Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer.
Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer.
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DOI：
10.1136/gutjnl-2017-315144
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发表时间：
2018-12
期刊：
影响因子：
24.5
通讯作者：
Pajic M
中科院分区：
文献类型：
--
作者：
Chou A;Froio D;Nagrial AM;Parkin A;Murphy KJ;Chin VT;Wohl D;Steinmann A;Stark R;Drury A;Walters SN;Vennin C;Burgess A;Pinese M;Chantrill LA;Cowley MJ;Molloy TJ;Australian Pancreatic Cancer Genome Initiative (APGI);Waddell N;Johns A;Grimmond SM;Chang DK;Biankin AV;Sansom OJ;Morton JP;Grey ST;Cox TR;Turchini J;Samra J;Clarke SJ;Timpson P;Gill AJ;Pajic M
胰腺导管腺癌（PDA）广泛的分子异质性、有效的治疗方法很少以及死亡率高，使得这种疾病成为推进定制疗法开发的主要模型。 p16-细胞周期蛋白 D-细胞周期蛋白依赖性激酶 4/6-视网膜母细胞瘤 (RB) 蛋白 (CDK4) 通路（细胞增殖的调节因子）在 PDA 中失调。我们的目标是开发一种基于 CDK4 的新型 PDA 个性化治疗策略。对强效 CDK4/6 抑制剂 PD-0332991 (palbociclib) 的敏感性与 19 个主要患者来源的 PDA 系中的蛋白质和基因组数据相关，以确定反应的生物标志物。 PD-0332991 和联合疗法的体内疗效是在源自基因组测序患者标本和基因工程模型的皮下、脾内和原位肿瘤模型中确定的。从机制上讲，在肿瘤细胞和细胞外基质（ECM）信号传导的背景下研究了单一疗法和联合疗法。在独立的 PDA 患者队列（> 500 个样本）中评估和验证了伴随生物标志物 RB 蛋白的预后相关性。首次在 PDA 进展的多个阶段观察到基于 PD-0332991 的治疗的亚型特异性体内疗效：原发性肿瘤生长、复发（二线治疗）和转移情况，并且可能由简单的生物标志物（RB 蛋白）指导。 PD-0332991 显着破坏周围的 ECM 组织，导致体内静息、细胞凋亡增加、化疗敏感性提高、侵袭、转移扩散和 PDA 进展减少。 RB 蛋白在原发性可手术和转移性 PDA 中普遍存在，可能提供一种有前途的预测生物标志物来指导这种治疗方法。这项研究证明了当应用于分子亚型特异性背景时，PDA 中 CDK4 抑制的前景优于标准疗法。
Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4. Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens). Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach. This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.
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影响因子：
29.4
作者：
Apte MV;Wilson JS;Lugea A;Pandol SJ
通讯作者：
Pandol SJ
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3.7
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51.1
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24.5
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通讯作者：
Boeck S
影响因子：
15.9
作者：
Cen, Ling;Carlson, Brett L.;Sarkaria, Jann N.
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Sarkaria, Jann N.