Imaging of alterations in SSTR2 expression with histone deacetylase (HDAC) inhibitors treatment for neuroendocrine tumors

摘要 神经内分泌肿瘤是一种分泌激素的肿瘤，包括类癌、胰岛细胞瘤和 甲状腺髓样癌。NETS的管理一直存在问题，因为这种疾病通常在 治疗选择有限的转移期。而正电子发射断层扫描(PET)/CT 在放射性标记的糖类似物[18F]FDG被用来诊断和阶段网络，它往往是次优的，因为 这些肿瘤的代谢活性低。最近，一种新批准的网络成像技术， [68Ga]针对生长抑素受体亚型2(SSTR2)的DOTATATE PET/CT正变得越来越多 标准，因为许多网络过度表达SSTR2。这种成像技术在病人护理中扮演着重要的角色 结果被用来对SSTR2靶向治疗的患者进行分层。然而，Net患者与 成像确定的SSTR2表达减弱不符合任何类型的SSTR2特异性 治疗。在这里，我们提出了一种方法，以加强和启用针对这些患者的靶向治疗。我们有 发现表观遗传修饰物，如组蛋白脱乙酰酶(HDAC)抑制剂：TDP-A和TDP-A 丙戊酸(VPA)可上调Net中SSTR2的表达。我们的方法可能会导致一种新的 针对治疗选择非常有限的网络患者的有针对性的治疗策略。具体的 本应用的目的是严格表征HDAC抑制剂增强的SSTR2的表达 Net细胞系和异种移植。我们建议使用黄金标准生物学方法和 然后将制定策略，以纵向的、非侵入性的方式在体内验证这种上调 现有最先进的临床可翻译成像技术。我们的中心假设是这些HDAC 抑制剂可以上调SSTR2，这可以通过先进的成像技术进行评估，从而使患者 有资格使用放射治疗性[177 Lu]DOTATE进行后续的SSTR2靶向治疗。为了测试这一点 假设，我们建议从两个特定的目标来全面评估这一靶向治疗。首先，我们将使用非 TDP-A和VPA细胞毒剂量诱导Net细胞表达SSTR2及其受体的研究 密度和功能活性。为此，我们还将评估Net患者SSTR2的基础表达。 组织芯片(TMA)块(Aim1)。接下来，我们将测试[68Ga]DOTATE在体内的摄取和生物分布 作为使用网络异种移植靶点上调的结果。我们将进行一种高度平移的成像方法 [68Ga]DOTATE Small治疗前后移植瘤SSTR2表达变化的研究 动物PET/CT(AIM2)。我们的长期目标是将这一新颖的战略转化为更好的成像和 通过特异性靶向增强SSTR2的表达进行潜在的治疗。

ABSTRACT Neuroendocrine tumors (NETs) are hormone secreting neoplasms, including carcinoids, islet cell tumors, and medullary thyroid cancers. Management of NETs has been problematic since the disease is often diagnosed at metastatic stage when therapeutic options are limited. While, Positron Emission Tomography (PET)/CT based on the radiolabeled sugar analogue [18F]FDG is used to diagnose and stage NETs, it is often suboptimal due to low metabolic activity in these tumors. More recently, a newly approved technique for NET imaging, [68Ga]DOTATATE PET/CT, that specifically targets somatostatin receptor subtype 2 (SSTR2) is becoming more standard, as many NETs overexpress SSTR2. This imaging technique plays an important role in patient care as the outcomes are used to stratify patients for SSTR2 targeted treatment. However, NET patients with diminished SSTR2 expression as determined by imaging are not eligible for any type of SSTR2-specific treatment. Herein, we propose a method to enhance and enable targeted therapies for these patients. We have found that the epigenetic modifiers such as histone deacetylase (HDAC) inhibitors: thailandepsin A (TDP-A) and valproic acid (VPA) can upregulate the expression of SSTR2 in NETs. Our approach will likely result in a new targeted treatment strategy for NET patients who have very limited therapeutic options. The specific objective of this application is to rigorously characterize the HDAC inhibitors enhanced SSTR2 expression in NET cell lines and xenografts. We propose to assess these changes using gold standard biological methods and will then develop strategies to validate this upregulation in vivo in a longitudinal, non-invasive manner using existing state-of-the-art clinically translatable imaging techniques. Our central hypothesis is that these HDAC inhibitors can upregulate SSTR2 which can be assessed by advanced imaging techniques thus making patients eligible for subsequent SSTR2 targeted therapy with the radiotherapeutic [177Lu]DOTATATE. To test this hypothesis, we propose to fully evaluate this targeted therapy in two Specific Aims. First, we will use a non- cytotoxic dose of TDP-A and VPA to induce SSTR2 expression in NET cell lines and elucidate the receptor density and functional activity. In this aim, we will also assess the SSTR2 basal expression in NET patients’ tissue microarray (TMA) blocks (Aim1). Next, we will test the in vivo [68Ga]DOTATATE uptake and biodistribution as a result of target upregulation using NET xenografts. We will conduct a highly translational method of imaging of SSTR2 expression alterations in NET xenografts before and after treatment using [68Ga]DOTATATE small animal PET/CT (Aim2). Our long-term goal is to translate this novel strategy to achieve improved imaging and potential curative therapy through the specific targeting of enhanced SSTR2 expression.