Dong W Kim MD, PhD, Presenter: Nothing to Disclose

Michelle L. Reyzer PhD, Abstract Co-Author: Nothing to Disclose

Jessica Huamani MS, Abstract Co-Author: Nothing to Disclose

Kenneth J. Niermann MD, Abstract Co-Author: Nothing to Disclose

Richard M. Caprioli PHD, Abstract Co-Author: Nothing to Disclose

Dennis E. Hallahan MD, Abstract Co-Author: Nothing to Disclose

Tumor vasculature targeted receptor tyrosine kinase inhibitors (TKI) combined with radiation therapy (RT) have demonstrated promising anti-tumor activity. Imaging mass spectrometry (MS) allows for detailed mapping of drug or protein distribution across a tissue sample. This technology can be applied to correlate changes in protein expression levels in response to therapy. Our purpose was to determine the spatial pharmacokinetics (PK) and pharmacodynamics (PD) of tumors of animals treated with TKI +/- RT, by tissue mass spectrometry (MS) imaging.

Animals bearing hindlimb tumor xenografts were treated with varying doses of TKIs +/- RT. Tumors were harvested at multiple time points following therapy. Frozen tumor tissues were analyzed on a Voyager DE-STR mass spectrometer or a QStarXL QqTOF mass spectrometer (Applied Biosystems) to image proteins or drugs respectively.

Imaging MS technology clearly demonstrates the spatial biodistribution of SU11248 and AEE788 (two broad spectrum TKIs targeting the tumor vasculature) in multiple tumor xenografts (lung, prostate, gliomas). Time and dose response experiments to these TKIs confirms that the spatial PK directly from tumor tissue sections, assessed by imaging MS, correlates with previously published conventional PK results. Protein peaks which may be potential surrogate markers of response to TKI therapy have been determined. One peak corresponds to the thymosin-β4 protein. Its level decreases as early as 2 hours post SU11248 therapy, and demonstrates potential to be a surrogate marker of early response to TKI therapy.

Imaging MS elegantly demonstrates spatial PK of TKI within tumors and effectively identified early protein markers that may be exploited in future treatment strategies. This technique has the advantage of being unbiased, reproducible, and amenable to high throughput screening. Importantly, these methods can be integrated into clinical protocols as a minimally invasive process, by analyzing frozen tumor tissues from biopsy specimens of patients receiving TKI therapy. (This work was supported by the Radiological Society of North America Research & Education Foundation)

Kim, D, Reyzer, M, Huamani, J, Niermann, K, Caprioli, R, Hallahan, D, Direct Analysis of Protein Markers of Therapeutic Response in Tumors Treated with Radiation and Receptor Tyrosine Kinase Inhibitors (TKI) by Imaging Mass Spectrometry.  Radiological Society of North America 2005 Scientific Assembly and Annual Meeting, November 27 - December 2, 2005 ,Chicago IL. http://archive.rsna.org/2005/4412875.html