Predicting response to sepantronium bromide (YM155), a survivin suppressant, by PET imaging with [11C]YM155

Abstract

Introduction: Sepantronium bromide (YM155) is a survivin suppressant that induces apoptosis in tumor cells. Although YM155 induces tumor regression in various tumor types in vivo, phase I and II studies demonstrated responding and non-responding patient populations. We investigated ¹¹C-labeled YM155 ([¹¹C]YM155) used as a positron emission tomography (PET) tracer to assess whether tumor uptake of [¹¹C]YM155 correlated with its anti-tumor effect, thereby allowing identification of patients who would respond to YM155 treatment.

Methods: (1) Uptake of YM155 was measured in 39 human cancer cell lines in vitro using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). (2) In vivo tumor uptake was assessed in xenografted mice and total body distribution was evaluated in a cynomolgus monkey using [¹¹C]YM155 with PET/computed tomography (CT) (mice) and PET (monkey) imaging.

Results: Intracellular uptake of YM155 in human cancer cell lines correlated well with its in vitro efficacy measured by GI₅₀ (Pearson's r = -0.5709). Similarly, in vivo studies using tumor xenografted mice showed that tumors sensitive to YM155 demonstrated robust uptake of [¹¹C]YM155, whereas insensitive tumors demonstrated low uptake. In the monkey, the biodistribution of [¹¹C]YM155 indicated low accumulation in lung, breast, head, and neck and was only significant in organs involved with drug clearance: i.e. liver, kidneys, and bladder.

Conclusions: Robust uptake of [¹¹C]YM155 by a tumor appears to be a positive predictive marker for a good response to YM155. The findings suggest the potential utility of PET/CT imaging with [¹¹C]YM155 for selection of patients whose tumors are likely to respond to YM155.

Advances in knowledge: YM155 efficacy correlated closely with its in vitro intracellular uptake and uptake on [¹¹C]YM155 PET imaging. [¹¹C]YM155 PET may predict tumor sensitivity to YM155.

Implications for patient care: The concept that tumor response can be accurately predicted prior to chemotherapy should be exploited to improve cancer treatment outcomes through judicious patient selection. The small molecule sepantronium bromide (YM155), a survivin suppressant, has been developed for the treatment of several cancers, including non-Hodgkin lymphoma, lung cancer, and breast cancer. The preferentially high in vitro uptake of YM155 by YM155-sensitive cancer cells and the high in vivo uptake of [¹¹C]YM155 in YM155-sensitive tumors demonstrated by PET imaging suggest the potential utility of performing [¹¹C]YM155 PET to allow the identification of patients with YM155-sensitive tumors.

Keywords: Apoptosis; Neoplasms; Positron emission tomography; Survivin; YM155.