Predicting response to sepantronium bromide (YM155), a survivin suppressant, by PET imaging with [11C]YM155☆,☆☆
Introduction
Anti-cancer drug development often relies on the meeting of two major goals: (1) identifying a molecular or metabolic target that can be manipulated to potentiate therapy by altering or biasing cellular processes; and (2) tailoring a drug with enhanced tumor uptake, half-life, and stability, with the aim of building a favorable drug absorption, distribution, metabolism and excretion (ADME) profile. In this context, one such target is survivin, a member of the apoptosis inhibitor family, which is highly expressed in almost all tumor types and is undetectable in most normal terminally-differentiated adult tissues [[1], [2], [3]]. The high expression of survivin has been correlated with aggressive progression and poor survival in a range of solid and hematological malignancies [4,5]. Given its ability to block apoptosis and to regulate cancer cell proliferation, survivin stands out as a promising candidate for cancer therapy [5].
Sepantronium bromide (YM155) suppresses the expression of survivin, and induces apoptosis in cancer cells in vitro and tumor regression in vivo [[6], [7], [8], [9], [10], [11]]. YM155 is a small molecule with high hydrophilicity; membrane permeability by passive diffusion is quite low [12,13], and a membrane transporter may play an important role in its incorporation into cancer cells. Favorable safety and tolerability profiles have been confirmed in Phase I and Phase II studies [[14], [15], [16], [17], [18], [19]]. However, in those studies, only some patients benefited from YM155 treatment. The selection of patients whose tumors will be responsive to therapy remains a challenge.
In previous studies, we have explored biomarkers predictive of a response to YM155. The GI50 value of YM155 for cell lines only marginally correlated with survivin mRNA expression levels, suggesting that the sensitivity of the cell lines to YM155 cannot simply be explained by survivin expression itself [20]. On the other hand, we found that YM155 showed >20-fold higher concentration in tumor tissue than in plasma [6]. Our past results have been supported by Winter et al. [21]. They reported that the efficacy of YM155 can be predicted by expression of SLC35F2, a solute carrier that has been known as the transporter of nucleotide sugars through biological membranes. Efforts are also underway to investigate the therapeutic effectiveness of YM155 in a subpopulation of patients who are selected based on a confirmed distribution of the drug at tumor sites, confirmed with positron emission tomography (PET) imaging. To explore the possibility of patient selection by PET imaging, we recently developed a radiosynthetic method for [11C]YM155 and found high tumor-to-blood and tumor-to-muscle accumulation ratios in nude mice [21]. In this study, we evaluated the relationship between intracellular concentration of YM155 and its GI50 values in 39 cancer cell lines. We also assessed in vivo tumor uptake of [11C]YM155 in YM155-sensitive and -insensitive tumors in mice using PET/CT, and measured the whole body distribution of [11C]YM155 in a monkey using PET.
Section snippets
Drugs
Sepantronium bromide (YM155) was synthesized by Astellas Pharma Inc. (Tokyo, Japan). For in vitro experiments, YM155 was dissolved in dimethyl sulfoxide (DMSO) and diluted in culture medium to a final DMSO concentration of ≤0.1% (v/v). For in vivo experiments, YM155 was dissolved and diluted in sterile saline immediately before administration. In the in vivo studies, dose levels are expressed in terms of the cationic moiety of YM155.
Cell lines
The origin and culture conditions of the human cancer cell
Correlation between YM155 intracellular concentration and GI50 in vitro for the different cell lines
To compare the concentration of YM155 in cells with its anti-proliferative efficacy, we examined the intracellular concentration of YM155 in the 39 human cancer cell lines in vitro (Fig. 2). The intracellular concentrations of YM155 on exposure to 1 μM YM155 for 4 h ranged from 4.1–169.3 pmol/mg protein (mean and SD, 61.5 ± 43.3 pmol/mg protein; median, 56.3 pmol/mg protein). Intracellular concentrations of YM155 closely correlated with the GI50 values of YM155(Pearson's r = −0.5709; p = 0.001).
Discussion
Sepantronium bromide (YM155), a small molecule survivin suppressant, has been investigated for the treatment of patients with several malignancies, including non-Hodgkin lymphoma, lung cancer, melanoma, and breast cancer [[14], [15], [16], [17], [18], [19]]. These trials demonstrated clinical benefit for some patients, but others experienced disease progression. Given those findings, effective use of YM155 requires that drug sensitivity be predicted before treatment is initiated. In this study,
Conclusions
[11C]YM155 tumor uptake correlates strongly with response to YM155 therapy and this PET tracer could be used to select patients with YM155-sensitive disease for treatment.
Acknowledgments
We thank Taishiro Kimura (Astellas Research Technologies Inc., Tokyo, Japan) and Jun Mizusawa (KAC Co., Ltd., Kyoto, Japan) for their technical assistance in animal handling, Masato Kobayashi (JFE Engineering Corporation, Tokyo, Japan) for operation of the cyclotron, and Dr. John Grierson (University of Washington) for critical reading of the manuscript. We thank Libby Cone, MD, MA, from DMC Corp. (www.dmed.co.jp <http://www.dmed.co.jp/>) for editing drafts of this manuscript.
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Cited by (1)
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Conflicts of Interest: This research was funded by Astellas Pharma Inc. All authors are employees of Astellas Pharma Inc.
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Note: This study was partly presented at the 2012 EANM Annual Meeting, Milan, Italy, October 27–31, 2012, PO524.