Surrogate biomarkers for assessing changes in pancreatic cancer tumor microenvironment

胰腺导管腺癌(PDAC)是一种致命性肿瘤，5年生存率不到10%。根部 手术切除是唯一的治愈选择；然而，很少有胰腺癌患者有可切除的疾病。 在诊断时。对于交界性可切除肿瘤的一部分患者，新辅助治疗可以降级。 并使手术切除成为可能。原肿瘤特征(即低氧、高间质密度、高 组织压力和大量免疫抑制细胞)会降低新辅助治疗的疗效。 立体定向全身放射治疗(SBRT)在降期方面比传统放射治疗更有效 PDAC，但不是所有的肿瘤都有反应。传统上，肿瘤的治疗反应是用 解剖肿瘤测量，但这是有限的，因为肿瘤大小通常与肿瘤无关 回应。为了改善这种情况，我们将建立一个全新的工具来对PDAC肿瘤进行成像 增强可用的诊断成像。我们将提高剪切模数(SM)和血管灌注量(VP) 作为评估肿瘤对新辅助治疗反应的替代成像生物标记物。以一种独特的方式 对于难以定性的肿瘤，这个项目将结合术前、术中和手术中的特点， 切除后的成像包括体内血流灌注评估和体外病理检查。我们广泛的临床前研究 结果表明，SM和VP对前肿瘤特性的改变很敏感。因此，我们 假设SM和VP的变化是肿瘤微环境的直接诊断，并可用于 评估治疗效果和反应。为了测试这一点，我们将结合横波弹性成像(SWE)和 吲哚青绿光学组织灌注示踪剂的荧光断层成像(OFT)评价 SM和吉西他滨对不同治疗方法的相互作用，提供更全面的 关于肿瘤反应的信息。我们将开发一种新的混合成像工具来系统地评估 SM和VP在新辅助治疗期间通过两个特定的目标而变化：在目标1中，我们将进行临床前 三种具有不同特征的进展性PDAC小鼠模型的研究 以评估SM和VP如何与(A)基质密度，(B)免疫支持细胞数量， 以及(C)SBRT、化疗和放化疗期间的缺氧程度。在目标2中，我们将 临床翻译这部作品。我们将把我们的介入性SWE和OFT成像与磁共振进行比较 弹性成像(MRE)和动态增强磁共振成像对肿瘤的评估 SBRT、化疗和放化疗过程中微环境的变化。我们还将表演 Swe切除PDAC以评估SM和VP与肿瘤微环境变化的关系。这些新的 影像特征是潜在的替代生物标志物，使临床医生能够识别治疗 成功或失败。这种改变实践的信息将允许新辅助治疗的优化 以患者个体化为基础的方案，从而产生更多有疗效的外科候选人。

Pancreatic ductal adenocarcinoma (PDAC) is lethal, with a 5-year survival rate of less than 10%. Radical surgical resection is the only curative option; however, few pancreatic cancer patients have resectable disease at diagnosis. For a subset of patients with borderline resectable tumors, neoadjuvant therapies can downstage the disease and enable surgical resection. Protumor characteristics (i.e., hypoxia, high stromal density, high tissue pressure, and a high number of immunosuppressive cells) reduce the efficacy of neoadjuvant therapies. Stereotactic body radiation therapy (SBRT) is more effective than traditional radiation therapy for downstaging PDAC, but not all tumors are responsive. Traditionally, tumor treatment response is evaluated using anatomical tumor measurements, but this is limited because tumor size often does not correlate with tumor response. To improve this situation, we will establish a fundamentally new tool to image PDAC tumors to augment the available diagnostic imaging. We will advance shear modulus (SM) and vascular perfusion (VP) as surrogate imaging biomarkers for assessing tumor response to neoadjuvant therapies. In a uniquely beneficial approach for a difficult tumor to characterize, this project will combine pre-surgical, intra-surgical, and post-resection imaging with in vivo perfusion assessment and ex vivo pathology. Our extensive pre-clinical results demonstrate that SM and VP are sensitive to changes in protumor characteristics. Therefore, we hypothesize that SM and VP changes are direct diagnostics of the tumor microenvironment and can be used to assess therapeutic efficacy and response. To test this, we will combine shear wave elastography (SWE) with optical fluorescence tomography (OFT) of indocyanine green optical tissue perfusion tracer to evaluate the interplay between SM and Gemcitabine perfusion for different therapies, providing more comprehensive information regarding tumor response. We will develop a new hybrid imaging tool to systematically assess how SM and VP vary during neoadjuvant therapies through two specific aims: In Aim 1, we will perform pre-clinical studies with three progressive PDAC murine models that have different features that recapitulate human disease to evaluate how SM and VP relate to (a) stromal density, (b) the number of immunosupportive cells, and (c) the degree of hypoxia during SBRT, chemotherapy, and chemoradiation therapy. In Aim 2, we will clinically translate this work. We will compare our interventional SWE and OFT imaging to magnetic resonance elastography (MRE) and dynamic-contrast-enhanced magnetic resonance imaging to assess tumor microenvironmental changes during SBRT, chemotherapy, and chemoradiation therapy. We will also perform SWE on excised PDAC to evaluate how SM and VP relates to tumor microenvironment changes. These new imaging features are potential surrogate biomarkers, enabling clinicians to recognize whether treatment succeeds or fails. This practice-changing information will allow for the optimization of neoadjuvant treatment protocols on an individualized patient basis, resulting in more curative surgical candidates.