A First-in-Class FAP-activated Protoxin to disrupt the Tumor-Stroma Parasitic Cycle fueling lethal Prostate Cancer Progression

前列腺癌(PCA)虽然最初对激素治疗有效，但总是进展到无法治愈的 转移性抗去势状态(MCRPC)。此外，雄激素受体患者的比例 (AR)-治疗后mCRPCe显著增加(例如-苯扎鲁胺/- 阿比特龙)治疗晚期致命性疾病的男性。无论是治疗诱导还是其他原因，这都强调了 迫切需要开发创新的非AR目标方法，如果我们想要做的不仅仅是提供 逐步增加患者的存活率，并与这种新出现的高度侵略性的致命表型作斗争。肿瘤- 浸润性成纤维细胞激活蛋白(FAP)阳性细胞(即MSCs、CAF和TAMs)被认为是关键 有利于肿瘤进展的促肿瘤和免疫抑制微环境的设计者。 这在一定程度上是通过它们产生富含能量的营养物质和癌细胞的代谢中间产物 从细胞外液中“寄生”以促进肿瘤的生长和进展。这些观察结果表明， FAP靶向治疗可同时提供AR非依赖的多方面抗肿瘤攻击 破坏对肿瘤间质的寄生依赖，消除多种免疫抑制细胞类型 在肿瘤微环境(TME)内。为了实现这一目标，我们合成了一种口服的 FDA批准的抗蠕虫药物氯硝柳胺的小分子FAP激活的线粒体原毒素 使线粒体氧化磷酸化与细胞周期无关的纳摩尔能力解偶联 使其成为低增殖指数的FAP+基质细胞的理想弹头。 该方案在概念和技术上具有创新性：1)多肿瘤浸润性FAP+ TME中的细胞被选择性地同时靶向以克服免疫屏障并破坏 “寄生循环”促进肿瘤生长；2)一流的酶激活的亲脂线粒体原毒素 旨在提高FDA批准的药物的治疗指数，同时减少对周围健康的毒性 组织被合成和表征；3)FAP在一系列独特的人类前列腺组织中的表达模式， 评估作为恶性肿瘤和治疗状态的函数的淋巴结和转移以确定临床 最有可能从FAP靶向治疗中受益的州；以及4)疗效、毒性和特异性被评估 使用一系列新的患者来源的异种移植(PDX)和同基因模型，概括了关键的临床 人主成分分析的特征及其在生物相关免疫依赖和免疫相关研究中的应用 抗肿瘤反应的潜在机制。此外，该策略结合了已经被 在患者中进行单独测试，这显著增强了近期患者受益的潜力。更多 该提案将立即为FAP+细胞在前列腺癌病理生理学中的作用提供重要的见解 特别是在它们与免疫系统的相互作用方面，同时提供必要的临床前 将这一创新的治疗平台转化为临床所需的原则证明数据。

Though initially responsive to hormonal therapy, prostate cancer (PCa) invariably progresses to an incurable metastatic castration-resistant state (mCRPC). Additionally, the proportion of patients with androgen receptor (AR)-indifferent mCRPCe has increased significantly in the post-supracastration (e.g. -enzalutamide/- abiraterone) era in men with late-stage lethal disease. Whether treatment-induced or otherwise, this emphasizes the urgent need to develop innovative non-AR targeted approaches if we want to do more than provide incremental increases in patient survival and combat this emerging highly-aggressive lethal phenotype. Tumor- infiltrating fibroblast activation protein (FAP)-positive cells (i.e. MSCs, CAFs, and TAMs) are recognized as key architects of the pro-tumorigenic and immunosuppressive microenvironment conducive to tumor progression. This is in part through their production of energy-rich nutrients and metabolic intermediates that the cancer cells “parasitize” from the extracellular fluid to fuel tumor growth and progression. These observations suggest that a FAP-targeted therapy could provide an AR-independent multi-faceted anti-tumor assault by simultaneously disrupting the parasitic dependence on the tumor stroma and eliminating multiple immunosuppressive cell types within the tumor microenvironment (TME). To accomplish this goal, we have synthesized an orally-available small molecule FAP-activated mitochondrial protoxin based on niclosamide, an FDA-approved anti-helminthic that uncouples mitochondrial oxidative phosphorylation with nanomolar potency in a cell cycle-independent manner, making it an ideal warhead for FAP+ stromal cells with a low proliferative index. This proposal is innovative from conceptual and technical perspectives: 1) multiple tumor-infiltrating FAP+ cells in the TME are selectively and simultaneously targeted to overcome the immune barrier and disrupt the “parasitic cycle” fueling tumor growth; 2) a first-in-class enzymatically-activated lipophilic mitochondrial protoxin designed to increase the therapeutic index of an FDA-approved drug while sparing toxicity to surrounding healthy tissue is synthesized and characterized; 3) FAP expression patterns in a unique series of human prostate tissues, lymph nodes, and metastases as a function of malignancy and treatment status are assessed to identify clinical states most likely to benefit from FAP-targeted therapy; and 4) efficacy, toxicity, and specificity are evaluated using a novel series of patient-derived xenograft (PDX) and syngeneic models that recapitulate key clinical features of human PCa in order to delineate biologically-relevant immune-independent and –dependent mechanisms underlying the anti-tumor response. Furthermore, this strategy combines agents that have been individually tested in patients, which significantly bolsters potential for near-term patient benefit. More immediately, the proposal will provide important insights into the role of FAP+ cells in PCa pathophysiology particularly with respect to their interaction with the immune system, while providing the necessary preclinical proof-of-principle data needed to translate this innovative therapeutic platform into the clinic.