分子影像引导下多种NF-kB通路抑制剂靶向性治疗MALT1变异型大B细胞淋巴瘤的研究

Activated B cell-type (ABC) of diffuse-large B cell lymphoma (DLBCL) represents one of the most aggressive lymphoma entities. ABC DLBCLs are addicted to chronic B cell receptor (BCR) signaling that triggers canonical NF-κB activation. Inhibition of BCR signaling pathway, such as BTK with ibrutinib has demonstrated an overall response rate (ORR) of 41% in ABC-DLBCL. CARMA1-BCL10-MALT1 complex plays a very important role in NF-κB activation. However, patients with CD79BWT and MYD88mut or CARD11mut did not respond to ibrutinib, indicating the need for therapies targeting BCR-independent activation of NF-kB induced by these mutations. The recent approval of the PI3K inhibitor idelalisib for the treatment of relapsed or refractory lymphomas in combination with rituximab, follicular lymphoma (FL), and small lymphocytic leukemia (SLL) confirmed the utility of PI3K inhibitors in these NHL subtypes. And furthermore, based on the genetic background combinatorial BTK and MALT1 inhibition has also improved to be effectiveness of therapeutic treatment and reduce the chances for the development of drug resistances. G-protein coupled receptor 4 (CXCR4) play significant roles in promoting migration and trafficking of malignant B cells in hematological malignancies. CXCR4 has been detected in several tissues, in particular hematopoietic cells. And CXCR4 expression is a marker of DLBCL recurrence and associated with shorter survival. Additionally, current studies also show that CXCR4 expression directly correlate with therapeutic response of cancer cells under PI3K/mTOR inhibition. .In this study, we would employ CDX model bearing different DLBCL cells with CARMA1 or MALT1 mutation Tumor or PDX mouse model. The therapeutic response of lymphoma cells under single or combined targeted drug treatment as well as CXCR4 expression would be detected in vitro and in vivo. PET/CT will be performed before and after targeted drug treatment on mouse. 18F-FDG and 68Ga-Pentixafor, a CXCR4-targeted high-affinity nuclear probe, would be employed to detect change of tracer uptake response to single and combined therapy. Results would be compared with histological outcome. .Aims of this study: clarify influence on anti-cancer therapy in DLBCL induced by NF-κB mutation and obtain the suitable therapy, confirm CXCR4 as a suitable biomarker for DLBCL therapy as well as for prediction of anti-cancer treatment, establish PET/CT as a suitable imaging method for early prediction of therapeutic response to targeted drug treatment in DLBCL.

ABC型是弥漫性大B细胞淋巴瘤（DLBCL）中最具侵袭及转移特性的亚型，NF-κB通路的变异是其耐药或复发的主要原因，研究变异发生及调节机制对治疗有重要意义。我们发现：MALT1及BTK抑制剂的联合大大提高了基因变异淋巴瘤细胞的抑制。CXCR4是检测PI3K / mTOR抑制剂对DLBCL治疗效果的标靶，更是其复发的标志。我们的合作组已成功研发了以CXCR4为靶点的示踪剂并用于临床试验已经取得了可喜进展。据此我们提出假说：68Ga-Pentixafor-PET可作为多种NF-kB通路抑制剂靶向性治疗变异型大B细胞淋巴瘤的有效指导工具。本研究拟从分子、细胞和整体水平，利用变异细胞和CDX、PDX模型；FACS、免疫组化、免疫共沉淀等方法，探讨NF-kB通路变异的影响，寻求最佳治疗方案。本研究将以68Ga-Pentixafor探针这个新视点为引导建立DLBCL在体精准诊断及治疗的新技术。

弥漫大B细胞淋巴瘤（DLBCL）是成人淋巴瘤中最常见的一种类型，并且是一组在临床表现和预后等多方面具有很大异质性的恶性肿瘤，占我国成人非霍奇金恶性淋巴瘤发病率的50%左右。一线化疗方案（R-CHOP）虽可有效治疗部分患者，仍有超过30%的患者对治疗有抗性或复发。因此，对DLBCL患者治疗初期的治疗响应预测，选择适合的治疗方式，以尽早进行治疗策略调整，将有效提高DLBCL患者的治疗效率。然而，传统的预后评分系统无法准确识别高危患者。弥漫性大B细胞淋巴瘤诊疗指南（2022年版）建议患者在治疗前、中期和终末行全身PET/CT检查，目前的临床结果也证明18F-FDG PET/CT是淋巴瘤特别是DLBCL最优且已用于常规分期和疗效评价的技术手段，但在预测DLBCL疗效时仍无法准确预后。在治疗方面，由于癌症的高度异质性，传统的放化疗不能实现所有患者的有效治疗，新的适合的治疗策略的探索势在必行。另外，随着医学的快速发展，显像及治疗技术的革新，为癌症的诊疗提供了新的可能，建立适合的诊疗技术成为有效抑制易复发难治疗癌症的必要手段。.本课题组临床问题为中心，以临床转化应用为目的，旨在解决癌症诊疗中的难题。.首先，认真研究18F-FDG PET/CT在DLBCL中的应用，建立结合患者临床及影像学参数的模型，预测患者的治疗响应及2年内疾病进展情况，辅助临床筛选易复发患者，并规划适当的治疗及随访方案（目前文章已接收）；.其次，针对传统放化疗不敏感或易复发难治疗患者，我们进一步探寻适用的治疗及显像方案，辅助临床建立新的诊疗策略，提高治疗效率，以期提高患者生存质量，延长生存期并有效节省医疗资源（已发表相关文章3篇，在研一篇）；.最后，随着核医学的发展，新的显像药物被研发，本课题组通过国际合作，引进高质量显像剂并完成自主生产，实现临床转化，为疾病诊疗的可视化提供保障，辅助临床提高疾病诊治准确率（已发表相关文章2篇，在研一篇）。