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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.

项目总结/文摘