Therapeutic Induction and Image Guided Exploitation of Cellular senescence for Cancer Therapy

在之前的资助期内获得的数据导致发现了一种新型的细胞衰老，称为核糖体检查点诱导衰老（RCIS）。功能性遗传筛选鉴定了RNA聚合酶I依赖转录的多蛋白复合物的组分，作为诱导RCIS的可药物靶点。体外和体内的概念验证研究表明，CX-5461是一种小分子干扰RNA聚合酶I依赖转录的物质，可有效诱导治疗诱导衰老（TIS）。并行开发一种新型的一流PET示踪剂，用于检测生物体中的衰老，使我们现在处于独特的位置，以探索图像引导使用CX-5461和其他促衰老疗法的概念。在癌基因诱导衰老（OIS）背景下的研究表明，衰老细胞的持续存在可能促进癌症的进展，但目前尚不清楚TIS是否也对邻近的非衰老癌细胞发挥致蛋白作用。因此，我们将着手解决衰老生物学中的这个基本问题，使用小鼠模型，允许在癌细胞亚部分中遗传诱导TIS。由于这些癌细胞将通过基因工程来表达小鼠HB-EGF，因此白喉毒素的系统应用将允许有效和定向地消除这些细胞。这些研究将模仿目前正在开发的药物抗衰老疗法的使用。概述的系统将使我们能够探索治疗诱导衰老（TIS）和衰老策略对肝癌维持和进展的影响。此外，我们将寻求双重核糖体靶向治疗结直肠癌和其他实体肿瘤的策略。我们最近观察到，CX-5461在一名携带Shwachman-Bodian-Diamond综合征（SBDS）蛋白杂合突变的晚期耐药结直肠癌（CRC）患者中出现了明显的治疗反应，这一目标可以被视为一种从床边到实验室的方法。我们假设患者表现出明显的反应，因为即使是SBDS功能的杂合丧失也可能与核糖体成熟缺陷和核糖体应激有关，因此可能与CX-5461介导的RNA聚合酶- 1抑制有关。在这个研究项目中，我们将使用体外和体内模型来机械地表征这种可能性。最后，我们与Antti Poso （Z02）密切合作，旨在开发直接或间接抑制SBDS功能的药理学工具和探针。

Data acquired in the previous funding period led to the discovery of a novel type of cellular senescence, designated ribosomal checkpoint induced senescence (RCIS). Functional genetic screens identified components of the multiprotein complex of RNA Polymerase I dependent transcription as druggable targets to induce RCIS. Proof-of-concept studies in vitro and in vivo showed that CX-5461, a small molecule disrupting RNA Polymerase I dependent transcription, robustly induced therapy induced senescence (TIS). The parallel development of a novel first in class PET tracer, to detect senescence in living organisms, brings us now in the unique position to explore the concept of an image guided use of CX-5461 and other pro-senescence therapies.Studies in the context of Oncogene Induced Senescence (OIS) have shown that a sustained presence of senescent cells might promote cancer progression, however it is currently unclear whether TIS also exerts protumorigenic effects on adjacent non-senescent cancer cells. We will therefore set out to address this fundamental question in senescence biology using mouse models allowing to genetically induce TIS in a subfraction of cancer cells. As these cancer cells will be genetically engineered to express murine HB-EGF, a systemic application of Diptheria Toxin will allow for an efficient and site directed elimination of these cells. These studies will mimick the use of pharmacological senolytic therapies which are currently under development. The outlined system will allow us to probe the impact of therapy induced senescence (TIS) and senolytic strategies on liver cancer maintenance and progression. We furthermore will pursue strategies for a dual ribosome targeting for the treatment of colorectal cancer and other solid tumors. This aim can be seen as a bedside to bench approach, as we recently observed a pronounced therapy response towards CX-5461 in a patient with advanced therapy resistant colorectal cancer (CRC) carrying a heterozygous mutation of the Shwachman-Bodian-Diamond syndrome (SBDS) protein. We hypothesize that the patient showed a pronounced response because even a heterozygous loss of SBDS function might be associated with a defect in ribosome maturation and ribosomal stress and might thus be synthetic lethal with CX-5461 mediated inhibition of RNA Polymerase-I. Within this research project we will mechanistically characterize this possibility using in vitro and in vivo models. Finally, in close collaboration with Antti Poso (Z02), we aim to develop pharmacological tools and probes for direct or indirect inhibition of SBDS function.