Lead identification using 3D models of pancreatic cancer.
Lead identification using 3D models of pancreatic cancer.
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DOI：
10.1016/j.slasd.2022.03.002
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发表时间：
2022-04
期刊：
影响因子：
3.1
通讯作者：
Spicer, Timothy P.
中科院分区：
文献类型：
--
作者：
Fernandez-Vega, Virneliz;Hou, Shurong;Plenker, Dennis;Tiriac, Herve;Baillargeon, Pierre;Shumate, Justin;Scampavia, Louis;Seldin, Jan;Souza, Glauco R.;Tuveson, David A.;Spicer, Timothy P.
最近的技术进步使3D组织培养模型能够用于快速和负担得起的HTS。我们不再局限于抗癌药物发现的2D模型，很明显，3D肿瘤模型为临床前研究的转化提供了更多的预测数据。在之前的研究中，我们验证了基于微板3D球体的技术与HTS自动化的兼容性。使用批准药物的小规模筛选表明，药物反应往往在2D和3D癌细胞增殖模型之间存在差异。在这里，我们将这种3D技术应用于有史以来第一次大规模的筛选工作，完成了针对原发性胰腺癌细胞的超过150K分子的HTS。这是第一次证明，使用直接从活检建立的临床相关的离体3D胰腺肿瘤模型的这种规模的筛选活动可以像使用2D细胞模型的传统药物筛选一样容易地实现。我们鉴定了四种独特的系列化合物，其具有亚微摩尔甚至低纳摩尔的效力，针对一组患者来源的胰腺类器官。我们还应用3D技术来测试自体癌症相关成纤维细胞中的铅功效，并发现了在癌症中优于野生型原代细胞的功效的有利特征，这是迈向更好的铅的重要里程碑。重要的是，最初的线索已在多个研究所得到进一步验证，结果一致。这里介绍的工作代表了使用原发性胰腺肿瘤细胞的3D模型发现的新小分子线索的起源。
Recent technological advances have enabled 3D tissue culture models for fast and affordable HTS. We are no longer bound to 2D models for anti-cancer agent discovery, and it is clear that 3D tumor models provide more predictive data for translation of preclinical studies. In a previous study, we validated a microplate 3D spheroid-based technology for its compatibility with HTS automation. Small-scale screens using approved drugs have demonstrated that drug responses tend to differ between 2D and 3D cancer cell proliferation models. Here, we applied this 3D technology to the first ever large-scale screening effort completing HTS on over 150K molecules against primary pancreatic cancer cells. It is the first demonstration that a screening campaign of this magnitude using clinically relevant, ex-vivo 3D pancreatic tumor models established directly from biopsy, can be readily achieved in a fashion like traditional drug screen using 2D cell models. We identified four unique series of compounds with sub micromolar and even low nanomolar potency against a panel of patient derived pancreatic organoids. We also applied the 3D technology to test lead efficacy in autologous cancer associated fibroblasts and found a favorable profile for better efficacy in the cancer over wild type primary cells, an important milestone towards better leads. Importantly, the initial leads have been further validated in across multiple institutes with concordant outcomes. The work presented here represents the genesis of new small molecule leads found using 3D models of primary pancreas tumor cells.
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影响因子：
3.8
作者：
Longati P;Jia X;Eimer J;Wagman A;Witt MR;Rehnmark S;Verbeke C;Toftgård R;Löhr M;Heuchel RL
通讯作者：
Heuchel RL
影响因子：
28.2
作者：
Tiriac H;Belleau P;Engle DD;Plenker D;Deschênes A;Somerville TDD;Froeling FEM;Burkhart RA;Denroche RE;Jang GH;Miyabayashi K;Young CM;Patel H;Ma M;LaComb JF;Palmaira RLD;Javed AA;Huynh JC;Johnson M;Arora K;Robine N;Shah M;Sanghvi R;Goetz AB;Lowder CY;Martello L;Driehuis E;LeComte N;Askan G;Iacobuzio-Donahue CA;Clevers H;Wood LD;Hruban RH;Thompson E;Aguirre AJ;Wolpin BM;Sasson A;Kim J;Wu M;Bucobo JC;Allen P;Sejpal DV;Nealon W;Sullivan JD;Winter JM;Gimotty PA;Grem JL;DiMaio DJ;Buscaglia JM;Grandgenett PM;Brody JR;Hollingsworth MA;O'Kane GM;Notta F;Kim E;Crawford JM;Devoe C;Ocean A;Wolfgang CL;Yu KH;Li E;Vakoc CR;Hubert B;Fischer SE;Wilson JM;Moffitt R;Knox J;Krasnitz A;Gallinger S;Tuveson DA
通讯作者：
Tuveson DA
影响因子：
7.3
作者：
Akce M;Zaidi MY;Waller EK;El-Rayes BF;Lesinski GB
通讯作者：
Lesinski GB
影响因子：
--
作者：
Wolff RA;Wang-Gillam A;Alvarez H;Tiriac H;Engle D;Hou S;Groff AF;San Lucas A;Bernard V;Allenson K;Castillo J;Kim D;Mulu F;Huang J;Stephens B;Wistuba II;Katz M;Varadhachary G;Park Y;Hicks J;Chinnaiyan A;Scampavia L;Spicer T;Gerhardinger C;Maitra A;Tuveson D;Rinn J;Lizee G;Yee C;Levine AJ
通讯作者：
Levine AJ
影响因子：
--
作者：
Pedró-Rosa L;Buckner FS;Ranade RM;Eberhart C;Madoux F;Gillespie JR;Koh CY;Brown S;Lohse J;Verlinde CL;Fan E;Bannister T;Scampavia L;Hol WG;Spicer T;Hodder P
通讯作者：
Hodder P