PROGNOSTIC RADIOLOGY AND THE PATHOPHYSIOLOGY OF TUMORS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本研究的目的是全面了解与肿瘤生长、发展和治疗反应有关的肿瘤生理学。一些非核磁共振方法，如光学技术正在开发中，然而，我们继续进行与测量氧分压和酶激活相关的磁共振工作。具体地说，我们将开发、演示和评估一种评估肿瘤氧合的新方法，以期快速应用于临床。我们认为这将与前列腺癌等疾病的大剂量低分割放射治疗最为相关。DOCUNT(由核磁共振T1和T2*评估的动态氧气挑战)利用BOLD(血氧水平依赖)和TELD(组织氧水平依赖)，与使用质子MRI非侵入性检测肿瘤氧合变化形成对比。我们建议开发一种强有力的预后检测方法来揭示肿瘤的缺氧情况。 虽然这里建议的研究完全是临床前的，但我们相信它们将证明在患者身上快速实施的强大理由。目的1通过与19F磁共振血氧测定仪的比较，严格证明DOUMENT将肿瘤分类为低氧(耐药或敏感)或氧化的能力。目的2将检查DONCENT是否确实能预测皮下生长的前列腺癌对低分割放射治疗的反应。AIM 3将把研究扩展到原位前列腺癌。AIM 4将寻求通过包括辐射增强来克服缺氧肿瘤的治疗阻力。 该项目是对最近一次由NCI赞助的评估低氧成像现状的研讨会的结论做出的回应。人们一致认为，需要一种强有力的实用方法来识别缺氧性肿瘤患者。必要的标准涉及侵袭性、辐射暴露、分辨率、安全性和潜在临床实施的时间。一种大胆的方法被认为是特别实际的，加上TELD评估可以使其更加有用。 靶向肿瘤的血管系统有望为前列腺癌提供一种新的有效治疗方法。我们提出了一种针对肿瘤血管的新方法。具体地说，Thorpe等人开发了一种新的抗体3G4，它针对肿瘤血管上表达的磷脂酰丝氨酸(PS)。并由百富勤制药公司开发用于临床试验。正常情况下，PS仅存在于质膜的胞质小叶上。然而，在肿瘤中，PS变得外部化，并提供了一个可行的靶点。该药物不仅针对各种肿瘤，而且还能诱导血管损伤和肿瘤消退，伴随毒性最小。在开发一种新的治疗方法时，关键问题包括时间安排、与其他干预措施的最佳组合以实现协同作用和早期疗效评估。磁共振成像使我们能够跟踪肿瘤血管损伤的诱导和发展，为空间和时间活动提供新的见解，并促进与缺氧细胞选择性细胞毒素替拉帕明的有效结合。重要的是，这种疗法在肿瘤发展的任何阶段都可能有效，对晚期疾病可能最有效。成功将证实这种新的治疗方法在人类前列腺癌中的潜力，并为未来的临床试验奠定基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this research is to gain a comprehensive understanding of tumor physiology as related to tumor growth, development and response to therapy. A number of nonNMR approaches such as optical techniques are under development, However, we continue to pursue our MRI efforts related to measurement of oxygen tension and enzyme activation. Specifically, we will develop, demonstrate, and evaluate a novel approach to assessing tumor oxygenation with a view to rapid translation to the clinic. We believe it will be most pertinent to high dose hypofractionated radiotherapy in diseases such as prostate cancer. DOCENT (Dynamic Oxygen Challenge Evaluated by NMR T1 and T2*) exploits BOLD (blood oxygen level dependent) and TOLD (tissue oxygen level dependent) contrast to non-invasively detect changes in tumor oxygenation using proton MRI. We propose to develop DOCENT as a robust prognostic test to reveal tumor hypoxia. While the investigations proposed here are entirely pre-clinical, we believe they will demonstrate a strong rationale for rapid implementation in patients. Aim 1 will rigorously demonstrate the ability of DOCENT to categorize tumors as hypoxic (resistant or responsive) or oxic by comparison with 19F MR oximetry. Aim 2 will examine whether DOCENT does indeed predict response to hypofractionated radiation in subcutaneously growing prostate tumors. Aim 3 will extend studies to orthotopic prostate tumors. Aim 4 will seek to overcome therapeutic resistance of hypoxic tumors by including a radiation boost. This project responds to conclusions of a recent NCI-sponsored workshop to assess the current status of hypoxia imaging. There was consensus that a robust practical method is needed to identify patients with hypoxic tumors. Requisite criteria relate to invasiveness, radiation exposure, resolution, safety, and time to potential clinical implementation. A BOLD approach was considered to be particularly practical and the addition of the TOLD assessment can make it even more useful. Targeting the vasculature of tumors promises a new effective therapy for prostate cancer. We propose a new approach targeting the blood vessels in the tumor. Specifically, a novel antibody 3G4, which targets phosphatidylserine (PS) expressed on tumor vasculature was developed by Thorpe et al. and is being developed by Peregrine Pharmaceuticals for clinical trials. Normally, PS exclusively resides on the cytosolic leaflet of the plasma membrane. However, in tumors PS becomes externalized and provides a viable target. The agent not only targets various tumors, but also induces vascular damage and tumor regression with minimal accompanying toxicity. In developing a new therapy, critical issues include scheduling, optimal combination with other interventions to achieve synergy and early assessment of efficacy. Magnetic resonance imaging allows us to follow the induction and development of tumor vascular damage providing new insight into spatial and temporal activity and facilitating effective combination with the hypoxic cell selective cytotoxin tirapazamine. Importantly, this therapy may be effective at any stage of tumor development, and could be most effective for advanced disease. Success will confirm the potential of this new therapeutic approach to prostate cancer in man and lay the foundation for future clinical trials.