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，骨内致癌病变的治疗也在不断发展;然而，根据现有临床缓解标准（RECIST），治疗缓解被认为是“不可测量的”。因此，肿瘤学家和放射科医生用于监测骨中癌症反应的生物标志物可用于评估治疗反应，需要取得巨大进展。这种需求的基础是骨是前列腺癌转移性肿瘤的常见驻留部位。使用骨骼CT、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要的，正电子发射断层扫描或单光子发射计算机断层扫描具有诊断骨转移存在的潜在适用性。然而，对于诊断这些病变或评估对治疗的反应的最佳方式还没有达成共识。在本申请中，我们假设肿瘤微环境（例如细胞密度）的变化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水处于受限环境中，因此细胞膜完整性的丧失已显示出降低肿瘤内水的扩散屏障（例如限制），这可以使用扩散MRI来量化。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。在本申请中，我们将评估FDM成像生物标志物用于定量转移性前列腺癌骨转移小鼠模型中治疗反应的能力。待评价的治疗包括电离辐射、细胞毒性化疗（多西他赛）、抗血管生成治疗、分子靶向药物和雄激素剥夺。动物研究将提供支持使用fDM成像生物标志物量化关键治疗干预有效性所需的数据。还将进行临床研究，以评估fDM生物标志物作为雄激素剥夺或多西他赛化疗患者结局评估的早期治疗应答标志物。本申请的最终目的是评价FDM方法作为一种可行的、可量化的成像生物标志物，用于早期监测骨转移性前列腺癌患者的治疗反应。公共卫生相关性：总体而言，这项研究工作将为启动细胞毒性和分子靶向疗法联合治疗骨癌的临床研究提供进一步的依据。此外，将对用于早期评估治疗反应的成像生物标志物进行评价和验证，从而实现骨癌患者治疗的个体化。

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.