Surrogate biomarkers for assessing changes in pancreatic cancer tumor microenvironment

用于评估胰腺癌肿瘤微环境变化的替代生物标志物

• 批准号: 10654024
• 负责人: Marvin M Doyley
• 金额: $ 62万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654024
• 关键词: Address; Aftercare; Anatomy; Assessment tool; Blood Vessels; Cells; Characteristics; Chemotherapy and/or radiation; Clinical; Clinical Data; Clinical Research; Curative Surgery; Data; Development; Diagnosis; Diagnostic Imaging; Disease; Distal; Distant Metastasis; Drug Delivery Systems; Eligibility Determination; Endoscopic Ultrasonography; Excision; Fluorescence; Geometry; Histologic; Human; Hybrids; Hypoxia; Image; Imaging Device; Imaging Techniques; Immune; Immunofluorescence Immunologic; Immunology; Indocyanine Green; Intervention; Interventional Imaging; Knowledge; Love; Magnetic Resonance Elastography; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Measures; Metastatic Neoplasm to the Liver; Modulus; Mus; Neoadjuvant Therapy; Neoplasm Metastasis; Oncology; Operative Surgical Procedures; Optics; Pancreatic Ductal Adenocarcinoma; Pathologic; Pathology; Patients; Perfusion; Phenotype; Pre-Clinical Model; Qualifying; Radiation therapy; Radiology Specialty; Recurrence; Research; Resectable; Resistance; Resources; Structure; Surrogate Markers; Survival Rate; Techniques; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Tracer; Translating; Treatment Efficacy; Treatment Protocols; Tumor Markers; Visualization; Work; X-Ray Computed Tomography; chemoradiation; chemotherapy; contrast enhanced; curative treatments; density; effective therapy; elastography; experience; fighting; flexibility; gemcitabine; human disease; imaging biomarker; imaging system; improved; in vivo; innovation; mouse model; novel; pancreas imaging; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; patient response; patient subsets; perfusion imaging; pre-clinical; preclinical study; pressure; response; statistics; tomography; tool; treatment response; tumor; tumor diagnostic; tumor microenvironment; ultrasound

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.

胰腺导管腺癌（PDAC）是致命的，5年生存率小于10％。激进的 手术切除是唯一的治愈方法。但是，很少有胰腺癌患者患有可切除的疾病 诊断。对于一部分可切除肿瘤的患者，新辅助疗法可以在舞台下 该疾病并实现手术切除。病特征（即缺氧，高间隙密度，高 组织压力和大量免疫抑制细胞）降低了新辅助疗法的功效。 立体定向的身体放射疗法（SBRT）比传统的放射治疗更有效 PDAC，但并非所有肿瘤都反应灵敏。传统上，使用 解剖肿瘤测量值，但这是有限的，因为肿瘤大小通常与肿瘤无关 回复。为了改善这种情况，我们将建立一个从根本上建立新工具，以对PDAC肿瘤进行成像 增强可用的诊断成像。我们将推进剪切模量（SM）和血管灌注（VP） 作为评估肿瘤对新辅助疗法的反应的替代成像生物标志物。独特 有益的方法可以表征难以表征的肿瘤，该项目将结合外科前的，手术性的， 和分离后成像，并具有体内灌注评估和体内病理学。我们广泛的临床前 结果表明，SM和VP对原始特征的变化敏感。因此，我们 假设SM和VP变化是肿瘤微环境的直接诊断，可用于 评估治疗功效和反应。为了测试这一点，我们将将剪切波弹性图（SWE）与 氨基氨基绿色光学组织灌注示踪剂的光学荧光断层扫描（通常）评估 用于不同疗法的SM和吉西他滨灌注之间的相互作用，提供更全面的 有关肿瘤反应的信息。我们将开发一种新的混合成像工具，以系统地评估 在新辅助疗法期间，SM和VP通过两个特定的目的而变化：在AIM 1中，我们将进行临床前的 使用三种进行性PDAC鼠模型的研究，这些模型具有不同的特征，可以概括人类 疾病评估SM和VP与（a）基质密度的关系，（b）免疫支持细胞的数量， （c）SBRT，化学疗法和化学放疗治疗期间缺氧程度。在AIM 2中，我们将 临床翻译这项工作。我们将将介入的SWE和FAST成像与磁共振进行比较 弹性图（MRE）和动态对比度增强磁共振成像以评估肿瘤 SBRT，化学疗法和化学放疗治疗期间的微环境变化。我们也会表演 SWE在切除的PDAC上评估SM和VP与肿瘤微环境的变化之间的关系。这些新 成像特征是潜在的替代生物标志物，使临床医生能够认识到是否治疗 成功或失败。这种改变的信息将允许优化新辅助治疗 基于个性化患者的方案，导致更治愈的手术候选者。

项目成果

Reverberant magnetic resonance elastographic imaging using a single mechanical driver.

• DOI: 10.1088/1361-6560/acbbb7
• 发表时间: 2023-02-27
• 期刊: Physics in medicine and biology
• 影响因子: 3.5

Shear wave elastography can stratify rectal cancer response to short-course radiation therapy.

• DOI: 10.1038/s41598-023-43383-5
• 发表时间: 2023-09-26
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Mislati, Reem;Uccello, Taylor P.;Lin, Zixi;Iliza, Katia T.;Toussaint, Kimani C.;Gerber, Scott A.;Doyley, Marvin M.
• 通讯作者: Doyley, Marvin M.

Subsurface fluorescence time-of-flight imaging using a large-format single-photon avalanche diode sensor for tumor depth assessment.

• DOI: 10.1117/1.jbo.29.1.016004
• 发表时间: 2024-01
• 期刊: Journal of biomedical optics
• 影响因子: 3.5