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

项目总结/摘要 骨转移是前列腺癌患者最常见和最致命的并发症。的相互作用 前列腺癌和基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，开展这种合作的一个主要挑战是， 是由于缺乏合适的实验系统，利用骨为中心的方法来测试治疗 选项.因此，建立新的模型，解释骨上皮相互作用，包括 多尺度计算模型与实验证据相结合，是改善结果的核心。 患有前列腺癌的男性在这种背景下，我们最近开发了一种基于多光子的策略， 前列腺癌骨转移的显微镜监测与基于Agent的骨转移模型的结合 称为A（BM）2，其由在无细胞骨隔室中生长的癌细胞组成。A（BM）2是 应用于镭223（223 Ra）的研究，镭223是一种骨靶向放射性同位素，被批准用于治疗 转移性前列腺癌223 Ra在骨界面诱导显著但区域性限制的癌细胞致死 而不干扰肿瘤核心。因此，微肿瘤被根除或显著减少， 由于α辐射的低组织透射率（~100 µm），巨大肿瘤持续存在并扩大。的相对 在控制大肿瘤方面的无效表明223 Ra在早期骨转移性疾病中的应用， 主要病变的组合方案。我们的初步发现赢得了泌尿生殖科临床医生的信心 医学肿瘤科，MD安德森，他们正在计划一项临床试验，以测试223 Ra在 少转移性前列腺癌患者。我们在这里假设223 Ra将与靶向 已建立的病变的核心，从而削弱了主要的阻力生态位。因此，我们将探讨 223 Ra与靶向肿瘤血管的激酶抑制剂卡博替尼的组合， 自由生存，并对微环境重塑产生深远影响。为此，我们将改进我们的 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的病理生理学特征。治疗反应 223 Ra和卡博替尼将基于自己的数据精确地整合到数学模型中，并进一步 泌尿生殖内科肿瘤科提供的临床前证据。使产生信心 A（BM）2，最初将模拟对卡博替尼的响应，然后进行与以下的组合实验： 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、治疗时间表和耐药机制的发生以及最佳预测结果将是 进一步通过专门的体内临床前实验进行验证。总的来说，这些迹象可以提供一个强有力的 这一组合方案的基本原理，并在临床试验中进一步利用，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.