Image Biomarker Development for TreatmentEfficacy of Prostate Cancer to the Bone

描述（由申请人提供）：随着治疗方法的不断增加，骨内肿瘤的治疗已经取得了进展；然而，根据现有的临床反应标准（RECIST），对治疗的反应被认为是“不可测量的”。因此，肿瘤学家和放射学家用来监测骨骼中癌症反应的可用于评估治疗反应的生物标志物需要一个巨大的进步。这种需求的基础是骨是前列腺癌转移性肿瘤的常见居住地。使用骨骼闪烁成像、x线平片、计算机断层扫描或磁共振成像进行成像仍然是必不可少的，正电子发射断层扫描或单光子发射计算机断层扫描对诊断骨转移的存在具有潜在的适用性。然而，对于诊断这些病变或评估治疗反应的最佳方式，目前尚无共识。在这个应用中，我们假设肿瘤微环境的变化（如细胞密度）将在成功治疗开始后早期发生。由于肿瘤细胞内的水相对于细胞外的水处于受限的环境中，细胞膜完整性的丧失已被证明会降低肿瘤内水的扩散屏障（例如限制），这可以使用扩散MRI进行量化。我们最近开发了功能扩散图（fDM），这是一种成像生物标志物分析方法，用于量化治疗诱导的肿瘤组织内水的布朗运动变化。在本应用中，我们将评估fDM成像生物标志物在转移性前列腺癌小鼠骨模型中量化治疗反应的能力。评估的治疗方法包括电离辐射、细胞毒性化疗（多西紫杉醇）、抗血管生成治疗、分子靶向药物和雄激素剥夺。动物研究将提供所需的数据，支持fDM成像生物标志物用于量化关键治疗干预措施的有效性。临床研究还将评估fDM生物标志物作为雄激素剥夺或多西他赛化疗患者预后评估的早期治疗反应标志物。本应用的最终目标是评估fDM方法作为一种可行的、可量化的成像生物标志物，用于早期监测转移性前列腺癌患者对骨的治疗反应。公共卫生相关性：总的来说，这项研究将为启动细胞毒性和分子靶向治疗骨癌的联合临床研究提供进一步的理论依据。此外，用于早期评估治疗反应的成像生物标志物将被评估和验证，从而导致骨癌患者的个体化治疗。

DESCRIPTION (provided by applicant): The treatment of oncogenic lesions residing in bone has advanced with an ever increasing array of therapies; however, response to treatment is considered "unmeasurable" according to existing clinical response criteria (RECIST). Therefore, the biomarkers available for assessment of treatment response used by oncologists and radiologists to monitor the response of cancer in the bone needs a quantum advance. Underlying this need is that bone is a common site of residence of metastatic tumors derived from prostate cancer. Imaging using skeletal scintigraphy, plain radiography, computed tomography, or magnetic resonance imaging remains essential, with positron emission tomography or single-photon emission computed tomography having potential applicability for diagnosing the presence of bone metastases. However, no consensus exists as to the best modality for diagnosing these lesions or for assessing response to treatment. In this application, we hypothesize that changes in tumor microenvironment (e.g. cell density) will occur early following initiation of successful therapy. Since water within tumor cells is in a restricted environment versus extracellular water, loss of cell membrane integrity has been shown to reduce the diffusion barriers (e.g. restrictions) of water within the tumor, which can be quantified using diffusion MRI. We have recently developed the functional diffusion map (fDM) which is an imaging biomarker analytical approach for quantifying therapeutic-induced changes in the Brownian motion of water within tumor tissue. In this application, we will evaluate the capability of the fDM imaging biomarker for quantification of treatment response in a mouse model of metastatic prostate cancer to the bone. Treatments to be evaluated include ionizing radiation, cytotoxic chemotherapy (docetaxel), anti-angiogenic therapy, molecularly targeted agents and androgen deprivation. Animal studies will provide the data needed to support the use of the fDM imaging biomarker for quantification of the effectiveness of key therapeutic interventions. Clinical studies will also be undertaken to assess the fDM biomarker as an early treatment response marker for outcome assessment in patients treated with androgen deprivation or docetaxel chemotherapy. The ultimate goal of this application is to evaluate the fDM method as a viable, quantifiable imaging biomarker for early monitoring o treatment response in patients with metastatic prostate cancer to the bone. PUBLIC HEALTH RELEVANCE: Overall, this research effort will provide further rationale for initiation of clinical studies with combinations of cytotoxic and molecularly targeted therapies for the treatment of bone cancer. In addition, imaging biomarkers for early assessment of treatment response will be evaluated and validated leading to individualization of treatment for bone cancer patients.