Project 3: Extending Clinical Benefit by Selective Treatment of Resistant Lesions in mCRPC

项目摘要 治疗耐药性的产生是mCRPC患者疾病进展的主要原因。什么 被低估的是，许多正在经历进展的患者的大多数个体 对治疗持续有效的病变。鉴定耐药病灶将允许施用 局部消融治疗，特别是如果全身治疗对大多数转移瘤仍然有效。 我们假设，对耐药病灶的选择性治疗（如立体定向体部放射治疗）将 延长mCRPC男性患者的临床获益持续时间。我们将通过使用我们独特的 先进的定量分子图像分析-定量全面可扩展成像（QTxI）， 治疗动力学的病变水平评估。我们将通过以下目标来检验我们的假设：（1） 描述接受第二代雄激素治疗的mCRPC男性患者早期进展时的耐药性- 通过采用PET/CT的QTxI，从最低PSA缓解、PSA进展开始， 12周内，（2）使用不同PET指标对靶病变进行虚拟选择性射频消融研究 选择耐药病灶，并模拟放射消融对总肿瘤负荷的影响， （3）验证SBRT用于选择性射频消融的临床可行性 在前瞻性治疗临床试验中的耐药病灶。 该项目具有高度创新性，因为它探索了mCRPC中病灶水平的治疗耐药性， 以我们的技术为特征，作为治疗目标。临床试验时的耐药性评估 进展是至关重要的，因为它引发了患者和提供者的高度焦虑，因此这是一个未满足的紧迫领域 临床需要我们将进行第一次同类试验，以确定和治疗耐药病变的背景下，广泛- 扩散转移性疾病，以提高临床获益。

PROJECT SUMMARY Development of treatment resistance is the main reason for disease progression in patients with mCRPC. What is under-appreciated is that many patients who are experiencing progression have the majority of individual lesions that continue to respond to therapy. Identification of resistant lesions would allow for administration of localized ablative therapies, especially if the systemic therapy is still effective for the majority of metastases. We hypothesize that selective treatment of resistant lesions (e.g. with stereotactic body radiation therapy) will extend duration of clinical benefit in men with mCRPC. We will identify resistant lesions by employing our unique advanced quantitative molecular image analytics - Quantitative Total Extensible Imaging (QTxI) which allows lesion-level assessment of treatment dynamics. We will test our hypothesis through the following aims: (1) To characterize resistance at early progression in men with mCRPC treated with second-generation androgen- signaling inhibitors by employing QTxI of PET/CT starting at nadir PSA response, PSA progression, and again in 12 weeks, (2) To conduct virtual selective radio-ablation study using different PET metrics for target lesion selection of resistant lesions and to model impact of radio-ablation on total tumor burden and anticipated improvement in clinical benefit and (3) To test clinical feasibility of radio-ablation using SBRT to selective resistant lesions in a prospective therapeutic clinical trial. This project is highly innovative as it explores lesion-level treatment resistance in mCRPC, uniquely characterized by our technology, as a treatment target. Assessment of resistance at the time of clinical progression is critical, as it triggers high anxiety in the patient and provider, and thus it is an urgent area of unmet clinical need. We will conduct the first trial of its kind to identify and treat resistant lesions in the setting of wide- spread metastatic disease with the goal of improving clinical benefit.