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

14年来，新辅助5-氟尿嘧啶化疗(5FU/RT)一直是 直肠癌(RC)患者的标准选择，这是我们退伍军人中的一种致命癌症。不幸的是，有治疗作用 在这些病例中，约80%存在明显的耐药性，增加了手术失败、疾病复发、 最终，死亡。这些问题突出表明，目前缺乏所需的有效治疗战略 高级护理部分是由于缺乏临床相关的RC研究模型。要解决这些关键问题 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(PDX)和 有机模型作为翻译平台，紧密地反映了人类的肿瘤。与设定的目标保持一致 在退伍军人管理局的卓越蓝图中，我们的项目寻求通过设计和测试新颖的 生物标记物导向的治疗策略，然后可以使用我们的 RC PDX。 具有干细胞样特性的肿瘤启动细胞(TICs)会导致肿瘤生长和治疗失败。我们的 已发表的研究发现，蜗牛家族转录抑制因子1(SNAI1)是RC的中心调节因子 自我更新能力与RT抗性密切相关。不幸的是，TICS和SNAI1正在挑战 靶向治疗。与南加州大学世界级的鞘脂研究团队一起，我们最近确定 SNAI1降低与必需鞘氨醇-1表达增加相关的神经酰胺水平- 磷酸(S1P)途径成员包括鞘氨醇激酶2(SK2)。生物活性鞘脂的作用 在促进SNAI1介导的治疗中，耐药性在很大程度上是未知的，可能是一种治疗性的 脆弱性。我们假设SNAI1通过激活S1P导致鞘磷脂代谢功能障碍 扩增TIC自我更新能力和RT抗性的途径。相反，我们假设SK2 抑制将靶向抗药性抽搐以增强RT反应，从而提高有效性和持久性 5FU/RT。我们建议对本项目开发的新型SK2抑制剂ABC294640进行评估 并且已经在代表RC患者下一代治疗策略的第一阶段试验中进行了测试。 在这项拨款提案中，我们将(1)定义S1P激活在调节SNAI1自我更新和 TIC表型，2)确定SNAI1驱动的RT抗性是否受神经酰胺增加的调节 代谢，以及(3)评价SK2抑制作为一种通过靶向TIC在RC中增强5FU/RT的策略 患者衍生的器官和异种移植模型。通过减少对当前最好疗法的抵抗力，这 Project有可能为退伍军人管理局的直肠癌患者提供更好的结果 需要更好的护理。已开发的高度翻译的RC重点研究项目的优势 独特的患者衍生RC模型与我们世界级的鞘脂集团相结合，该集团开创了 已经准备好进行临床试验的S1P导向疗法。我们一起为一部小说构思了一个理论基础 实验性疗法，以及一种测试它的策略，承诺产生可以迅速推进的结果 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.