Abstract 1685: Identification of PDGFR-a as a predictive biomarker for response to Zalypsis®

Abstract

Abstract This work was focused on the identification of predictive biomarkers for response to Zalypsis®, a bis-tetrahydroisoquinoline derivative structurally related to the marine-derived compounds jorumycin and renieramycins. Zalypsis® binds to the minor groove of DNA through its reactive carbinolamine group, establishing covalent bonds with the amino group of selected guanines in the DNA, with preference for the triplets AGG, GGC, AGC, CGG and TGG. This particular molecular interaction of Zalypsis® with the DNA creates the equivalent to a functional interstrand crosslink that lead to a strong inhibition of the early phases of transcription. Zalypsis® showed potent antitumor activity both in vitro and in vivo, in preclinical models, against a wide variety of human tumors and is currently in phase II clinical trials for solid tumors, showing a tolerable toxicologic profile. In order to gain knowledge on the molecular basis of sensitivity/resistance to Zalypsis®, we used a panel of cell lines from untreated sarcoma tumor samples, keeping the cell lines low passaged to avoid extensive genetic alterations as a consequence of genetic instability of the tumor. These cell lines were extensively characterized for molecular markers and for response to chemotherapeutic drugs, including Zalypsis®. When analyzing the correlation of the sensitivity of these sarcoma cell lines to Zalypsis® and the expression of different molecular markers, it was found that, in general, high basal protein expression levels of PDGFR-a were associated with increased resistance to the drug in vitro. However, among the 20 cell lines studied, two of them expressed low levels of PDGFR-a and were quite resistant to the drug. After analysing other markers, it was found that these cell lines expressed constitutively phosphorylated c-kit receptor, which could have accounted for the observed resistance. To validate the predictive value of PDGFR-a in vivo, and due to the fact that the established sarcoma cells were not tumorigenic in mice, we selected a panel of 9 human epithelial tumor cell lines and tested their sensitivity to Zalypsis® in xenograft models, and, in parallel, the expression of PDGFR-a. HGC27, SW1990, Calu-6 and A2780 showed relative high levels of expression of PDGFR-a in vitro, while UM-UC-3, MX1, MDA-MB-231 and HepG2 showed relative low levels. The subset of cells expressing high levels of PDGFR-a was consistently resistant to Zalypsis®. SKOV-3 cells, which expressed low levels of the marker, were also resistant to the drug. However, after analyzing the expression of other molecular markers, we found that these cells expressed high levels of constitutively phosphorylated EGF receptor that, again, could have accounted for the relative resistance to the drug. Altogether, these results suggest that PDGFR-a could be considered as a useful predictive biomarker of response to Zalypsis®. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1685.