Integrating in vivo and in silico models of prostate cancer-bone interactions to overcome anti-tumor therapy resistance

项目摘要/摘要 骨转移是前列腺癌患者最常见和最致命的并发症。互动 前列腺癌和间质细胞之间的关系最近成为支持疾病的关键因素 进展和治疗反应(和复发)。然而，解决这一合作的一个主要挑战是， 是因为缺乏合适的实验系统来利用以骨骼为中心的方法来测试治疗 选择。因此，解释骨-上皮相互作用的新模型的建立，包括 多尺度计算模型与实验证据相结合，是改善研究结果的核心 患有前列腺癌的男性骨骼病变。在这种背景下，我们最近开发了一种基于多光子的策略 结合药物骨转移模型的骨内前列腺癌的显微镜监测 命名为A(BM)2，由生长在无细胞骨室内的癌细胞组成。A(BM)2是 应用于Re 223(223Ra)的研究，这是一种骨靶向放射性同位素，被批准用于治疗糖尿病 转移性前列腺癌。223Ra在骨界面上诱导深刻但局限于带状区域的癌细胞杀伤力 没有肿瘤核心的扰动。因此，微肿瘤被根除或显著减少，而 由于阿尔法辐射的组织透过率低(约100微米)，巨大的肿瘤持续并扩大。相对的 在控制大肿瘤方面的无效指向223Ra在早期骨转移疾病中的应用或在 主要病变的联合治疗方案。我们的初步发现赢得了泌尿生殖临床医生的信任 他们正计划进行一项临床试验，以测试223Ra在 少转移性前列腺癌患者。我们在这里假设223Ra将与药物靶向协同作用 已建立的核心损伤，从而损害了主要的抗性生态位。因此，我们将探索 223Ra与卡波赞替尼(一种针对肿瘤血管的激酶抑制剂)联合应用可延长进展 自由生存，并深刻影响着微环境的重塑。为此，我们将完善我们的 A(BM)2通过添加肿瘤血管和骨基质细胞(成骨细胞、破骨细胞)，恢复其 先进的体外多光子显微镜实验的病理生理特征。治疗的反应 223Ra和Cabozantinib将根据自己的数据精确地集成在数学模型中，并进一步 泌尿生殖内科肿瘤科提供的临床前证据。在……中建立信心 首先将模拟A(BM)2对卡波赞替尼的反应，然后进行组合实验 223Ra。这一策略将探索多种可能的组合，包括不同的肿瘤大小， 药物剂量、治疗计划和耐药机制的启动以及最佳预测结果将是 进一步通过特别的体内临床前实验进行验证。总体而言，这些迹象可能会提供一个强有力的 这种联合疗法的理论基础，并将在临床试验中进一步开发，直接影响患者护理。

PROJECT SUMMARY/ABSTRACT Bone metastasis is the most frequent and lethal complication in prostate cancer patients. The interaction between prostate cancer and stromal cells has recently emerged as a key player in supporting disease progression and therapeutic response (and relapse). A major challenge in addressing this cooperation, however, is due to the lack of suitable experimental systems that exploit a bone-centric approach for testing treatment options. Consequently, the establishment of novel models that account for bone-epithelial interplays, including multiscale computational models integrated with experimental evidence, is central to improve the outcome of men with prostate cancer lesions in bone. In this context, we recently developed a strategy based on multiphoton microscopy monitoring of prostate cancer in bone combined to an Agent-Based Model of Bone Metastasis named A(BM)2, which consists of cancer cells growing within an acellular bone compartment. The A(BM)2 was applied to the study of Radium 223 (223Ra), a bone-targeting radioisotope approved for the treatment of metastatic prostate cancer. 223Ra induces profound but zonally confined cancer cell lethality at the bone interface with no perturbation of the tumor core. Therefore, micro-tumors are eradicated or significantly reduced while macro-tumors persist and expand due to low tissue penetrance of alpha radiation (~100 µm). The relative inefficacy in controlling large tumors points to application of 223Ra in early bone-metastatic disease or in combinatorial regimens for major lesions. Our initial findings gained the confidence of clinicians at Genitourinary Medical Oncology Department, MD Anderson, which are planning a clinical trial to test efficacy of 223Ra in oligometastatic prostate cancer patients. We here hypothesize that 223Ra will synergize with an agent targeting the core of established lesions, thus impairing the main resistance niche. Accordingly, we will explore the combination of 223Ra with cabozantinib, a kinase inhibitor that targets tumor blood vessels, prolongs progression free survival, and exerts a profound impact on microenvironment remodeling. To this purpose, we will refine our A(BM)2 by adding tumor vessels and bone stromal cells (osteoblasts, osteoclasts), retrieving their pathophysiological features by advanced ex vivo multiphoton microscopy experiments. The therapy response to 223Ra and cabozantinib will be precisely integrated in the mathematical model based on own data and further preclinical evidence made available by Genitourinary Medical Oncology Department. To generate confidence in the A(BM)2, the response to cabozantinib will be initially simulated, followed by combinatorial experiments with 223Ra. This strategy will explore an extensive number of possible combinations, including different tumor sizes, drug doses, treatment schedules and onset of resistance mechanisms and the best predicted outcome will be further validated with ad hoc in vivo preclinical experiments. Overall, these indications could provide a strong rationale for this combined regimen and be further exploited in clinical trials, directly impacting patient care.