Targeting Sphinogsine-1-phosphate to overcome SNAI1-mediated therapy resistance in rectal cancer

14年来，新辅助5-氟尿嘧啶放化疗（5 FU/RT）一直是 直肠癌（RC）患者的标准选择，这是我们退伍军人的致命癌症。不幸的是， 在这些病例中，约80%的患者存在明显的耐药性，增加了手术失败，疾病复发， 最终导致死亡这些问题突出了目前缺乏有效的治疗策略， 部分原因是缺乏临床相关的RC研究模型。以应对这些严峻的 障碍，我们的多学科团队建立了免费的RC患者来源的异种移植物（PDX）， 类器官模型作为紧密反映人类肿瘤的翻译平台。与提出的目标保持一致 在VA的卓越蓝图中，我们的项目旨在通过设计和测试新的 生物标志物导向的治疗策略，然后可以迅速转化为临床应用， RC PDX。 具有干细胞样特性的肿瘤起始细胞（TIC）驱动肿瘤生长和治疗失败。我们 已发表的工作将Snail家族转录抑制因子1（SNAI 1）确定为RC的中心介导者 自我更新能力和密切相关的RT抗性。不幸的是，TIC和SNAI 1具有挑战性， 治疗目标。与MUSC的世界级鞘脂研究团队一起，我们最近确定了 SNAI 1降低神经酰胺水平，这与必需鞘氨醇-1-磷酸化的表达增加有关。 磷酸（S1 P）途径成员，包括鞘氨醇激酶2（SK 2）。生物活性鞘脂的作用 在促进SNAI 1介导的治疗抗性方面， 易损性.我们假设SNAI 1通过激活S1 P来驱动鞘脂代谢功能障碍 增强TIC自我更新能力和RT抗性的途径。相反，我们假设SK2 抑制将靶向抗性TIC以增强RT反应，从而提高有效性和持久性 我们建议评估我们的项目开发的新型SK2抑制剂ABC 294640 并且已经在1期试验中进行了测试，代表了RC患者的下一代治疗策略。 在这项资助提案中，我们将（1）定义S1 P激活在介导SNAI 1自我更新中的作用， TIC表型，2）确定SNAI 1驱动RT抗性是否受增加的神经酰胺调节 （3）评价SK2抑制作为通过靶向RC中的TIC来增强5 FU/RT的策略 患者来源的类器官和异种移植模型。通过减少对当前最佳疗法的抵抗， 该项目有可能为退伍军人事务部的直肠癌患者提供更好的结果， 需要更好的护理。一个高度转化的RC重点研究项目的优势， 独特的患者衍生RC模型与我们世界一流的鞘脂团队相结合， S1 P导向疗法已准备好进行临床试验。我们一起设计了一部小说的基本原理 实验性治疗，以及测试它的策略，承诺产生的结果，可以迅速推进， 临床应用

For over fourteen years, neoadjuvant 5-fluorouracil chemoradiation (5FU/RT) has remained the standard option for patients with rectal cancer (RC), a deadly cancer in our veterans. Unfortunately, therapeutic resistance is evident in ~80% of these cases, increasing the chances of surgical failure, disease recurrence, and ultimately, death. These issues highlight the current lack of effective therapeutic strategies required to advance care due, in part, to the lack of clinically relevant RC research models. To address these critical barriers, our multi-disciplinary team established complimentary RC patient-derived xenograft (PDX) and organoid models as translational platforms that closely mirror the human tumor. Aligned with the goals set forth in the VA’s Blueprint for Excellence, our project seeks to transform RC care by designing and testing novel biomarker-directed therapeutic strategies which can then be translated rapidly to clinical application using our RC PDX. Tumor-initiating cells (TICs) with stem cell-like properties drive tumor growth and therapy failure. Our published work identified the Snail Family Transcriptional Repressor 1 (SNAI1) as a central mediator of RC self-renewal capacity and, closely related, RT resistance. Unfortunately, TICs and SNAI1 are challenging to target therapeutically. Together with MUSC’s world-class sphingolipid research team, we recently determined that SNAI1 decreases ceramide levels associated with increased expression of essential sphingosine-1- phosphate (S1P) pathway members including sphingosine kinase 2 (SK2). The role of bioactive sphingolipids in promoting SNAI1-mediated therapy resistance is largely unexplored and may represent a therapeutic vulnerability. We hypothesize that SNAI1 drives dysfunction of sphingolipid metabolism by activating S1P pathways to amplify TIC self-renewal capacity and RT resistance. Conversely, we hypothesize that SK2 inhibition will target resistant TICs to enhance RT response, thereby improving the effectiveness and durability of 5FU/RT. We propose to evaluate the novel SK2 inhibitor ABC294640 that was developed by our program and already tested in Phase 1 trials representing a next-generation therapeutic strategy for RC patients. In this grant proposal, we will (1) define the role of S1P activation in mediating SNAI1- self renewal and the TIC phenotype, 2) determine if SNAI1-driven RT resistance is regulated by increased ceramide metabolism, and (3) evaluate SK2 inhibition as a strategy to enhance 5FU/RT by targeting the TIC in RC patient-derived organoid and xenograft models. By decreasing resistance to the best current therapies, this project has the potential to provide better outcomes for the VA’s rectal cancer patients who so desperately need improved care. The strengths of a highly translational RC-focused research program that has developed unique patient-derived RC models are combined with our world-class sphingolipid group that has pioneered S1P-directed therapies that are ready for clinical trials. Together we have devised a rationale for a novel experimental therapy, and a strategy to test it, that promise to yield results that can be advanced rapidly to clinical application.