LOCATE: Local Oesophageal CAncer Treatment Engineering to advance the understanding and treatment of oesophageal adenocarcinoma.

在英国，每年约有9000人被诊断出患有食道癌，这种疾病导致了5%的癌症相关死亡。研究工作必须继续发现新的治疗方法，特别是对于食管癌（OAC，西方国家最常见的食管癌亚型），因为即使在可手术阶段诊断的癌症在手术和化疗后复发的风险也有50%，并且诊断和治疗后5年的生存率仍然很低（10-15%）（https://www.cancerresearchuk.org/about-cancer/oesophageal-cancer）。因此，英国癌症研究中心和医学研究理事会将OAC描述为急需满足的需求。增强免疫系统抗癌能力的新药（免疫疗法）可以延长OAC患者的生命，平均对10-20%的患者有效。许多癌症对这些药物不起作用的原因之一与局部免疫抑制有关，这种抑制会关闭抗癌反应。我们小组的研究已经确定了癌症关闭抗癌反应的关键机制之一，因此我们提出了一种新的策略来释放抗癌防御的刹车。我们建议使用RNA疗法，这需要制备成类似于covid - 19 mRNA疫苗的纳米药物。由于在治疗方案中加入许多全身药物（口服或静脉注射药物）可以显着增加毒性，同时在需要的地方（例如癌症内部）保留稀释效果，我们还建议进行深入的工程研究，结合定制的生化技术，使这种新型rna纳米药物能够在癌症内部最佳地传递，针对负责阻碍抗癌免疫的特定细胞群。在我们位于伦敦、爱丁堡和曼彻斯特的工程、物理、生物化学和免疫生物学实验室中，我们将测试我们的想法是否可行（工程和物理模拟能否推动一种新的纳米药物的创造，这种药物能够实现有效的局部递送并解决肿瘤内特定类型的细胞？）这种新的、非常精确的纳米药物能有效地恢复抗癌免疫反应吗？如果我们的结果被证明是积极的，这种新的治疗方法将为OAC患者带来新的希望：虽然这个提议是一个原理验证，早期临床前研究，但我们的长期计划是走向临床应用（我们将开始申请必要的临床前测试的资金，并在工作包3期间确定I期临床试验的资金和利益相关者）。本项目的研究成果不仅将为工程、生物化学和免疫肿瘤学的学术知识做出贡献，而且还将为未来的医学研究提供潜在的有用工具。此外，我们的研究结果将间接促进其他癌症的治疗，因为我们设计纳米药物的新策略可以应用于其他疾病。

Every year ~9000 people are diagnosed with oesophageal cancers in UK, and this disease is responsible for 5% of cancer-related deaths. Research efforts must continue to discover new therapies, in particular for oesophageal adenocarcinoma (OAC, the most common subtype of oesophageal cancers in Western Countries), because even cancers diagnosed at an operable stage have 50% of risk to recur after surgery and chemotherapy and the survival at 5 year from diagnosis and treatment remains very low (10-15%) (https://www.cancerresearchuk.org/about-cancer/oesophageal-cancer). Therefore, Cancer Research UK and Medical Research Council have described OAC as having urgent unmet need. New medicines that boost the immune system against cancer (immunotherapies) can prolong life of patients with OAC and are effective in average for 10-20% of patients. One of the reasons why many cancers defy these medicines is related to a local immune-suppression that shuts the anti-cancer responses down. The research of our group has identified one of the critical mechanisms by which cancers shut the anti-cancer responses down, hence we are proposing a new strategy to release the brakes of the anti-cancer defences. We propose to use an RNA therapeutic, which requires to be prepared into nanomedicine similar to the COVID19 mRNA vaccines. Since adding up many systemic drugs (oral or intravenous medicines) to treatment protocols can significantly increase toxicity while retaining diluted effects where they are needed (e.g. inside the cancer), we also propose to perform an in-depth engineering study combined with bespoke biochemical technologies to allow this novel RNA-based nanomedicine to be delivered optimally inside the cancer, targeting a specific group of cells responsible for hampering the anti-cancer immunity. In our engineering, physics, biochemistry and immune-biology labs in London, Edinburgh and Manchester we will test if our ideas are feasible (Can engineering and physical simulations drive the creation of a new nanomedicine capable to achieve effective localised delivery and address a specific type of cells within the tumour? Can this new, very precise nanomedicine effectively restore anti-cancer immune responses?). If our results are demonstrated to be positive, this new therapeutic will bring new hope to OAC patients: although this proposal is for a proof of principle, early-stage preclinical study, our long-term plan is to move towards a clinical application (we will start to apply for funding for the necessary pre-clinical testing and identify funding and stakeholders for a Phase I clinical trial during Work Package 3). The results of our project will contribute not only to the engineering, biochemistry and immune-oncology academic knowledge, but also provide a potential useful tool against OAC for the medicine of the future. Also, our results would indirectly contribute to advance treatment of other cancers since our new strategy to design nanomedicines could be applied to other diseases.