PO.ET02.10 · 实验与分子治疗
在分子学定义的腹膜转移性结直肠癌(pmCRC)亚组中重新利用PARP抑制剂：患者来源异种移植(PDX)模型的临床前分析
Repurposing PARP inhibitors in molecularly defined subgroups of peritoneal metastatic colorectal cancer (pmCRC): Preclinical analysis of patient-derived xenograft (PDX) models
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作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
与其他器官（如肝或肺）发生转移的转移性结直肠癌(CRC)患者相比，腹膜转移性结直肠癌(pmCRC)的预后最差。更重要的是，尽管系统性治疗和腹膜特异性治疗均有所改善，仍有50%至90%的患者出现疾病复发和进展，导致过早死亡。精准肿瘤学已成功改善了多种实体和非实体恶性肿瘤的总生存期。对于CRC，人们已获得大量有关分子畸变的信息，对来自CRC的肺转移和肝转移进行了表征，从而推动了更加个体化的治疗方法。相反，对于pmCRC，这一工作尚未开展。为弥合这一空白并识别pmCRC中药物应答的新预测特征，我们此前建立了一个匹配的pmCRC临床前模型新平台，包括来自共10例pmCRC患者的腹膜转移灶的14个患者来源异种移植(PDX)，并表明对5-氟尿嘧啶(5-FU)固有耐药的肿瘤富集了DNA损伤应答与修复(DDR)机制的改变。因此我们假设，这些肿瘤对奥拉帕利(olaparib)等DDR抑制剂敏感。为验证这一假设，我们生成了一个由48个pmCRC PDX组成的新队列，并通过RNA测序进行了表征。基于转录组和突变谱，我们将14个PDX归类为同源重组缺陷(HRD)，将34个PDX归类为同源重组完备。在HRD阳性组中识别出的最常见改变是BRCA1/2的功能缺失性移码插入/缺失，以及其他同源重组修复基因的改变(HRRmut)。临床数据（尤其是治疗应答数据）与相应PDX模型的基因组谱相结合，支持了对5-FU耐药的预测。随后，共12个预测对基于5-FU的治疗方案耐药、但因HRD而对PARP敏感的pmCRC模型，分别接受了5-FU或奥拉帕利单药以及两者联合的治疗。应答数据将予以呈现。我们的研究凸显了分子分型对于改善个体化治疗的重要性。
查看英文原文 English abstract
Peritoneal metastatic colorectal cancer (pmCRC) has the worst outcome compared to metastatic CRC patients with metastases in other organs, such as liver or lung. More importantly, despite of the improvement of both systemic and peritoneal specific treatment, 50% to 90% of patients experience relapse and progression of the disease, leading to premature death. Precision oncology has successfully improved the overall survival of several solid and non-solid malignancies. For CRC, large volumes of information have been acquired regarding the molecular aberrations, characterizing both lung and liver metastases from CRC, thus leading to a more personalized treatment approach. On the contrary, this has not yet been done for pmCRC. In a comprehensive effort to close this gap and to identify new predictive signatures to drug responses in pmCRC, we previously established a novel platform of matched preclinical pmCRC models, including 14 patient-derived xenografts (PDX) of peritoneal metastases from a total of 10 pmCRC patients and showed that tumors intrinsically resistant to 5‑Fluorouracil (5‑FU) were enriched in alterations of the DNA damage response and repair (DDR) machinery. We therefore hypothesize, that those tumors are responsive to DDR inhibitors such as olaparib. In order to prove our hypothesis, we generated a new cohort of 48 pmCRC PDX, characterized by RNA sequencing. Based on both transcriptomic and mutational profiles, we classified 14 PDX as homologous recombination deficient (HRD) and 34 PDX as proficient. The most common alteration identified in the HRD positive group were loss-of-function frameshift insertions/deletions in BRCA1/2, in addition to other homologous recombination repair genes (HRRmut). Clinical data, in particular treatment response data, were combined with the genomic profiles of the respective PDX models, supporting the prediction of 5‑FU resistance. Subsequently, a total of 12 pmCRC models predicted to be resistant to 5‑FU-based treatment regimens, but sensitive to PARP due to HRD, were treated with 5‑FU or olaparib alone, as well as in combination. Response data will be presented. Our study highlights the importance of molecular profiling for better personalized treatment.
利益披露 Disclosure
M. Dahlmann, None..
B. Rau, None..
S. Gül-Klein, None..
B. Brzezicha, None..
M. Keil, None..
A. Wengner, None..
J. Hoffmann, None..
S. Stintzing, None..
U. S. Stein, None..
W. Walther, None..
L. Vecchione, None.