Molecular regulation and expression of Trop-2 in advanced prostate cancer: Identifying optimal therapeutic niches

项目总结/摘要 在过去的十年中，FDA批准的男性治疗方法数量显著增加 转移性去势抵抗性前列腺癌（mCRPC）。在生存率上有更大的提高 在接受化疗的转移性去势敏感性PC（mCSPC）男性中观察到， 雄激素受体信号传导抑制剂与单独激素治疗相比（尽管这些进展 在mCSPC中，mCRPC男性患者的中位OS仍低于2年， 相同类别的治疗（例如Enzalutamide和阿比特龙）发生在>90%的患者中，限制了 从mCRPC的有效治疗到OS改善范围仅为2-4个月的药物。那里 是一个关键的需要，以确定新的代理，可以消除耐药疾病5。了解 驱动耐药性的分子关联可能会在这些侵袭性疾病中发现新的治疗敏感性。 癌症，以改善mCRPC男性患者的生活质量和数量。转化研究 专注于了解CRPC中驱动治疗耐药性的潜在机制， 鉴定了广泛的基因组、表观基因组和转录改变。约15-20% 的mCRPC患者发生谱系可塑性，小细胞神经内分泌CRPC（SCNPC） 代表了最具攻击性的亚型然而，该领域缺乏对 在mCRPC中观察到不同的谱系可塑性表型，很少有治疗靶点被发现。 发展至今。在这项研究中，我们提出Trop-2（滋养层细胞表面抗原）作为一个高价值 用于用抗体-药物缀合物Sacituzumab Govitecan（SG）治疗mCRPC的靶向。我们 假设mCRPC中的ARSI耐药表型可以通过整合的实体瘤来鉴定， 肿瘤和液体活检分析和具有SG的靶向治疗。为了验证这个假设，我们 建议在临床前和临床标本中研究Trop-2调节，并在 ARSI耐药mCRPC的前瞻性II期临床试验。在目标1中，我们将进行分子空间 分析mCRPC PDX组织以及实体瘤和液体活检组织中Trop-2的表达， 在目标2中，我们将评估实体瘤和液体活检 在前瞻性II期试验中从接受SG治疗的mCRPC患者中纵向收集。目的 2将表征编码Trop-2的TACSTD 2基因中的染色质增强子谱，以鉴定 前列腺癌中调节Trop-2水平的因素。我们将测试Trop-2水平是否决定对 SG治疗，并确定基于SG的联合方案，增强体外治疗效果 和体内。

PROJECT SUMMARY/ABSTRACT The last decade has seen a significant increase in the number of FDA approved treatments for men with metastatic castrate resistant prostate cancer (mCRPC). Even greater improvements in survival were observed for men with metastatic castration sensitive PC (mCSPC) treated with chemotherapy or androgen receptor signaling inhibitors compared to hormone therapy alone (Despite these advances in mCSPC, median OS for men with mCRPC remains less than two years and cross-resistance to therapies within the same class (e.g. Enzalutamide and Abiraterone) occurs in >90% of patients, limiting effective treatments in mCRPC to agents with OS improvements ranging from only 2-4 months. There is a critical need to identify new agents that can eliminate resistant disease5. Understanding the molecular associations driving resistance may identify new therapeutic sensitivities in these aggressive cancers to improve quality and quantity of life for men with mCRPC. Translational research studies focused on understanding the underlying mechanisms driving treatment resistance in CRPC have identified a wide range of genomic, epigenomic and transcriptional alterations. Approximately 15-20% of patients with mCRPC develop lineage plasticity, with small cell neuroendocrine CRPC (SCNPC) representing the most aggressive subtype. However, the field lacks consensus definitions for the diverse lineage plasticity phenotypes observed in mCRPC, and few therapeutic targets have been developed to date. In this study, we propose Trop-2 (Trophoblastic cell-surface antigen) as a high value target for therapy of mCRPC with an antibody-drug conjugate Sacituzumab Govitecan (SG). We hypothesize that ARSI-resistant phenotypes in mCRPC can be identified through integrated solid tumor and liquid biopsy analysis and targeted therapeutically with SG. To test this hypothesis, we propose to study Trop-2 regulation in pre-clinical and clinical specimens and test this agent in a prospective Phase II clinical trial for ARSI-resistant mCRPC. In Aim 1, we will conduct molecular-spatial analysis of Trop-2 expression in mCRPC PDX tissues as well as solid tumor and liquid biopsies from patients with CSPC, CRPC and SCNPC In Aim 2, we will evaluate solid tumor and liquid biopsies collected longitudinally from patients with mCRPC treated with SG in a prospective Phase II trial. Aim 2 will characterize chromatin enhancer profiles in the TACSTD2 gene encoding Trop-2 to identify factors regulating Trop-2 levels in prostate cancer. We will test if Trop-2 levels determine sensitivity to SG therapy, and identify SG-based combination regimens that enhance therapeutic efficacy in vitro and in vivo.