Radiation modulation of cell plasticity programs determine prostate cancer oligometastatic potential

前列腺癌(PCA)的疾病失败模式表明，了解转移将导致最大 治疗收益，并允许更合理的临床管理。整合所有地点的重要性 包括阻止进一步转移扩散的原发疾病在内的宏观疾病的支持是有限的 前瞻性随机研究。然而，是否通过处理 前列腺癌的放射转移进一步阻碍了转移过程，其存活率尚无答案。它是 通常认为转移是循环中的肿瘤细胞(CTCs)离开原发区域的单向流动。 肿瘤并在远处种植转移，每个转移独立于其他转移生长。 然而，CTCs可能会经历一个周期性的“自我播种”过程，在这个过程中，具有转移潜能的细胞返回到 原发肿瘤和其他宏观肿瘤沉积的“理想化”微环境导致更多 强大的CTC。上皮-间充质可塑性(EMP)程序由上皮-间充质组成 转化(EMT)和间充质-上皮转化(MET)是一种发育程序，可以 产生具有转移特性的上皮细胞。我们提出了动态电磁脉冲程序来引导PCA细胞 在EMT-MET之间来回切换，以便于进行自我播种。立体定向消融放射治疗是一种 高聚焦、高剂量、短疗程，适合治疗转移瘤，因为它针对的是 癌细胞和肿瘤微环境(TME)细胞。有效针对TME的干预措施 SABR等组成部分似乎准备阻止转移瘤的自我播种和随后的成熟。 我们正在最后阶段启动我们的Terps试验--转移性肿瘤随机彻底根除的第二阶段 前列腺癌首次放射治疗后前列腺癌的损害。因此，我们 提出了以下假设：(1)电磁脉冲程序控制自播种和转移 (2)低EMT和/或高MET标志物的CTC是男性 (3)转移性SABR改变了少转移性PCa的自然病程； 而且，(4)巩固的SABR改变了未来转移的成熟潜力，可以通过以下方式检测到 CTC标志物分布和计数水平和/或组织、液体或成像生物标志物的变化。我们会 测试以下两个目标。目的#1：循环肿瘤细胞(CTCs)的上皮-间充质可塑性 SABR治疗男性少转移前列腺癌的生物标记物。我们将推行多项措施 来自我们的Terps试验的相关组织、液体、成像和免疫研究，以检查EMP标志物- EMT和MET。目的#2：确定SABR对前列腺癌上皮细胞自体种植的影响。 间充质可塑性前列腺癌小鼠模型。使用基于单元的EMP PCA模型和序列非 在小鼠中进行侵入性成像，以测试PCA的自种播假说以及电磁脉冲因素是否调节自种播。

Patterns of disease failure in prostate cancer (PCa) suggest understanding metastasis will result in the largest therapeutic gains and allow for more rationale clinical management. The importance of consolidating all sites of macroscopic disease including the primary to impede further metastatic dissemination is backed by limited prospective randomized studies. However, the question of whether total consolidation by treating the metastases with radiation in PCa further impedes the metastatic process and survival is unanswered. It is generally assumed that metastasis is a unidirectional flow of circulating tumor cells (CTCs) leaving the primary tumor and seeding a metastasis at a distant site with each metastasis growing independently of the others. However, CTCs may undergo a cyclical “self-seeding” process, wherein cells with metastatic potential return to the “idealized” microenvironment of the primary tumor and other macroscopic tumor deposits resulting in more robust CTCs. Epithelial-mesenchymal plasticity (EMP) programs composed of the epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET) are developmental programs that can engender epithelial cells with metastatic properties. We propose the dynamic EMP program directs PCa cells to revert back and forth from EMT-MET to facilitate self-seeding. Stereotactic ablative radiation (SABR) is a highly focused, high-dose short radiation course that is suited for treatment of metastases as it targets the cancer cells and tumor microenvironment (TME) cells. Interventions that effectively target the TME component, such as SABR, appear poised to arrest self-seeding and subsequent maturation of metastases. We are in the final stages to launch our TERPS trial - Phase 2 randomized Total Eradication of metastatic lesions following definitive Radiation to the Prostate in de novo oligometaStatic prostate cancer. Thus, we have developed the following HYPOTHESES: (1) EMP programs control self-seeding and the metastatic potential of PCa; (2) CTCs with low EMT and/or high MET markers are representative of men with oligometastatic PCa; (3) Consolidative SABR of metastases alters the natural history of oligometastatic PCa; and, (4) Consolidative SABR alters the potential for maturation of future metastases that can be detected by changes in CTC marker profiles and enumeration levels and/or tissue, liquid or imaging biomarkers. We will test the following two aims. AIM #1: Epithelial-mesenchymal plasticity of circulating tumor cells (CTCs) are biomarkers for men with oligometastatic prostate cancer treated with SABR. We will pursue a number of correlative tissue, liquid, imaging and immune studies from our TERPS trial to examine for EMP markers - EMT and MET. AIM #2: To determine the effects of SABR on prostate cancer self-seeding in epithelial- mesenchymal plasticity prostate cancer mouse models. Use cell based EMP PCa models and serial non- invasive imaging in mice to test the self-seeding hypothesis for PCa and if EMP factors modulate self-seeding.