Imaging Habitats in Sarcoma

 描述（由申请人提供）：软组织肉瘤（STS）是一组异质性间叶组织癌，具有超过50种组织学亚型。无论哪种类型，几乎所有STS的治疗方法都是相同的;即使用阿霉素（DOX），然后切除，如果可能的话。超过20%的STS是不可切除的，并且在那些不可切除的STS中，超过20%复发。对于不可切除或复发的患者，中位生存期为18个月。也许是因为它的稀有性，几十年来没有为STS开发新的前线代理商。在为STS开发的新药剂中，TH-302显示出非凡的前景。TH-302是一种烷基化前药，仅在严重缺氧区域活化，目前正在与DOX联合治疗不可切除STS的III期临床试验中。本试验的主要终点是总生存期，次要终点是客观放射学缓解（RECIST 1.1）。然而，在软组织肉瘤中，RECIST反应很少与生存反应相关。这项工作的目的是开发可以预测对DOX和/或TH-302的反应的MR成像生物标志物，其总体假设是不同的MRI定义的肿瘤子区域将对这些药物具有不同的反应。因为这些子区域是由它们通过结合多个MR扫描而照亮的不同生理学来定义的，所以我们将这些称为不同的“栖息地”。因为TH-302仅在缺氧中有活性，并且缺氧应该由特定的栖息地表示，我们特别假设缺氧栖息地的成像可以用于预测和监测对TH-302的反应。缺氧生境被分类为具有低灌注和高细胞密度。相比之下，DOX反应的栖息地应该是灌注良好的（产生更高的药物浓度），并具有高细胞密度（具有更多的药物靶点）。这代表了概念上的进步，因为这种栖息地可以在STS的多种组织学亚型中提供共同的预测生物标志物，用于患者分层和治疗决策支持。该方法将遵循的初步工作，其中划定的栖息地定量确定跨多种组织学类型和等级的 通过结合T1、对比增强T1和T2 STIR MR图像进行STS。目前的建议完全是临床前的，期望本文的发现可以迅速转化为临床护理。临床前工作是合理的，因为有更大的灵活性来询问更广泛的MRI脉冲序列和治疗策略，可以与潜在的组织学和分子谱。目的1将定量比较MR可见的栖息地异种移植肿瘤的组织学和分子特征。目的2将检验具有不同生境特征的肿瘤将对DOX和/或TH-302有差异性响应的假设。在目标3中，我们将研究代谢扰动影响缺氧生境的作用，从而改善对TH-302的反应。在本研究结束时，我们将开发一套新的MR成像生物标志物，用于预测和监测这种异质性疾病组的反应，并期望这些发现将为临床后续研究提供信息。

 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.