Abstract 2888: Computational analysis of microtubule dynamics for personalized cancer therapy.
Authors: Alexandre Matov, Dragi Kimovski, Giuseppe Galletti, Nancy Chan, Benet Pera, William T. Harkcom, David S. Rickman, Paraskevi Giannakakou
Journal: Cancer Research (2013)

Abstract Metastatic prostate cancer (PC) is treated primarily by means of taxane-based chemotherapy with one of the clinically used taxanes: paclitaxel, docetaxel and cabazitaxel. At the cellular level, the taxanes bind microtubules (MTs), inhibit MT dynamics and alter the spatial organization of the MT network. Thereby the taxanes inhibit the intracellular trafficking of transcription factors critical for tumor survival. In PC, taxanes are the only chemotherapy class shown to improve survival, however, the emergence of clinical taxane resistance hampers their clinical efficacy. In addition, patients resistant to one taxane often respond to another, yet, currently we do not have the ability to match individual patients to a specific taxane. In cells, different taxanes have differential effects on microtubule dynamics which may ultimately pre-determine their efficacy for each individual patient. Thus, we hypothesized that the particular pattern of dynamic behavior of the MT cytoskeleton in individual patients could be exploited therapeutically. Therefore, we looked into dissecting the concrete effects of each of the taxanes for several PC cells lines. Preliminary unpublished data have revealed that PC cells expressing the TMPRSS2-ERG fusion protein exhibit taxane resistance. In addition, we have recently shown that the androgen receptor (AR) binds MTs in order to traffic to the nucleus and that taxane-mediated inhibition of AR nuclear accumulation correlates with patient clinical response to taxane therapy. Moreover, we have shown that the two clinically relevant AR splice variants, ARv567 and ARv7, show differential response to taxane therapy. Therefore, we set out to investigate the hypothesis that ERG fusion and/or AR variants might modulate endogenous microtubule dynamics in a way that determines cellular response to taxane treatment. Xenografts PC models expressing the ARv7 variant exhibit reduced sensitivity to docetaxel treatment. In addition, docetaxel's ability to induce MT stabilization is significantly impaired in ERG+ cells. We have recently established isogenic PC cell line series with inducible ERG (DU145 ERG+ and ERG-), as well as M12 cells without endogenous AR that stably express, wt-AR, ARv567 and ARv7. We then tested in a systematic way endogenous MT dynamics using live cell confocal microscopy of labeled MT tips following EGFP-EB1 lentiviral transduction. We use computer vision algorithms to obtain statistically representative results for the effects of ERG or AR on microtubule homeostasis following treatment with each of the three taxanes. We measure changes in MT behavior as statistically significant shifts in different parameters of MT dynamics measured from &amp;gt;20,000 MTs for each condition. Our preliminary results revealed that the presence of ERG fusion a correlation between MT dynamics and AR variant expression in PC cell lines. Citation Format: Alexandre Matov, Dragi Kimovski, Giuseppe Galletti, Nancy Chan, Benet Pera, William T. Harkcom, David S. Rickman, Paraskevi Giannakakou. Computational analysis of microtubule dynamics for personalized cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2888. doi:10.1158/1538-7445.AM2013-2888