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

一流的 FAP 激活原毒素，可破坏肿瘤-间质寄生循环，促进致命的前列腺癌进展

• 批准号: 10532698
• 负责人: William Nathaniel Brennen
• 金额: $ 40.69万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532698
• 关键词: Androgen Receptor; Androgens; Anthelmintics; Antitumor Response; Binding; Biological Models; Cancer Patient; Carcinoma; Castration; Cell Cycle; Cells; Classification; Clinic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cytotoxic T-Lymphocytes; Data; Dependence; Disease; Disease Progression; Distant Metastasis; Drug Kinetics; Embryo; Extracellular Fluid; FDA approved; Fibroblasts; Functional disorder; Future; Genetically Engineered Mouse; Goals; Growth; Hormonal; Human; Immune; Immune system; Immunologic Surveillance; Immunologics; In Vitro; Individual; Infiltration; Knockout Mice; Laboratories; Malignant Neoplasms; Malignant neoplasm of prostate; Membrane; Mesenchymal Stem Cells; Metabolic; Metastatic Prostate Cancer; Mitochondria; Modeling; Mus; Myeloid-derived suppressor cells; Neoplasm Metastasis; Neurosecretory Systems; Normal tissue morphology; Nutrient; Oral; Outcome; Oxidative Phosphorylation; Parasites; Patients; Pattern; Pelvic lymph node group; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Population; Pre-Clinical Model; Production; Property; Prostate; Prostate Cancer therapy; Reporting; Resistance; Role; Series; Specificity; Specimen; Stromal Cells; Stromal Neoplasm; Surface; T cell infiltration; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; Transgenic Model; Transgenic Organisms; Translating; Translations; Tumor-associated macrophages; Xenograft procedure; abiraterone; advanced disease; anti-tumor immune response; assault; cancer cell; cell type; clinically relevant; combat; design; effectiveness evaluation; efficacy evaluation; enzalutamide; experimental study; extracellular; fibroblast-activating factor; hormone therapy; immune checkpoint blockade; in vivo; indexing; innovation; insight; lipophilicity; lymph nodes; men; nanomolar; novel; patient derived xenograft model; patient population; permissiveness; pre-clinical; prostate cancer progression; protein expression; recruit; resistance mechanism; response; small molecule; targeted treatment; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenic

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.

虽然最初对激素治疗有反应，但前列腺癌（PCa）总是进展为无法治愈的癌症。 转移性去势抵抗状态（mCRPC）。此外，雄激素受体阳性患者的比例 （AR）-中性mCRPCe在超去势后显著增加（例如-enzalutamide/- 阿比特龙）时代的男性与晚期致命疾病。无论是治疗引起的还是其他原因，这都强调了 迫切需要开发创新的非AR针对性方法，如果我们想做的不仅仅是提供 患者存活率的逐步增加，并对抗这种新出现的高侵袭性致死表型。肿瘤- 浸润性成纤维细胞活化蛋白（FAP）阳性细胞（即MSC，CAF和TAM）被认为是关键的 促进肿瘤进展的促肿瘤发生和免疫抑制微环境的设计师。 这部分是通过它们产生富含能量的营养物质和代谢中间产物， 从细胞外液“寄生”以促进肿瘤生长和进展。这些观察表明， FAP靶向治疗可以通过同时使用抗肿瘤药物来提供不依赖AR的多方面抗肿瘤攻击。 破坏对肿瘤间质的寄生依赖性并消除多种免疫抑制细胞类型 肿瘤微环境（TME）为了实现这一目标，我们合成了一种口服的 基于氯硝柳胺（FDA批准的抗蠕虫药）的小分子FAP激活的线粒体原毒素 在不依赖细胞周期的情况下， 方式，使其成为具有低增殖指数的FAP+基质细胞的理想弹头。 该提案在概念和技术方面具有创新性：1）多个肿瘤浸润性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免疫屏障。 “寄生循环”促进肿瘤生长; 2）一流的酶促活化亲脂性线粒体原毒素 旨在增加FDA批准的药物的治疗指数，同时避免对周围健康 合成并表征组织; 3）在一系列独特的人前列腺组织中的FAP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靶向治疗中获益的国家;以及4）评估疗效、毒性和特异性 使用一系列新的患者来源的异种移植物（PDX）和同基因模型， 人PCa的特征，以描述生物学相关的免疫非依赖性和依赖性 抗肿瘤反应的潜在机制。此外，这种策略结合了已经被 在患者中进行单独测试，这显著增强了近期患者获益的可能性。更 该提案将立即为FAP+细胞在PCa病理生理学中的作用提供重要见解 特别是关于它们与免疫系统的相互作用，同时提供必要的临床前 将这一创新治疗平台转化为临床所需的原理验证数据。