image showing endoxifen and 4-OH-Tamoxifen are Equipotent as Inhibitors of Estrogen Stimulated Cell Proliferation

[Image] showing endoxifen and 4-OH-tamoxifen are equipotent as inhibitors of estrogen stimulated cell proliferation.

Source: Johnson M.D. et al. Breast Cancer Research and Treatment. 2004;85:151–159.


Slide 6 of 8: Image indicating CYP2D6*4 is the most common genetic variant associated with the CYP2D6 poor metabolizer state and genotype determines endoxifen blood concentration

[Image] showing research published by Jin Y. et al. JNCI. 2005; 97(1): 30-39. Image indicates CYP2D6*4 is the most common genetic variant associated with the CYP2D6 poor metabolizer state and genotype determines endoxifen blood concentration.


Slide 7 of 8: Image showing time to recurrence according to CYP2D6 Metabolizer Status in Women Receiving Adjuvant Tamoxifen

[Image] showing an association between CYP2D6 genotypes and clinical outcome of recurrence. Image is from Jin Y. et al. JNCI. 2005; 9 (1):30-39. Reprinted by permission of Oxford University Press.


Slide 8 of 8: Crossing the Pharmacogenetic Divide

  • CYP2D6 critical for endoxifen exposure and, thus, tamoxifen drug effect; endoxifen potently inhibits ERα as well as other traditional mechanisms
    • Metabolic activation of tamoxifen limits drug activity
    • Administration of endoxifen would bypass pharmacogenetic limitations of tamoxifen
  • However, no IP possible for 30-year old metabolite, even though it is a new “drug”
    • Preclinical pharmacology, toxicology
    • Drug formulation and GMP production
    • IND submission
    • Phase I clinical trial

NCI has undertaken to produce clinical grade drug to begin the development process leading to a phase I study of endoxifen.

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