Bayesian bioluminescence image reconstruction for therapy monitoring of hormone-r

描述(申请人提供)：激素抵抗型肿瘤是最致命的前列腺癌。目前还没有治愈这些非常侵袭性和高度转移性肿瘤的患者。因此，为晚期前列腺癌患者设计有效的治疗方法对于提高患者的生存和生活质量是非常必要的。了解不同的细胞信号通路是如何导致这种致命疾病的，对于治疗开发也是绝对关键的。事实上，灵敏的成像技术可以在激素抵抗型前列腺癌的小动物模型中洞察这些分子机制。此外，在体内监测肿瘤的发展也可以评估前列腺癌治疗的即时反应。因此，生物发光成像已经成为动物肿瘤发展成像的有力工具，但定量成像还不可能。为了确定用于治疗评估的实际肿瘤质量，仍然需要在治疗终点处死动物。因此，发展一种新的断层生物发光成像方法，可以在体内和研究过程中的所有时间点直接确定肿瘤体积，对于开发这种高效的治疗方法具有极其重要的意义。这一应用的主要假设是，在激素抵抗型前列腺癌的小动物模型中，生物发光图像重建方法将在治疗期间的所有中间时间点提供关于肿瘤生长/退化的详细体积信息。我们的技术将有助于测试哪些特定的药物和疗法可以在体内阻止激素难治性前列腺癌，因此，将极大地帮助治疗开发并促进其转化为临床。我们将重点关注支持这一假说的两个具体目标。首先，我们将开发一种具有熵先验和进化策略的多光谱多视角贝叶斯图像重建方法，用于对组织内未知生物发光源分布的全局搜索空间进行采样。我们的方法将采用基于SPN方程的高阶辐射传输模型和曲线几何形状的自适应网格加密方法。我们还将在动物床上实现MRI和CT的联合配准方法，以将解剖组织结构纳入图像重建过程。其次，我们将重建荷尔蒙耐药前列腺癌Nkx3.1/Pten小鼠模型治疗过程中肿瘤体积的变化。我们将通过测定治疗过程中不同时间点肿瘤体积的微小变化来研究Akt/mTOR和B-Ref/Erk Map Kinase信号通路的药理学操作。 公共卫生相关性：贝叶斯生物发光图像重建方法将有助于在小动物模型中测试哪些特定的药物和治疗方法可以阻止激素抵抗型前列腺癌。它不仅将大大帮助临床前研究中的治疗发展，而且还将促进其转化为临床。因此，建议的成像方法将有很大可能直接影响男性前列腺癌患者的治疗，并将提高存活率。

DESCRIPTION (provided by applicant): Hormone-refractory tumors are the most deadly form of prostate cancer. There is currently no cure for patients with these very aggressive and highly metastatic tumors. Thus, the design of effective therapies for patients with such advanced prostate cancer is very essential for increasing patient survival and quality of life. It also is absolutely critical for therapy development to understand how different cell signaling pathways give rise to this deadly disease. In fact, sensitive imaging technology could give insight into these molecular mechanisms in a small animal model of hormone-refractory prostate cancer. Moreover, in vivo monitoring of tumor development could also assess immediate responses to prostate cancer therapy. Hence, bioluminescence imaging has already become a powerful tool for imaging tumor development in animals, but quantitative imaging has not been possible yet. Animals still need to be sacrificed at the endpoint of therapy in order to determine the actual tumor mass for therapy evaluation. Therefore, the development of a novel tomographic bioluminescence imaging method, where tumor volume can directly be determined in vivo and at all time points during studies, is of utmost significance for developing such highly effective therapies. The main hypothesis of this application is that a bioluminescence image reconstruction method will provide detailed volume information about tumor growth/regression at all intermediate time points during therapy in a small animal model of hormone-refractory prostate cancer. Our technology will help testing what specific drugs and therapies could block hormone-refractory prostate cancer in vivo and, thus, would significantly aid therapy development and facilitate its translation into the clinic. We will focus on two specific aims to support the hypothesis. First, we will develop a multi-spectral and multiple-view Bayesian image reconstruction method with an entropic prior and an evolution strategy for sampling the global search space of the unknown bioluminescent source distributions inside tissue. Our method will employ a high-order radiative transfer model based on the SPN equations and an adaptive grid refinement method for curved geometries. We will also implement a MRI and CT co-registration method with an animal bed for including anatomical tissue structure into the image reconstruction process. Second, we will reconstruct changes in tumor volume during therapy in a Nkx3.1/Pten mouse model of hormone-refractory prostate cancer. We will study the pharmacological manipulation of the Akt/mTOR and B-Ref/Erk Map kinase signaling pathways by determining small changes in tumor volume at various time points during therapy. PUBLIC HEALTH RELEVANCE: A Bayesian bioluminescence image reconstruction method will help testing what specific drugs and therapies can block hormone-refractory prostate cancer in small animal models. It will not only significantly aid therapy development in pre-clinical studies but will also facilitate its translation into the clinic. Therefore, the proposed imaging method will have a high probability of directly impacting the treatment of male patients with the deadliest form of prostate cancer and would increase survival rate.