Pharmacodynamic markers of perifosine efficacy

Bryan T. Hennessy, Yiling Lu, Enrique Poradosu, Qianghua Yu, Shuangxing Yu, Hassan Hall, Mark S. Carey, Murali Ravoori, Ana Maria Gonzalez-Angulo, Robert Birch, I. Craig Henderson, Vikas Kundra, Gordon B. Mills

    Research output: Contribution to journalArticle

    104 Scopus citations

    Abstract

    Purpose: It is critical to develop methods to quantify the early pharmacodynamic effects of targeted therapeutics in vivo to make drug development more efficient and ensure biologically relevant dosing. Furthermore, an ability to identify patients likely to respond to targeted therapeutics would decrease the size, duration, and cost of clinical trials, resulting in more efficient translation to improved patient outcomes. Recent studies suggest that perifosine inhibits the phosphatidylinositol-3′-kinase (PI3K) pathway by preventing cell membrane recruitment of the AKT pleckstrin homology domain. Experimental Design: A novel functional proteomics technology, reverse phase protein array, was used to establish and quantify pharmacodynamic markers of perifosine efficacy. Results: Perifosine selectively prevents AKT recruitment to the membrane and blocks activation of downstream effectors. Perifosine inhibited breast, ovarian, and prostate cancer models. Growth inhibition was associated with apoptosis. Activation of AKT as a consequence of genomic aberrations predicted perifosine efficacy. In cell lines and xenografts, there was a highly statistically significant correlation between the degree of antitumor efficacy of different perifosine doses and quantified down-regulation of phosphorylation of AKT and of its downstream targets, particularly S6. Conclusions: Because of a strong correlation between proportional modulation of PI3K pathway biomarkers and quantified perifosine efficacy, it is likely that early measurement of such pharmacodynamic biomarkers with reverse phase protein array will optimize selection of responding patients and guide perifosine dosing. Furthermore, PI3K pathway activation status may allow baseline selection of patients most likely to respond to perifosine alone or in combination with other therapies.

    Original languageEnglish (US)
    Pages (from-to)7421-7431
    Number of pages11
    JournalClinical Cancer Research
    Volume13
    Issue number24
    DOIs
    StatePublished - Dec 15 2007

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Fingerprint Dive into the research topics of 'Pharmacodynamic markers of perifosine efficacy'. Together they form a unique fingerprint.

  • Cite this

    Hennessy, B. T., Lu, Y., Poradosu, E., Yu, Q., Yu, S., Hall, H., Carey, M. S., Ravoori, M., Gonzalez-Angulo, A. M., Birch, R., Henderson, I. C., Kundra, V., & Mills, G. B. (2007). Pharmacodynamic markers of perifosine efficacy. Clinical Cancer Research, 13(24), 7421-7431. https://doi.org/10.1158/1078-0432.CCR-07-0760