Imaging Habitats in Sarcoma

肉瘤的成像栖息地

• 批准号: 9047257
• 负责人: Robert J. Gillies
• 金额: $ 43.89万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-06 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047257
• 关键词: Accounting; Affect; Area; Biochemistry; Blood Cells; Carcinoma; Caring; Cell Density; Cell Line; Child; Childhood; Clinic; Clinical; Connective Tissue; Data Set; Diagnostic Neoplasm Staging; Diffusion; Disease; Disease remission; Dose; Doxorubicin; Drug Targeting; Environment; Evaluation; Excision; Habitats; Half-Life; Health; Histology; Hypoxia; Image; Immunohistochemistry; In Vitro; Individual; Intention; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Measurable; Measures; Mesenchymal; Metabolic; Methods; Molecular; Molecular Profiling; Monitor; Morphology; Mus; New Agents; Oxygen; Oxygen Consumption; Patients; Perfusion; Pharmaceutical Preparations; Physiologic pulse; Physiological; Physiology; Plasma; Preclinical Testing; Prodrugs; Progression-Free Survivals; Pyruvate; Scanning; Schedule; Soft tissue sarcoma; Solid Neoplasm; Testing; Therapeutic; Therapeutic Effect; Therapy trial; Tissues; Toxic effect; Translating; Tumor Tissue; Tumor stage; Uncertainty; Unresectable; Vascular blood supply; Work; base; cancer cell; chemotherapy; contrast enhanced; expectation; flexibility; imaging biomarker; improved; in vivo; malignant breast neoplasm; patient stratification; phase III trial; pre-clinical; predicting response; predictive marker; programs; response; sarcoma; treatment planning; treatment strategy; trial design; tumor

 DESCRIPTION (provided by applicant): Soft tissue sarcomas (STS) are a heterogeneous group of mesenchymal tissue cancers, with over 50 histological sub-types. Regardless of type, virtually all STS are treated the same; i.e. with doxorubicin (DOX) followed by resection, if possible. More than 20% of STS are non-resectable and, of those that are, more than 20% recur. For non-resectable or recurring patients, median survival is a dismal 18 months. Perhaps because of its rarity, no new front-line agents have been developed for STS in decades. Among newer agents being developed for STS, TH-302 is showing exceptional promise. TH-302 is an alkylating pro-drug that is activated only in regions of severe hypoxia, and is currently in a phas III trial in combination with DOX in unresectable STS. The primary endpoint of this trial is overal survival with a secondary endpoint of objective radiological response with RECIST 1.1. RECIST responses rarely correlate with survival responses in soft tissue sarcomas, however. The purpose of this work is to develop MR imaging biomarkers that can predict response to DOX and/or TH-302, with the overarching hypothesis that distinct MRI-defined sub-regions of tumors will have differential responses to these agents. Because these sub-regions are defined by their distinct physiology illuminated by combining multiple MR scans, we have termed these as distinct "habitats". Because TH-302 is active only in hypoxia, and hypoxia should be represented by a specific habitat, we specifically hypothesize that imaging of the hypoxic habitat can be used to predict and monitor responses to TH-302. The hypoxia habitat is classified as having low perfusion and high cell density. In contrast, the DOX-responsive habitat should be well perfused (yielding higher drug concentrations) and have high cell density (with more drug targets). This represents a conceptual advance as such habitats may provide a common predictive biomarker across the multiple histological sub-types of STS for patient stratification and therapeutic decision support. The approach will follow on preliminary work, wherein delineated habitats were quantitatively identified across multiple histological types and grades of STS by combining T1, contrast- enhanced T1, and T2 STIR MR images. The current proposal is entirely pre-clinical, with the expectation that findings herein can be rapidly translated to clinial care. Preclinical work is justified in that there is greater flexibility to interrogate a wider porfolio of MRI pulse sequences and treatment strategies that can be related to underlying histology and molecular profiling. Aim 1 will quantitatively compare MR-visible habitats to histology and molecular profiles of xenotransplanted tumors. Aim 2 will test the hypothesis that tumors with different habitat profiles will be differentially responsive to DOX and/or TH-302. In Aim 3, we wil investigate the effects of metabolic perturbations to affect the hypoxic habitat and thus improve response to TH-302. At the end of this study, we will have developed a new set of MR imaging biomarkers for predicting and monitoring response in this heterogeneous group of diseases, with the expectation that these finding will inform a follow-on study in the clinic.

 描述（由适用提供）：软组织肉瘤（STS）是一组异质组织癌的异质组，具有50多个组织学亚型。无论类型如何，几乎所有的ST都被对待相同。即，如果可能的话，用阿霉素（dox）进行切除。超过20％的ST是不可察觉的，其中有超过20％的重复发生。对于不可切除或反复出现的患者，中位生存期是一个令人沮丧的18个月。也许由于它的稀有性，几十年来没有开发新的前线代​​理。在为STS开发的新代理商中，TH-302表现出非凡的承诺。 TH-302是一种仅在严重缺氧区域中激活的烷基化促毒液，目前正在PHAS III试验中与DOX结合使用，在无法切除的STS中。该试验的主要终点是生存期，其次要放射学反应的次要终点与recist 1.1。但是，恢复反应很少与软组织肉瘤中的生存反应相关。这项工作的目的是开发MR成像生物标志物，可以预测对DOX和/或TH-302的反应，并具有总体假设，即明显的MRI定义的肿瘤子区域将对这些药物具有不同的反应。由于这些子区域是通过将多个MR扫描结合起来阐明的独特生理学来定义的，因此我们将其称为不同的“栖息地”。由于TH-302仅在缺氧中活跃，并且缺氧应由特定的栖息地表示，因此我们特别假设低氧栖息地的成像可用于预测和监测对TH-302的反应。缺氧栖息地被归类为低灌注和高细胞密度。相反，DOX反应性栖息地应充分灌注（产生较高的药物浓度）并具有高细胞密度（具有更多的药物靶标）。这代表了概念上的进步，因为此类栖息地可能会在STS的多种组织学子类型中提供常见的预测生物标志物，以用于患者分层和治疗决策。该方法将遵循初步工作，其中在多种组织学类型和等级中定量鉴定了所述的栖息地 通过将T1，对比增强的T1和T2搅拌MR图像结合使用ST。当前的提议完全是临床前的，期望此处的发现可以迅速转化为临床护理。临床前的工作是合理的，因为它具有更大的灵活性来审问可能与潜在的组织学和分子分析有关的MRI脉冲序列和治疗策略。 AIM 1将定量将MR可见栖息地与异种移植肿瘤的组织学和分子谱进行比较。 AIM 2将检验以下假设：具有不同栖息地特征的肿瘤对DOX和/或TH-302的反应有所不同。在AIM 3中，我们将研究代谢扰动影响低氧栖息地的影响，从而改善对TH-302的反应。在这项研究结束时，我们将开发一组新的MR成像生物标志物，用于预测和监测这种异质疾病组中的反应，并期望这些发现将为诊所中的一项后续研究提供信息。