Skin biopsies for the measurement of clinical pharmacodynamic biomarkers

Phillips, Robert L.; Sachs, Alan B.

doi:10.1016/j.copbio.2005.10.010

Cited by 10 publications

(10 citation statements)

References 20 publications

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“…Whereas blood sampling is easier than skin biopsy, skin biopsy has distinct advantages as surrogate tissue source for biomarkers. Blood contains mainly mature cells that do not undergo further proliferation and differentiation, whereas skin contains a variety of cell types at different stages of development in which signaling networks for cell growth are activated (Phillips and Sachs, 2005). Furthermore, hedgehog signaling is activated in human skin (Rittie et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Modeling of Hedgehog Inhibitor TAK-441 for the Inhibition of Gli1 messenger RNA Expression and Antitumor Efficacy in Xenografted Tumor Model Mice

et al. 2013

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6-Ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo [3,2-c]pyridine-2-carboxamide (TAK-441) is a potent, selective hedgehog signaling pathway inhibitor that binds to Smo and is being developed for the treatment of cancer. The objectives of these studies were to explore the possibility of establishing of a link between the pharmacokinetics of TAK-441 and the responses of Gli1 mRNA in tumor-associated stromal or skin cells and the antitumor effect of hedgehog inhibition. To this end, we built pharmacokinetic and pharmacodynamic models that describe the relationship of the concentrations of TAK-441 plasma to the responses of Gli1 mRNA in the tumor (target) and skin (surrogate) and to tumor growth inhibition in mice bearing xenografts of human pancreatic tumors (PAN-04). The responses of Gli1 mRNA and tumor growth were described by an indirect response model and an exponential tumor growth model, respectively. The IC 50 values for Gli1 mRNA inhibition in the tumor and skin by TAK-441 were estimated to be 0.0457 and 0.113 mg/ml, respectively. The IC 90 value for tumor growth inhibition was estimated to be 0.68 mg/ml. These results suggest that a >83% inhibition of Gli1 mRNA expression in the skin or a >94% inhibition of Gli1 mRNA expression in the tumor would be required to sufficiently inhibit (>90%) hedgehog-related tumor growth in the xenografted model mice. We conclude that Gli1 mRNA expression in the tumor and skin could be a useful biomarker for predicting the antitumor effect of hedgehog inhibitors

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Modeling of Hedgehog Inhibitor TAK-441 for the Inhibition of Gli1 messenger RNA Expression and Antitumor Efficacy in Xenografted Tumor Model Mice

et al. 2013

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“…For these reasons, we focused instead on skin, which, although containing relatively few proliferating cells, is a continuously developing system encompassing several distinct stem cell populations, where many of the most important developmental signaling networks are active (reviewed in ref. 3).…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, an early development biomarker analysis that attempts to replicate preclinical pharmacokinetic/pharmacodynamic models requires pretreatment and posttreatment samples, limiting the analysis to patients for which tumor biopsies can be obtained. For this reason, other biological samples, such as blood, skin, and hair follicles, are being studied as surrogate tissues for biomarker analysis (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Analysis of an E2F Gene Signature as a Biomarker of Activity of the Cyclin-Dependent Kinase Inhibitor PHA-793887 in Tumor and Skin Biopsies from a Phase I Clinical Study

Locatelli

Bosotti

Ciomei

et al. 2010

Molecular Cancer Therapeutics

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A transcriptional signature of the pan-cyclin-dependent kinase (Cdk) inhibitor PHA-793887 was evaluated as a potential pharmacodynamic and/or response biomarker in tumor and skin biopsies from patients treated in a phase I clinical study. We first analyzed the expression of a number of known E2F-dependent genes that were predicted to be modulated after Cdk2 and Cdk4 inhibition in xenograft tumor and skin samples of mice treated with the compound. This panel of 58 selected genes was then analyzed in biopsies from seven patients treated with PHA-793887 in a phase I dose escalation clinical trial in solid tumors. Quantitative real-time PCR or microarray analyses were done in paired skin and tumor biopsies obtained at baseline and at cycle 1. Analysis by quantitative real-time PCR of the signature in skin biopsies of patients treated at three different doses showed significant transcriptional downregulation with a dose-response correlation. These data show that PHA-793887 modulates genes involved in cell cycle regulation and proliferation in a clinical setting. The observed changes are consistent with its mechanism of action and correlate with target modulation in skin and with clinical benefit in tumors.

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“…There are other techniques which may be of particular value during the early stages of clinical development; for example spot counts in the treatment of acne. Skin biopsies may provide useful information on the pharmacodynamics of the drug at the site of action (Phillips and Sachs, 2005). Micro-dialysis can give information on the pharmacokinetics in skin (Tettey-Amalo et al, 2009) and can also be useful in determination of the optimum therapeutic concentration, or for 'proof of concept' studies (Brunner et al, 2005).…”

Section: Introductionmentioning

confidence: 99%