Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
Departments of Environmental Medicine and Radiation Oncology, University of Rochester Medical Center, Rochester, NY, USA.
Int J Radiat Biol. 2023;99(7):1046-1054. doi: 10.1080/09553002.2023.2182000. Epub 2023 Mar 7.
For decades, Dr. John Moulder has been a leading radiation biologist and one of the few who consistently supported the study of normal tissue responses to radiation. His meticulous modeling and collaborations across the field have offered a prime example of how research can be taken from the bench to the bedside and back, with the ultimate goal of providing benefit to patients. Much of the focus of John's work was on mitigating damage to the kidney, whether as the result of accidental or deliberate clinical exposures. Following in his footsteps, we offer here a brief overview of work conducted in the field of radiation-induced bladder injury. We then describe our own preclinical experimental studies which originated as a response to reports from a clinical genome-wide association study (GWAS) investigating genomic biomarkers of normal tissue toxicity in prostate cancer patients treated with radiotherapy. In particular, we discuss the use of Renin-Angiotensin System (RAS) inhibitors as modulators of injury, agents championed by the Moulder group, and how RAS inhibitors are associated with a reduction in some measures of toxicity. Using a murine model, along with precise CT-image guided irradiation of the bladder using single and fractionated dosing regimens, we have been able to demonstrate radiation-induced functional injury to the bladder and mitigation of this functional damage by an inhibitor of angiotensin-converting enzyme targeting the RAS, an experimental approach akin to that used by the Moulder group. We consider our scientific trajectory as a bedside-to-bench approach because the observation was made clinically and investigated in a preclinical model; this experimental approach aligns with the exemplary career of Dr. John Moulder.
Despite the differences in functional endpoints, recent findings indicate a commonality between bladder late effects and the work in kidney pioneered by Dr. John Moulder. We offer evidence that targeting the RAS pathway may provide a targetable pathway to reducing late bladder toxicity.
几十年来，约翰·莫德尔博士一直是一位领先的辐射生物学家，也是少数几位一直支持研究正常组织对辐射反应的人之一。他细致的建模和跨领域的合作为研究如何从实验室到临床再回到实验室提供了一个典范，最终目标是为患者带来益处。约翰的工作重点很多是减轻肾脏的损伤，无论是由于意外还是故意的临床暴露。我们在这里效仿他的脚步，简要概述一下辐射诱导的膀胱损伤领域的工作。然后，我们描述了自己的临床前实验研究，这些研究源于对一项临床全基因组关联研究（GWAS）的报告的回应，该研究调查了接受放射治疗的前列腺癌患者正常组织毒性的基因组生物标志物。特别是，我们讨论了肾素-血管紧张素系统（RAS）抑制剂作为损伤调节剂的使用，这是莫德尔小组所支持的药物，以及 RAS 抑制剂如何与某些毒性指标的降低相关联。我们使用了一种鼠模型，以及使用精确的 CT 图像引导的膀胱单次和分次照射方案，能够证明辐射对膀胱的功能损伤，并通过针对 RAS 的血管紧张素转换酶抑制剂减轻这种功能损伤，这种实验方法类似于莫德尔小组使用的方法。我们认为我们的科学轨迹是从临床到实验室的方法，因为这一观察是在临床上做出的，并在临床前模型中进行了研究；这种实验方法与约翰·莫德尔博士的开创性工作相吻合。
尽管功能终点不同，但最近的发现表明，膀胱迟发性效应与约翰·莫德尔博士在肾脏开创性工作之间存在共同性。我们提供的证据表明，靶向 RAS 途径可能为减少晚期膀胱毒性提供一个可靶向的途径。
