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

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.

(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.

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.

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.

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.

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.