Feasibility of Ultra-High-Throughput Functional Screening of Melanoma Biopsies for Discovery of Novel Cancer Drug Combinations

被引:6
|
作者
Friedman, Adam A. [1 ,2 ]
Xia, Yun [2 ,3 ]
Trippa, Lorenzo [4 ]
Long Phi Le [1 ]
Igras, Vivien [1 ,2 ]
Frederick, Dennie T. [1 ]
Wargo, Jennifer A. [1 ,5 ,6 ,7 ]
Tanabe, Kenneth K. [1 ,5 ]
Lawrence, Donald P. [1 ]
Neuberg, Donna S. [4 ]
Flaherty, Keith T. [1 ]
Fisher, David E. [1 ,2 ]
机构
[1] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Boston, MA USA
[2] Massachusetts Gen Hosp, Dermatol & Cutaneous Biol Res Ctr, Charlestown, MA USA
[3] Huazhong Univ Sci & Technol, Union Hosp, Dept Plast Surg, Tongji Med Coll, Wuhan, Hubei, Peoples R China
[4] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA
[5] Massachusetts Gen Hosp, Div Surg Oncol, Charlestown, MA USA
[6] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA
[7] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA
关键词
PHASE-I TRIAL; INHIBITOR; EXPRESSION; BORTEZOMIB; PATHWAY; KINASE; GROWTH; CELLS; BRAF; CARCINOGENESIS;
D O I
10.1158/1078-0432.CCR-16-3029
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Successful development of targeted therapy combinations for cancer patients depends on first discovering such combinations in predictive preclinical models. Stable cell lines and mouse xenograft models can have genetic and phenotypic drift and may take too long to generate to be useful as a personalized medicine tool. Experimental Design: To overcome these limitations, we have used a platform of ultra-high-throughput functional screening of primary biopsies preserving both cancer and stroma cell populations from melanoma patients to nominate such novel combinations from a library of thousands of drug combinations in a patient-specific manner within days of biopsy. In parallel, patientderived xenograft (PDX) mouse models were created and novel combinations tested for their ability to shrink matched PDXs. Results: The screening method identifies specific drug combinations in tumor cells with patterns that are distinct from those obtained from stable cell lines. Screening results were highly specific to individual patients. For patients with matched PDX models, we confirmed that individualized novel targeted therapy combinations could inhibit tumor growth. In particular, a combination of multi-kinase and PI3K/ Akt inhibitors was effective in some BRAF-wild-type melanomas, and the addition of cediranib to the BRAF inhibitor PLX4720 was effective in a PDX model with BRAF mutation. Conclusions: This proof-of-concept study demonstrates the feasibility of using primary biopsies directly for combinatorial drug discovery, complementing stable cell lines and xenografts, but with much greater speed and efficiency. This process could potentially be used in a clinical setting to rapidly identify therapeutic strategies for individual patients. (C) 2017 AACR.
引用
收藏
页码:4680 / 4692
页数:13
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