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

整合前列腺癌-骨相互作用的体内和计算机模型以克服抗肿瘤治疗耐药性

基本信息

批准号：
10669771
负责人：
Stefano Casarin
金额：
$ 22.24万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10669771
关键词：
Address Alpha Particles Androgen Receptor Angiogenesis Inhibitors Animals Biological Biology Calibration Cancer Model Cancer Patient Cells Cessation of life Clinical Clinical Trials Collaborations Communication Complication Data Diagnosis Disease Disease Progression Distant Distress Dose Epithelium Ethics Event Experimental Designs Experimental Models Failure Genitourinary system Goals Impairment Intervention Lesion Link Malignant Bone Neoplasm Malignant neoplasm of prostate Mediating Medical Oncology Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modality Modeling Molecular Monitor Morbidity - disease rate Morphology Names Neoplasm Metastasis Neoplasms in Vascular Tissue Osteoblasts Osteoclasts Outcome Patient Care Patients Penetrance Pharmaceutical Preparations Preclinical Testing Progression-Free Survivals Radiation Radioisotopes Radium Receptor Signaling Regimen Relapse Resistance Role Solid Source Stromal Cells System Testing Therapeutic Effect Time Tissues Translational Research Treatment Protocols Validation Work bone bone cell cancer cell cancer therapy chemotherapy clinically relevant combinatorial cost effective cytotoxicity data integration design drug testing efficacy testing experimental study improved improved outcome in silico in vivo in vivo Model inhibitor therapy innovation kinase inhibitor mathematical model men meter mortality mouse model multi-scale modeling multidisciplinary multiphoton microscopy neoplastic cell novel outcome prediction pre-clinical predicting response prostate cancer cell prostate cancer model prostate cancer progression resistance mechanism response success synergism systemic toxicity targeted agent targeted treatment therapy resistant treatment response tumor tumor eradication tumor growth tumor progression

项目摘要

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.

项目摘要/摘要骨转移是前列腺癌患者中最常见，最致命的并发症。相互作用前列腺癌和基质细胞之间已成为支持疾病的关键人物进展和热响应（和继电器）。但是，解决这一合作的主要挑战由于缺乏适当的实验系统来利用以骨为中心的测试治疗方法选项。因此，建立了解释骨上皮相互作用的新颖模型，包括与实验证据集成的多尺度计算模型是改善结果骨骼中前列腺癌病变的男性。在这种情况下，我们最近制定了一种基于多人的策略骨中前列腺癌的显微镜监测结合到基于药剂的骨转移模型命名为A（BM）2，由癌细胞组成，在细胞室内生长。 A（BM）2是应用于赖赖赖斯223（223RA）的研究，这是一种批准治疗的骨靶向放射性同位素转移性前列腺癌。 223RA在骨界面诱导了深刻但占地限制的癌细胞致死率没有肿瘤核的扰动。因此，微肿瘤被放射或显着降低，而由于α辐射（〜100 µM）的组织渗透率低，宏观肿瘤持续存在并扩展。亲戚在控制大肿瘤中的效率低下表明223RA在早期的骨 - 骨疾病中或在主要病变的组合方案。我们的最初发现获得了临床医生对泌尿生殖器的信心医学肿瘤科，医学博士安德森（Anderson），正在计划进行临床试验，以测试223RA的效率寡聚前列腺癌患者。我们在这里假设223ra将与定位代理协同作用既定病变的核心，因此损害了主要的抗药性生态位。根据，我们将探索 223RA与卡博替尼的组合是一种靶向肿瘤血管的激酶抑制剂，延长进展自由生存，并对微环境重塑产生深远的影响。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），检索其晚期多光子显微镜显微镜实验的病理生理特征。疗法对 223ra和Cabozantinib将根据自己的数据精确地集成在数学模型中，并进一步集成临床前医学肿瘤科提供了临床前证据。为了产生信心 A（BM）2最初将模拟对Cabozantinib的响应，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，治疗时间表和抵抗机制的发作以及最佳预测结果将是通过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大的该组合方案的基本原理，并在临床试验中进一步探讨，直接影响患者护理。