Ex vivo treatment of patient biopsies as a novel method to assess colorectal tumour response to the MEK1/2 inhibitor, Selumetinib.
Ex vivo treatment of patient biopsies as a novel method to assess colorectal tumour response to the MEK1/2 inhibitor, Selumetinib.
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DOI：
10.1038/s41598-017-12222-9
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发表时间：
2017-09-20
影响因子：
4.6
通讯作者：
Stark LA
中科院分区：
文献类型：
--
作者：
Novo SM;Wedge SR;Stark LA
尽管已经出现了一系列用于治疗结直肠癌的新疗法，但它们的使用受到患者反应变化的显著影响。更好的临床前模型可以大大提高疗效，因为它可以将患者分层到正确的治疗方案中。在这里，我们探讨急性，离体治疗新鲜的，手术切除的人类结直肠肿瘤活检作为一种新的临床前模型，用于确定患者对特定治疗的反应。使用MEK 1/2抑制剂司美替尼（AZD 6244，ARRY-142886）作为工具化合物。首先，我们建立了一个急性治疗方案，并证明该方案可以区分对司美替尼（0-3uM）的表型和药效学反应。然后，我们使用该方案来评估来自23名结肠癌患者的肿瘤中的Selumetinib反应。这些研究表明，该药物抑制所有肿瘤中的pERK 1/2磷酸化，导致5/23（22%）肿瘤的增殖显著降低，并且KRAS/BRAF突变肿瘤对该药物的抗增殖作用特别敏感。这些数据与Selumetinib临床试验的数据一致，表明小肿瘤活检的急性治疗值得进一步探索，作为临床前模型来评估结直肠癌对新疗法的反应。
Although an array of new therapeutics has emerged for the treatment of colorectal cancer, their use is significantly impacted by variability in patient response. Better pre-clinical models could substantially improve efficacy as it may allow stratification of patients into the correct treatment regime. Here we explore acute, ex vivo treatment of fresh, surgically resected human colorectal tumour biopsies as a novel pre-clinical model for identifying patient response to specific therapeutics. The MEK1/2 inhibitor, Selumetinib (AZD6244, ARRY-142886) was used as a tool compound. Firstly, we established an acute treatment protocol and demonstrated this protocol could differentiate phenotypic and pharmacodynamic responses to Selumetinib (0–3uM). We then used the protocol to evaluate Selumetinib response in tumours from 23 colon cancer patients. These studies revealed that the agent inhibited pERK1/2 phosphorylation in all tumours, caused a significant decrease in proliferation in 5/23 (22%) tumours, and that KRAS/BRAF mutant tumours were particularly sensitive to the anti-proliferative effects of the agent. These data are consistent with data from clinical trials of Selumetinib, suggesting that acute treatment of small tumour biopsies is worthy of further exploration as a pre-clinical model to evaluate colorectal cancer response to novel therapies.
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影响因子：
6.3
作者：
Golovko D;Kedrin D;Yilmaz ÖH;Roper J
通讯作者：
Roper J
影响因子：
3
作者：
Leijen, Suzanne;Soetekouw, Patricia M. M. B.;Evans, T. R. Jeffry;Nicolson, Marianne;Schellens, Jan H. M.;Learoyd, Maria;Grinsted, Lynda;Zazulina, Victoria;Pwint, Thinn;Middleton, Mark
通讯作者：
Middleton, Mark
影响因子：
16.6
作者：
Majumder, Biswanath;Baraneedharan, Ulaganathan;Thiyagarajan, Saravanan;Radhakrishnan, Padhma;Narasimhan, Harikrishna;Dhandapani, Muthu;Brijwani, Nilesh;Pinto, Dency D.;Prasath, Arun;Shanthappa, Basavaraja U.;Thayakumar, Allen;Surendran, Rajagopalan;Babu, Govind K.;Shenoy, Ashok M.;Kuriakose, Moni A.;Bergthold, Guillaume;Horowitz, Peleg;Loda, Massimo;Beroukhim, Rameen;Agarwal, Shivani;Sengupta, Shiladitya;Sundaram, Mallikarjun;Majumder, Pradip K.
通讯作者：
Majumder, Pradip K.
影响因子：
5.7
作者：
Davies, Barry R.;Logie, Armelle;Smith, Paul D.
通讯作者：
Smith, Paul D.
影响因子：
64.5
作者：
van de Wetering M;Francies HE;Francis JM;Bounova G;Iorio F;Pronk A;van Houdt W;van Gorp J;Taylor-Weiner A;Kester L;McLaren-Douglas A;Blokker J;Jaksani S;Bartfeld S;Volckman R;van Sluis P;Li VS;Seepo S;Sekhar Pedamallu C;Cibulskis K;Carter SL;McKenna A;Lawrence MS;Lichtenstein L;Stewart C;Koster J;Versteeg R;van Oudenaarden A;Saez-Rodriguez J;Vries RG;Getz G;Wessels L;Stratton MR;McDermott U;Meyerson M;Garnett MJ;Clevers H
通讯作者：
Clevers H