Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland.
Clinical Radiopharmacy, Department of Clinical Research, University Hospital Bern, Bern, Switzerland.
J Nucl Med. 2016 Nov;57(11):1805-1810. doi: 10.2967/jnumed.115.165092. Epub 2016 Jun 30.
Targeted diagnosis and therapy enable precise tumor detection and treatment. Successful examples for precise tumor targeting are diagnostic and therapeutic radioligands. However, patients with tumors expressing low levels of the relevant molecular targets are deemed ineligible for such targeted approaches.
We performed a screen for drugs that upregulate the somatostatin receptor subtype 2 (sstr). Then, we characterized the effects of these drugs on transcriptional, translational, and functional levels in vitro and in vivo.
We identified 9 drugs that act as epigenetic modifiers, including the inhibitor of DNA methyltransferase decitabine as well as the inhibitors of histone deacetylase tacedinaline and romidepsin. In vitro, these drugs upregulated sstr on transcriptional, translational, and functional levels in a time- and dose-dependent manner. Thereby, their combinations revealed synergistic effects. In vivo, drug-based sstr upregulation improved the tumor-to-background and tumor-to-kidney ratios, which are the key determinants of successful sstr-targeted imaging and radiopeptide therapy.
We present an approach that uses epigenetic modifiers to improve sstr targeting in vitro and in vivo. Translation of this method into the clinic may potentially convert patients ineligible for targeted imaging and therapy to eligible candidates.
靶向诊断和治疗能够实现精确的肿瘤检测和治疗。成功的精确肿瘤靶向治疗的例子是诊断和治疗放射性配体。然而，表达低水平相关分子靶标的肿瘤患者被认为不符合此类靶向方法的条件。
我们进行了筛选，以寻找上调生长抑素受体亚型 2（sstr）的药物。然后，我们在体外和体内研究了这些药物在转录、翻译和功能水平上的作用。
我们确定了 9 种作为表观遗传修饰剂的药物，包括 DNA 甲基转移酶抑制剂地西他滨以及组蛋白去乙酰化酶抑制剂 tacedinaline 和 romidepsin。在体外，这些药物以时间和剂量依赖的方式在转录、翻译和功能水平上上调 sstr。因此，它们的组合显示出协同作用。在体内，基于药物的 sstr 上调提高了肿瘤与背景和肿瘤与肾脏的比值，这是成功进行 sstr 靶向成像和放射性肽治疗的关键决定因素。
我们提出了一种使用表观遗传修饰剂来提高体外和体内 sstr 靶向性的方法。将这种方法转化为临床应用可能会使那些不符合靶向成像和治疗条件的患者转化为合格的候选者。
