PROGNOSTIC RADIOLOGY AND THE PATHOPHYSIOLOGY OF TUMORS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究的目的是全面了解肿瘤生理学与肿瘤生长、发展和治疗反应的关系。 一些非核磁共振方法，如光学技术正在开发中，然而，我们继续追求我们的MRI努力与测量的氧张力和酶的活化。 具体来说，我们将开发，演示和评估一种新的方法来评估肿瘤氧合，以期快速转化为临床。我们相信，它将是最相关的高剂量低分割放射治疗的疾病，如前列腺癌。DOCENT（通过NMR T1和T2* 评估的动态氧挑战）利用BOLD（血氧水平依赖性）和TOLD（组织氧水平依赖性）对比度，使用质子MRI无创检测肿瘤氧合的变化。我们建议开发DOCENT作为一个强大的预后测试，以揭示肿瘤缺氧。 虽然本文提出的研究完全是临床前研究，但我们相信它们将证明在患者中快速实施的有力依据。目标1将通过与19 F MR血氧测定法进行比较，严格证明DOCENT将肿瘤分类为缺氧（耐药或反应性）或氧化的能力。目的2将检验DOCENT是否确实预测皮下生长的前列腺肿瘤对大分割放射的反应。目标3将研究扩展到原位前列腺肿瘤。目标4将寻求通过包括辐射增强来克服缺氧肿瘤的治疗抗性。 该项目响应了最近一次由国家癌症研究所主办的评估缺氧成像现状的研讨会的结论。人们一致认为，需要一种强大的实用方法来识别缺氧肿瘤患者。要求标准涉及侵入性、辐射暴露、分辨率、安全性和潜在临床实施时间。BOLD方法被认为是特别实用的，增加TOLD评估可以使其更加有用。 靶向肿瘤血管有望成为治疗前列腺癌的新的有效方法。我们提出了一种靶向肿瘤血管的新方法。具体而言，Thorpe等人开发了一种靶向肿瘤血管系统上表达的磷脂酰丝氨酸（PS）的新型抗体3G 4，Peregrine Pharmaceuticals正在开发该抗体用于临床试验。通常，PS仅存在于质膜的胞质小叶上。然而，在肿瘤中，PS变得外在化并提供了可行的靶点。该药剂不仅靶向各种肿瘤，而且诱导血管损伤和肿瘤消退，伴随的毒性最小。在开发新疗法时，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扎明的有效结合。重要的是，这种疗法可能在肿瘤发展的任何阶段都有效，并且可能对晚期疾病最有效。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.