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

项目概要/摘要 骨转移是前列腺癌患者最常见和致命的并发症。互动 前列腺癌和基质细胞之间的关系最近已成为支持疾病的关键因素 进展和治疗反应（和复发）。然而，解决这种合作的一个主要挑战是 是由于缺乏合适的实验系统来利用以骨为中心的方法来测试治疗 选项。因此，建立了解释骨-上皮相互作用的新模型，包括 与实验证据相结合的多尺度计算模型对于改善结果至关重要 患有前列腺癌骨骼病变的男性。在此背景下，我们最近开发了一种基于多光子的策略 骨中前列腺癌的显微镜监测与基于药物的骨转移模型相结合 命名为 A(BM)2，由在无细胞骨室内生长的癌细胞组成。 A(BM)2 是 应用于镭 223 (223Ra) 的研究，这是一种被批准用于治疗骨靶向放射性同位素 转移性前列腺癌。 223Ra 在骨界面处诱导深度但区域性限制的癌细胞致死率 不干扰肿瘤核心。因此，微肿瘤被根除或显着减少，同时 由于 α 辐射的组织渗透率较低（~100 µm），大肿瘤持续存在并扩大。亲戚 控制大肿瘤无效表明 223Ra 在早期骨转移性疾病或骨转移性疾病中的应用 主要病变的联合治疗方案。我们的初步研究结果赢得了泌尿生殖临床医生的信任 MD 安德森肿瘤内科正计划进行一项临床试验，以测试 223Ra 在 寡转移性前列腺癌患者。我们在此假设 223Ra 将与靶向药物产生协同作用 已形成病变的核心，从而损害主要的抵抗生态位。据此，我们将探讨 223Ra 与卡博替尼（一种针对肿瘤血管的激酶抑制剂）组合可延长进展 自由生存，并对微环境重塑产生深远影响。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），检索它们的 通过先进的离体多光子显微镜实验获得病理生理学特征。治疗反应 223Ra和卡博替尼将根据自身数据并进一步精确整合到数学模型中 泌尿生殖肿瘤内科提供的临床前证据。建立信心 A(BM)2，将首先模拟对卡博替尼的反应，然后进行组合实验 223Ra。该策略将探索大量可能的组合，包括不同的肿瘤大小， 药物剂量、治疗方案和耐药机制的发生以及最佳预测结果将是 通过临时体内临床前实验进一步验证。总体而言，这些迹象可以提供强有力的 这种联合治疗方案的基本原理，并在临床试验中得到进一步利用，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.