Imaging Habitats in Sarcoma

肉瘤的成像栖息地

• 批准号: 9461334
• 负责人: Robert J. Gillies
• 金额: $ 24.99万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9461334
• 关键词: Acute; Affect; Algorithms; Area; Biochemistry; Blood Cells; Carcinoma; Caring; Cell Density; Cell Line; Child; Childhood; Clinic; Clinical; Connective Tissue; Data Set; Diffusion; Disease; Disease remission; Dose; Doxorubicin; Drug Targeting; Environment; Evaluation; Excision; Habitats; Half-Life; Histologic; Histology; Hypoxia; Image; Immunohistochemistry; In Vitro; Individual; Intention; 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; Phenotype; Physiologic pulse; Physiological; Physiology; Plasma; Preclinical Testing; Prodrugs; Progression-Free Survivals; Pyruvate; Radiology Specialty; 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; novel drug class; patient stratification; phase III trial; pre-clinical; predicting response; predictive marker; programs; public health relevance; response; sarcoma; treatment planning; treatment strategy; trial design; tumor; virtual

 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(申请人提供)：软组织肉瘤(STS)是一组不同类型的间叶组织癌，有50多种组织学亚型。无论是哪种类型，几乎所有的STS都得到相同的治疗；即，如果可能的话，先用阿霉素(DOX)，然后再切除。超过20%的STS是不可切除的，在那些不可切除的STS中，超过20%是复发的。对于不能切除或复发的患者，中位生存期为令人沮丧的18个月。也许是因为它的稀有，几十年来没有为STS开发新的一线药物。在为STS开发的较新药物中，TH-302表现出了非凡的前景。TH-302是一种烷基化前体药物，只在严重缺氧的区域激活，目前正在进行PHAS III试验，与DOX联合治疗无法切除的STS。这项试验的主要终点是总存活率，次要终点是RECIST 1.1的客观放射反应。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的反应的磁共振成像生物标记物，总体假设是不同的MRI定义的肿瘤亚区对这些药物有不同的反应。因为这些亚区是通过组合多个磁共振扫描而被照亮的不同的生理区域来定义的，所以我们将它们称为不同的“栖息地”。由于TH-302只有在低氧条件下才活跃，而低氧应由特定的栖息地代表，因此我们特别假设低氧栖息地的成像可以用于预测和监测对TH-302的反应。低氧生境被归类为低灌注量和高细胞密度。相比之下，对DOX敏感的栖息地应该是充分灌流的(产生更高的药物浓度)和高细胞密度(具有更多的药物靶点)。这代表了概念上的进步，因为这样的栖息地可以为患者分层和治疗决策支持提供跨多个组织学亚型的共同预测生物标记物。该方法将在初步工作之后进行，其中所描绘的栖息地被定量地确定在多种组织类型和等级的 STS通过组合T1、对比度增强的T1和T2来搅动MR图像。目前的建议完全是临床前的，期望这里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可能与潜在的组织学和分子图谱相关的更广泛的MRI脉冲序列和治疗策略。目的1将MR可见生境与异种移植肿瘤的组织学和分子图谱进行定量比较。目标2将验证这样的假设，即具有不同栖息地特征的肿瘤对DOX和/或TH-302的反应不同。在目标3中，我们将研究代谢扰动对低氧栖息地的影响，从而改善对TH-302的反应。在这项研究结束时，我们将开发一套新的磁共振成像生物标记物来预测和监测这一异质性疾病组的反应，期望这些发现将为临床的后续研究提供参考。