A pre-clinical x-ray/optical tomography-guided radiation research platform for pancreatic cancer

临床前 X 射线/光学断层扫描引导的胰腺癌放射研究平台

• 批准号: 10302945
• 负责人: Ken Kang-Hsin Wang
• 金额: $ 1.83万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302945
• 关键词: pre; clinical; ray; optical; tomography

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease. Although surgery is the primary curative option, more than 75% of patients are ineligible and respond only transiently, to chemo- and radiotherapy (RT). New and effective treatment option is desperately needed. Recently, the development of RT as a therapeutic modulator for systemic treatment such as immunotherapy has cast the use of radiation into a pivotal role in the management of PDAC, inspiring several clinical trials. Given these early clinical studies, there is a compelling need to establish a clinically-relevant experimental system to further advance our understanding of the role of RT . A genetically engineered mouse model would provide a powerful model system to dissect the radiobiological mechanism of RT. The majority of PDAC (>90%) has somatic mutations in the KRAS signaling pathway. Importantly, using publicly available gene expression datasets, we found that TWIST1 is overexpressed in human PDAC which represents the most aggressive “squamous variant” subset of pancreatic cancer. We hypothesize that the generation of a pancreas specific Kras-Twist1 autochthonous mouse model provides an innovative resource to determine how TWIST1 contributes to tumorigenesis and progression. As for the important pre-clinical research to study treatment response of the murine PDAC model, radiation needs to mimic RT used for human. Such advanced technology is now available in the form of the small animal radiation research platform (SARRP) pioneered at our group. The SARRP is equipped with on- board cone-beam CT (CBCT) to guide irradiation. Recognizing that CBCT imaging is inadequate for localizing the PDAC growing in a low image contrast tissue environment, we innovated bioluminescence tomography (BLT) on board the SARRP to complement CBCT guidance. As an important complement, we engineered inducible Twist1-Luc gene expression in our PDAC model such that the disease progression can be monitored by bioluminescence imaging and the spontaneous PDAC can also be localized with BLT for radiation delivery. In response to PAR-16-176, we propose to integrate the inducible Kras-Twist1-Luc PDAC model and the CBCT-BLT-guided SARRP to establish a novel experimental system that will enable researchers to evaluate and develop new treatment options for human squamous variant PDAC in ways that have not been feasible before. To achieve this goal, we propose to (1) develop an inducible Twist1 transgenic autochthonous PDAC model and determine if Twist1 overexpression can cooperate with KrasG12D to accelerate PDAC tumorigenesis; (2) advance the targeting and quantitative imaging capabilities of the BLT-guided SARRP system for the PDAC model. The success of this proposal will provide a model system with strong pre-clinical foundation to study the effectiveness of combining radiation and other therapeutic agents for PDAC in great translational opportunity.

项目概要/摘要 胰腺导管腺癌（PDAC） 是一种致命的疾病。 虽然手术是主要的治疗方法 超过 75% 的患者不符合化疗和放疗 (RT) 的条件，且仅对化疗和放疗 (RT) 产生短暂反应。 迫切需要新的有效的治疗方案。最近，RT 作为一种治疗方法的发展 用于全身治疗（例如免疫疗法）的调节剂使放射的使用在治疗中发挥着关键作用 PDAC 的管理，启发了多项临床试验。鉴于这些早期的临床研究，有令人信服的证据 需要建立临床相关的实验系统，以进一步加深我们对其作用的理解 RT 。基因工程小鼠模型将提供一个强大的模型系统来剖析 RT的放射生物学机制。 大多数 PDAC (>90%) 的 KRAS 信号传导存在体细胞突变 途径。重要的是，使用公开的基因表达数据集，我们发现 TWIST1 在人类 PDAC 中过度表达，代表最具攻击性的“鳞状变体”子集 胰腺癌。我们假设胰腺特异性 Kras-Twist1 的产生是自发的 小鼠模型提供了一种创新资源来确定 TWIST1 如何促进肿瘤发生和 进展。对于研究小鼠PDAC模型治疗反应的重要临床前研究， 辐射需要模仿人类使用的 RT。这种先进的技术现在可以以 我们小组首创了小动物辐射研究平台（SARRP）。 SARRP 配备了 板锥束 CT (CBCT) 引导照射。认识到 CBCT 成像不足以定位 PDAC 在低图像对比度组织环境中生长，我们创新了生物发光断层扫描 (BLT) 纳入 SARRP 以补充 CBCT 指南。作为重要的补充，我们设计了 在我们的 PDAC 模型中诱导 Twist1-Luc 基因表达，以便监测疾病进展 通过生物发光成像，自发性 PDAC 也可以通过 BLT 进行定位以进行辐射传输。 为了响应 PAR-16-176，我们建议整合可诱导的 Kras-Twist1-Luc PDAC 模型和 CBCT-BLT 指导的 SARRP 建立了一个新颖的实验系统，使研究人员能够评估 并以以前不可行的方式为人类鳞状变异型 PDAC 开发新的治疗方案 前。为了实现这一目标，我们建议 (1) 开发诱导型 Twist1 转基因本土 PDAC 模型并确定Twist1过表达是否可以与KrasG12D协同加速PDAC肿瘤发生； (2) 提高PDAC BLT制导SARRP系统的瞄准和定量成像能力 模型。该提案的成功将为研究该疾病提供一个具有坚实临床前基础的模型系统。 结合放射治疗和其他 PDAC 治疗药物的有效性，具有巨大的转化机会。

项目成果

Development of a Mobile Fluorescence Tomography-guided System for Pre-clinical Radiotherapy Research.

开发用于临床前放射治疗研究的移动荧光断层扫描引导系统。

• DOI: 10.1364/ots.2020.sw1d.6
• 发表时间: 2020
• 期刊: Biomedical optics (Washington, D.C.)
• 作者: Hardy,Luke;Sforza,Daniel;Iordachita,Iulian;Xu,Xiangkun;Wong,JohnW;Wang,KenKang-Hsin
• 通讯作者: Wang,KenKang-Hsin

Geometric Reproducibility of Fiducial Markers and Efficacy of a Patient-Specific Margin Design Using Deep Inspiration Breath Hold for Stereotactic Body Radiation Therapy for Pancreatic Cancer.

• DOI: 10.1016/j.adro.2021.100655
• 发表时间: 2021-03
• 期刊: Advances in radiation oncology
• 影响因子: 2.3
• 作者: Han-Oh S;Hill C;Kang-Hsin Wang K;Ding K;Wright JL;Alcorn S;Meyer J;Herman J;Narang A
• 通讯作者: Narang A

Quantitative Bioluminescence Tomography for In Vivo Volumetric-Guided Radiotherapy.

• DOI: 10.1007/978-1-0716-1803-5_38
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)

Fiducial-based image-guided SBRT for pancreatic adenocarcinoma: Does inter-and intra-fraction treatment variation warrant adaptive therapy?

• DOI: 10.1186/s13014-021-01782-w
• 发表时间: 2021-03-19
• 期刊: Radiation oncology (London, England)
• 作者: Hill CS;Han-Oh S;Cheng Z;Wang KK;Meyer JJ;Herman JM;Narang AK
• 通讯作者: Narang AK