Macro-to-micro (M2µ) Activity Apportionment for αRPT
αRPT 的宏观到微观 (M2µ) 活动分配
基本信息
- 批准号:10713712
- 负责人:
- 金额:$ 49.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-19 至 2028-08-31
- 项目状态:未结题
- 来源:
- 关键词:Alpha Particle EmitterAlpha ParticlesAnatomyAnimalsAntibodiesBone MarrowClinicalClinical TrialsCombined Modality TherapyDataDoseDose LimitingDrug KineticsERBB2 geneFDA approvedFOLH1 geneFamily suidaeFractionationGoalsHumanImageKidneyLacrimal gland structureLinkLiteratureLiverLungMalignant NeoplasmsMalignant neoplasm of prostateMeasurementMeasuresMedicineMetastatic Neoplasm to the BoneMethodologyMethodsMicroscopicMiniature SwineModalityModelingMusOrganOrgan ModelPatientsPeptidesPre-Clinical ModelProcessPublishingRadiobiologyRadioisotopesRadiopharmaceuticalsReportingRiskSalivary GlandsSmall IntestinesStandardizationTestingTherapeuticTherapeutic UsesTimeToxic effectTranslatingTranslationsUncertaintyUnited States National Institutes of HealthWorkabsorptioncancer therapyclinical practiceclinically relevantdesigndosimetryinterestmouse modelparticleparticle therapyporcine modelpre-clinicalpredicting responseprogramsresponsesingle photon emission computed tomographysmall moleculespatiotemporaltargeted deliverytargeted treatmenttranslation to humanstreatment planning
项目摘要
Recent advances in the targeted delivery of radionuclides and the increased availability of -emitters appropriate
for clinical use have led to patient trials of multiple α-emitter radiopharmaceutical therapeutics (RPTs). One of
these, Xofigo (223RaCl2) was FDA-approved and is in routine clinical practice, with many others likely to follow.
One of the stated goals (pillars) of the NIH is a greater level of personalization in medicine. In the realm of
radiopharmaceutical therapy (RPT) this translates directly as a need for more accurate personalized dosimetry
in order to enable fractionation and administered activity tailored to each patient. However, current dosimetry
paradigms are poorly suited to RPT. This reality is reflected by the discrepancies between clinical (or
experimental) toxicity and expected toxicity calculated using standard organ-level (or voxel-level) dosimetry,
including most notably: (a) hematotoxicity in 223Ra therapy of bone metastases, (b) renal and salivary gland
toxicity in pre-clinical models and patients. The objective of this work is to create a dosimetric methodology more
suited to αRPT, namely the Macro to micro (M2) methodology, which requires sub-organ activity apportionment
factors for organs at risk. This will be accomplished via the following Aims: 1. In murine models, measure αRPT
activity concentration in selected whole organs and in relevant organ sub-regions; generate apportionment factor
histograms. The translation to human assumes that the link between macroscopic and microscopic
spatiotemporal relationship for a given agent measured in a pre-clinical model will apply to the human as the
distribution of the agent to the different microscopic compartments should remain the same. We will test and
quantify the validity of this assumption and refine the human apportionment factors by introducing a third species,
the mini-pig In Aim 2. We will assess apportionment factor transferability, by obtaining corresponding
apportionment factor histograms for a porcine model. In Aim 3. We will demonstrate that M2µ predicts toxicity in
the porcine model. 4. Apply the M2µ methodology to clinical trial data to quantify the potential benefit of
personalized M2µ dosimetry and/or derive dose–response relationships. Successful completion of the proposal
will reconcile experimental and clinical results not currently understood and provide a robust standardized
dosimetry for personalized dosimetry-based treatment planning of αRPT. Such standardization will enable the
dosimetry to be normalized to EQD2, thus enabling rational combinations with other RPTs or external beam
therapy as well as relevant absorbed dose reporting. Here we plan to expand this approach to encompass the
wide range of RPT/organ combinations that have either been shown to be or are potentially dose-limiting and
that require the Macro to micro (M2) methodology to properly correlate dosimetry with toxicity thresholds and
provide a deliverable that will allow end-users to convert macroscopically-measured activity to standardized
dosimetry at the organ and (clinically relevant) sub-organ-level for a wide range of RPTs and correspondingly
relevant organs.
