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.

项目摘要/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愈性 选项，超过75％的患者没有资格，并且仅对化学和放射疗法（RT）做出反应。 迫切需要新的有效的治疗选择。最近，RT作为一种疗法的发展 用于全身治疗的调节剂，例如免疫疗法已将辐射的使用变为关键作用 PDAC的管理，启发了几项临床试验。鉴于这些早期的临床研究，有令人信服的 需要建立一个与临床相关的实验系统，以进一步促进我们对 RT 一般设计的鼠标模型将提供强大的模型系统，以剖析 RT的放射生物学机制。 大多数PDAC（> 90％）在KRAS信号中具有体细胞突变 路径。重要的是，使用公开可用的基因表达数据集，我们发现Twist1是 在人类PDAC中过表达，它代表了最具侵略性的“鳞状变体”子集 胰腺癌。我们假设胰腺特异性Kras-Twist1自动摄取的产生 鼠标模型提供了一种创新的资源，以确定Twist1如何对肿瘤发生和 进展。至于重要的临床前研究，以研究鼠PDAC模型的治疗反应， 辐射需要模仿用于人类的RT。现在，这种先进的技术现在以 小型动物辐射研究平台（SARRP）在我们的小组中率先进行。 SARRP等于 板锥束CT（CBCT）指导辐射。认识到CBCT成像不足以定位 在低图像对比组织环境中生长的PDAC，我们是创新的生物发光断层扫描 （BLT）在SARRP上以补充CBCT指导。作为重要的完成，我们设计了 在我们的PDAC模型中诱导的扭曲1-luc基因表达，以便可以监测疾病进展 通过生物发光成像和赞助PDAC也可以与BLT定位，以进行辐射递送。 为了响应16-176 par，我们建议将诱导的Kras-Twist1-Luc PDAC模型和该模型整合在一起 CBCT-BLT引导的SARRP建立了一个新型的实验系统，该系统将使研究人员能够评估 并以不可行的方式为人类鳞状变体PDAC开发新的治疗选择 前。为了实现这一目标，我们建议（1）开发诱导型Twist1转基因自pdac 模型并确定Twist1的过表达是否可以与Krasg12d坐标以加速PDAC肿瘤发生； （2）推进BLT引导SARRP系统的靶向和定量成像功能 模型。该提案的成功将为模型系统提供强大的临床前基础，以研究 在巨大的转化机会中，将辐射和其他治疗剂相结合的有效性。

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