Imaging of alterations in SSTR2 expression with histone deacetylase (HDAC) inhibitors treatment for neuroendocrine tumors
Imaging of alterations in SSTR2 expression with histone deacetylase (HDAC) inhibitors treatment for neuroendocrine tumors
批准号:
10044579
负责人:
Renata Jaskula-Sztul
金额:
$38.18万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-07-07 至 2023-06-30
关键词:
AftercareAnimalsBiodistributionBiologicalCarcinoid TumorClinicClinical ManagementClinical TrialsDataDetectionDiagnosisDiagnostic SensitivityDiseaseDoseEpigenetic ProcessFDA approvedFibroblastsGenetic TranscriptionGoalsGoldHistone DeacetylaseHistone Deacetylase InhibitorHormonesHumanImageImaging TechniquesImmunohistochemistryIn VitroIslet Cell TumorLesionLungMaximum Tolerated DoseMeasuresMediatingMetabolicMethodsMusNeoplasmsNeuroendocrine TumorsOutcomePancreasPatient CarePatientsPharmaceutical PreparationsPharmacologyPlayPositron-Emission TomographyRadiation therapyRadiolabeledRadiopharmaceuticalsRoleSiteSomatostatin ReceptorStainsTechniquesTestingTherapeuticThyroid GlandTimeTissue MicroarrayTranslatingTranslationsTumor Cell LineUp-RegulationValproic AcidWI 38 cellWestern BlottingXenograft procedureanalogbasecancer imagingclinically translatablecurative treatmentsexperimental studyfluorodeoxyglucoseimaging agentimaging modalityimprovedin vivoin vivo evaluationmedullary thyroid carcinomamolecular imagingnovel strategiesoutcome predictionoverexpressionpatient stratificationreceptor densitysubcutaneoussugartargeted imagingtargeted treatmenttreatment strategytumortumor xenograftuptake
中文摘要
摘要
神经内分泌肿瘤(NET)是激素分泌肿瘤,包括类癌、胰岛细胞瘤和神经内分泌肿瘤。
甲状腺髓样癌NET的管理一直存在问题,因为这种疾病通常在
转移阶段,治疗选择有限。而基于正电子发射断层扫描(PET)/CT
在放射性标记的糖类似物[18F]FDG用于诊断和分期NETs时,由于
低代谢活性的肿瘤。最近,一种新批准的NET映像技术,
[68 Ga]DOTATATE PET/CT,特异性靶向生长抑素受体亚型2(SSTR 2),
标准,因为许多NET过表达SSTR 2。这种成像技术在患者护理中起着重要作用,
结果用于对SSTR 2靶向治疗的患者进行分层。然而,NET患者
通过成像确定的SSTR 2表达减少不适合任何类型的SSTR 2特异性
治疗在此,我们提出了一种方法,以加强和使这些患者的靶向治疗。我们有
发现表观遗传修饰剂,如组蛋白脱乙酰酶(HDAC)抑制剂:thailandepsin A(TDP-A)和
丙戊酸(VPA)可上调NET中SSTR 2的表达。我们的方法可能会导致一个新的
为治疗选择非常有限的NET患者提供有针对性的治疗策略。具体
本申请的目的是严格表征HDAC抑制剂增强的SSTR 2表达,
NET细胞系和异种移植物。我们建议使用金标准生物学方法评估这些变化,
然后将开发策略,以纵向,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转换成像技术。我们的中心假设是这些HDAC
抑制剂可以上调SSTR 2,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[177 Lu]DOTATATE进行后续SSTR 2靶向治疗。为了验证这一
假设,我们建议在两个具体目标中充分评估这种靶向治疗。首先,我们将使用非-
细胞毒性剂量的TDP-A和VPA诱导NET细胞系中的SSTR 2表达并阐明受体
密度和功能活性。在这个目标中,我们还将评估NET患者的SSTR 2基础表达。
组织微阵列(TMA)块(Aim 1)。接下来,我们将测试体内[68 Ga]DOTATATE摄取和生物分布。
由于使用NET异种移植物的靶上调。我们将采用一种高度平移的成像方法
使用[68 Ga]DOTATATE小剂量治疗前后NET异种移植物中SSTR 2表达的变化
动物PET/CT(Aim 2)。我们的长期目标是将这一新策略转化为改善成像,
通过特异性靶向增强的SSTR 2表达的潜在治愈性疗法。
英文摘要
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.
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会议论文
Targeted neuroendocrine cancer therapy using Verrucarin A
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批准号:10356245
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项目类别:
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资助金额:$20.83万
-
财政年份:2021
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负责人:Renata Jaskula-Sztul
-
依托单位:
Targeted neuroendocrine cancer therapy using Verrucarin A
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批准号:10538603
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项目类别:
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资助金额:$17.01万
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财政年份:2021
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负责人:Renata Jaskula-Sztul
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依托单位:
Somatostatin receptor 2 (SSTR2) antibody-drug conjugate for pancreatic neuroendocrine tumor (PanNET) therapy
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批准号:9895383
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项目类别:
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资助金额:$19.95万
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财政年份:2020
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负责人:Renata Jaskula-Sztul
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依托单位:
海外基金