最近在放射性核素定向投放方面取得的进展以及适当的放射性核素发射器供应的增加,
用于临床的放射性药物疗法(α-emitter radiopharmacological therapeutic,α-RPTs)的临床试验。之一
Xofigo(223 RaCl 2)已获得FDA批准,并已进入常规临床实践,许多其他药物可能会跟进。
NIH的既定目标(支柱)之一是更高水平的医学个性化。领域的
放射性药物治疗(RPT),这直接转化为需要更准确的个性化剂量测定
以便能够针对每个患者进行分级和施用的活性。然而,目前的剂量测定
范式不太适合非RPT。这一现实反映在临床(或
实验)毒性和使用标准器官水平(或体素水平)剂量测定法计算的预期毒性,
最显著地包括:(a)骨转移的223 Ra治疗中的血液毒性,(B)肾和唾液腺
临床前模型和患者中的毒性。这项工作的目的是建立一个剂量测定方法,
适用于αRPT,即宏观到微观(M2)方法,该方法需要子器官活动分配
危险器官的因素。这将通过以下目标来实现:1。在鼠模型中,测量αRPT
选定的整个器官和相关器官子区域中的放射性浓度;生成分配因子
直方图翻译成人类假设宏观和微观之间的联系
在临床前模型中测量的给定药剂的时空关系将应用于人类,
试剂在不同显微室中的分布应保持相同。我们将测试和
量化这一假设的有效性,并通过引入第三个物种来完善人类分配因子,
迷你猪In Aim 2我们将评估分摊系数的可转移性,
猪模型的分配因子直方图。目标3.我们将证明M2µ预测毒性,
猪的模型4.将M2µ方法应用于临床试验数据,以量化
个性化M2µ剂量测定和/或推导剂量-反应关系。成功完成提案
将协调目前尚不清楚的实验和临床结果,并提供一个强大的标准化
αRPT基于剂量测定的个性化治疗计划的剂量测定。这种标准化将使
将剂量测定标准化为EQD 2,从而能够与其他RPT或外部射束合理组合
治疗以及相关的吸收剂量报告。在这里,我们计划扩展这种方法,以包括
已显示或潜在具有剂量限制性的广泛的ARRPT/器官组合,
这需要宏观到微观(M2/M)方法,以正确地将剂量测定与毒性阈值相关联,
提供一个可交付成果,使最终用户能够将宏观衡量的活动转换为标准化的活动。
在器官和(临床相关)亚器官水平上对各种RPT进行剂量测定,
有关机关。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Robert Francois Hobbs其他文献
Robert Francois Hobbs的其他文献
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{{ truncateString('Robert Francois Hobbs', 18)}}的其他基金
Combination Radiopharmaceutical Therapy and External Beam Radiotherapy
放射药物治疗与外照射放射治疗的联合治疗
- 批准号:
10473785 - 财政年份:2020
- 资助金额:
$ 49.89万 - 项目类别:
Combination Radiopharmaceutical Therapy and External Beam Radiotherapy
放射药物治疗与外照射放射治疗的联合治疗
- 批准号:
10252753 - 财政年份:2020
- 资助金额:
$ 49.89万 - 项目类别:
Combination Radiopharmaceutical Therapy and External Beam Radiotherapy
放射药物治疗与外照射放射治疗的联合治疗
- 批准号:
10668390 - 财政年份:2020
- 资助金额:
$ 49.89万 - 项目类别:
Modeling Targeted Alpha Particle Therapy of Cancer
癌症靶向阿尔法粒子治疗建模
- 批准号:
8295112 - 财政年份:2012
- 资助金额:
$ 49.89万 - 项目类别:
Modeling Targeted Alpha Particle Therapy of Cancer
癌症靶向阿尔法粒子治疗建模
- 批准号:
8468664 - 财政年份:2012
- 资助金额:
$ 49.89万 - 项目类别:
Modeling Targeted Alpha Particle Therapy of Cancer
癌症靶向阿尔法粒子治疗建模
- 批准号:
8658040 - 财政年份:2012
- 资助金额:
$ 49.89万 - 项目类别:
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