Baseline tumor gene expression signatures correlate with chemoimmunotherapy treatment responsiveness in canine B cell lymphoma.
Baseline tumor gene expression signatures correlate with chemoimmunotherapy treatment responsiveness in canine B cell lymphoma.
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DOI：
10.1371/journal.pone.0290428
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
宠物狗发生自发性弥漫性大B细胞淋巴瘤（DLBCL），并且兽医临床试验已用于治疗犬DLBCL并告知其人类同伴的临床试验。仍然存在的一个挑战是选择治疗以改善结果。本研究中的犬是一项大型临床试验的一部分，该试验评价了多柔比星化疗、抗CD 20单克隆抗体和三种小分子抑制剂之一（KPT-9274、TAK-981或RV 1001）的联合使用。我们假设，在基线时肿瘤中基因（DEG）的显著差异表达可以帮助预测哪些狗对每种药物靶向的分子途径的每种治疗反应更好。为此，我们使用NanoString nCounter犬免疫肿瘤学（IO）面板评估了18只试验犬淋巴结抽吸物中的基因表达。我们将良好反应者定义为90天后复发的患者，将不良反应者定义为90天前复发的患者。我们分析了基线时的所有狗，并将不良反应者与良好反应者进行了比较，发现CCND 3增加与不良预后相关，CD 36增加与良好预后相关，正如在人类中观察到的那样。治疗组之间的DEG重叠最少，因此需要对每个治疗队列进行单独分析。KPT-9274的CREBBP和CDKN 1A升高，TAK-981的TLR 3升高，RV 1001的PI 3 K δ、AKT 3和PTEN升高以及NRAS降低与更好的治疗相关。通过qPCR确认所选候选生物标志物基因的趋势。我们的研究结果强调了DLBCL的异质性，犬和人DLBCL之间的相似性和差异性，并最终确定了可能有助于指导犬选择化学免疫治疗的生物标志物。
Pet dogs develop spontaneous diffuse large B cell lymphoma (DLBCL), and veterinary clinical trials have been employed to treat canine DLBCL and to inform clinical trials for their human companions. A challenge that remains is selection of treatment to improve outcomes. The dogs in this study were part of a larger clinical trial evaluating the use of combinations of doxorubicin chemotherapy, anti-CD20 monoclonal antibody, and one of three small molecule inhibitors: KPT-9274, TAK-981, or RV1001. We hypothesized that significant differential expression of genes (DEGs) in the tumors at baseline could help predict which dogs would respond better to each treatment based on the molecular pathways targeted by each drug. To this end, we evaluated gene expression in lymph node aspirates from 18 trial dogs using the NanoString nCounter Canine Immuno-oncology (IO) Panel. We defined good responders as those who relapsed after 90 days, and poor responders as those who relapsed prior to 90 days. We analyzed all dogs at baseline and compared poor responders to good responders, and found increased CCND3 correlated with poor prognosis and increased CD36 correlated with good prognosis, as is observed in humans. There was minimal DEG overlap between treatment arms, prompting separate analyses for each treatment cohort. Increased CREBBP and CDKN1A for KPT-9274, increased TLR3 for TAK-981, and increased PI3Kδ, AKT3, and PTEN, and decreased NRAS for RV1001 were associated with better prognoses. Trends for selected candidate biomarker genes were confirmed via qPCR. Our findings emphasize the heterogeneity in DLBCL, similarities and differences between canine and human DLBCL, and ultimately identify biomarkers that may help guide the choice of chemoimmunotherapy treatment in dogs.
影响因子：
3.7
作者：
Gardner HL;Rippy SB;Bear MD;Cronin KL;Heeb H;Burr H;Cannon CM;Penmetsa KV;Viswanadha S;Vakkalanka S;London CA
通讯作者：
London CA
影响因子：
3.7
作者：
Pinheiro D;Chang YM;Bryant H;Szladovits B;Dalessandri T;Davison LJ;Yallop E;Mills E;Leo C;Lara A;Stell A;Polton G;Garden OA
通讯作者：
Garden OA