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【35under35】沙欢欢医生：从临床发现问题，回临床解决问题

2023年08月22日

作者：沙欢欢

医院：江苏省肿瘤医院

沙欢欢

主治医师

江苏省肿瘤医院肿瘤内科
至今发表SCI论文20余篇。其中第一/共一作者14篇，累计总影响因子55+。
主持国自然青年项目1项，参与国自然面上项目1项。

近年来，转化医学被越来越高频地提及，在一定程度上，转化医学从临床发现问题，继而开展科学研究，再将研究成果应用于临床，促进成果转化。是实现医学技术从临床中来，到临床中去。基于临床需求，明确研究方向、构建临床选题，聚焦主要障碍，开展科学研究，最终使科研成果回归临床，满足临床需求。
一．确定研究目的
开展探索性科研前首先要明确研究方向和临床意义：是研究某种疾病的病因及发生发展机制？还是如何提高某种疾病诊断的精确度？或是某种治疗方法是否能影响某种疾病的转归？又或是研究某种干预对疾病预后的影响？以近年结直肠癌研究为例，研究者发现肿瘤相关细菌在肿瘤中起着至关重要的作用，常规的放化疗导致相关细菌的失活从而影响疗效导致肿瘤进一步发展^[1]；DYNAMIC研究表明使用MRD进行预后风险评估，或可使一部分II期的患者免于术后辅助治疗^[2]；最新研究表明免疫治疗能提高部分局晚期MSI直肠癌患者的保肛率甚至使患者免于手术治疗[3]。这些基础或临床研究均从临床实际需求出发，聚焦于疾病发展机制或临床转归，最终达到提高疗效，延长生命，提高生存质量的目标。
二．构建科研选题
基于研究方向和临床需求构建临床问题。例如靶向和免疫治疗时代，结直肠癌对比其他常见肿瘤如肺癌、乳腺癌等，其治疗药物种类、方案选择及有效率仍非常有限。究其原因，结直肠癌是一个异质性很强的瘤种,不同患者个体间可表现为不同的遗传背景、不同的病理类型、不同的分化状态、不同的基因突变谱和转录组、蛋白质组表达谱等。甚至同一个体在疾病进展中的不同时期、不同病灶间, 都会出现明显的异质性。尽管TCGA和ICGC已经定义了人类最常见恶性肿瘤的复杂遗传景观^[4-10]。然而，只有小比例的癌症突变可被作为治疗靶点^{[11, 12]}，在结直肠癌中更是少之又少。近年来，抗HER-2治疗、NTRK抑制剂、KRAS G12C靶向药物在肠癌中的临床研究正在开展。如何针对结直肠癌异质性设计更为有效的个体化治疗方案是目前亟待解决的问题。而实现精准治疗的一个主要障碍是我们不完全了解肿瘤基因型和药物敏感性之间的关系。
另外，尽管制药技术水平和人类对疾病的认知在提高，但这些进步转化为新药研发的速度远远慢于预期。一个新药的研发耗时长，成本高，风险未知。随着对药物安全性及有效性的要求不断提高，开发新药的成本还将持续上涨。为了解决这些问题，许多研究者已经转向在基因注释的人类肿瘤细胞系中进行大规模的化学药物筛选^[13-16]。近年来，癌症细胞系药物筛选的规模也急剧扩大^[17-23]。与此同时，寻找现有药物的新适应症也已成为极具吸引力的新策略[24, 25]。
三．开展研究计划
目前仍有多个瘤种的抗肿瘤治疗所基于的分子分层并不能完全反应肿瘤的复杂性、基因型和表型，尤其是像结直肠癌这种异质性强的病种。随着多组学检测技术的迅猛发展，通过关注并整合空间基因组学、染色质构象、空间转录组和蛋白质组以及液态活检等，可以发现一些新的肿瘤驱动基因、耐药基因及位点；可以帮助理解肿瘤的三维分子结构，并揭示肿瘤内的异质性、肿瘤细胞与免疫微环境之间的作用；可以解析肿瘤治疗过程中分子结构的动态变化。基于以上技术，全方位整合个体患者水平上肿瘤基因改变、蛋白表达、免疫能力及它们在疾病发生发展过程中的动态变化，可建立和验证可靠的疾病预测和预后生物标志物，以及开发新的靶向药物和治疗策略。
然而将科学研究成果转化为抗肿瘤有效疗法还存在一大瓶颈，也即药物有效性评估的模型。传统经典的癌症模型，细胞培养体系不具备免疫细胞、微环境和器官特异性的功能；PDX需要经历小鼠特异性的肿瘤演化^{[26, 27]}，二者均不能很好地复制肿瘤的组织复杂性与遗传异质性。因此，建立一个系统、完善的肿瘤研究模型是完成个体化精准治疗的基础条件。组织类器官技术近年来打破了上述瓶颈，其本质是具备三维结构的微器官，拥有类似真实器官的复杂结构，并能部分模拟来源组织或器官的生理功能^{[28, 29]}，还能保持基因表达的稳定性。在基因、转录、代谢、细胞和组织学上均较高水平地重现了其来源肿瘤的多样性和复杂性^[30]。因此在疾病研究，药物筛选，毒理测试等领域展现出其应用潜力^[31-34]。可见此项技术或可搭建从科学研究到临床转化的快速通道，为肿瘤患者药物研究和个体化治疗提供新的平台。
四．回归临床需求
随着生命科学高通量技术、计算机数据分析和处理能力的迅速发展，结合多组学的研究，尤其是基因组、转录组、蛋白质组、代谢组以及生物信息学的迅猛发展，可以更为精细、更为系统地揭示肿瘤的分子机制和异质性。在将其应用于临床实践之前，需具备可重复性的稳定可靠技术方法。建立高效疾病研究、药物筛选、毒理测试模型，针对每一名患者寻找和开发个体化的疗法，或许可更快、更好地把个体化精准疗法疗法带向临床。

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