A patient-derived-xenograft platform to study BRCA-deficient ovarian cancers

被引：53

作者：

George, Erin ^{[1
]}

Kim, Hyoung ^{[1
]}

Krepler, Clemens ^{[2
]}

Wenz, Brandon ^{[3
]}

Makvandi, Mehran ^{[4
]}

Tanyi, Janos L. ^{[1
]}

Brown, Eric ^{[5
]}

Zhang, Rugang ^{[2
]}

Brafford, Patricia ^{[2
]}

Jean, Stephanie ^{[1
]}

Mach, Robert H. ^{[4
]}

Lu, Yiling ^{[6
]}

Mills, Gordon B. ^{[6
]}

Herlyn, Meenhard ^{[2
]}

Morgan, Mark ^{[1
]}

Zhang, Xiaochen ^{[1
]}

Soslow, Robert ^{[7
]}

Drapkin, Ronny ^{[1
]}

Johnson, Neil ^{[8
]}

Zheng, Ying ^{[9
]}

Cotsarelis, George ^{[9
]}

Nathanson, Katherine L. ^{[3
]}

Simpkins, Fiona ^{[1
,2
]}

机构：

[1] Univ Penn, Dept Obstet & Gynecol, Div Gynecol Oncol, Ovarian Canc Res Ctr, Philadelphia, PA 19104 USA

[2] Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA

[3] Abramson Canc Ctr, Oncogen, Philadelphia, PA USA

[4] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA

[5] Univ Penn, Canc Biol, Philadelphia, PA 19104 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[7] Mem Sloan Kettering, Dept Pathol, New York, NY USA

[8] Fox Chase Canc Ctr, Mol Therapeut Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA

[9] Univ Penn, Dept Dermatol, Perelman Sch Med, Philadelphia, PA 19104 USA

来源：

JCI INSIGHT | 2017年 / 2卷 / 01期

关键词：

CELL-LINES; TUMOR HETEROGENEITY; SYNTHETIC LETHALITY; MOLECULAR PATHWAYS; TARGETING ATR; DNA-REPAIR; REPLICATION; CHK1; INHIBITION; MODELS;

D O I：

10.1172/jci.insight.89760

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e., BRCA1/2). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors. Fourteen orthotopic HGSOC PDX models with BRCA mutations (BRCAMUT) were established with a 93% success rate. The orthotopic PDX model emulates the natural progression of HGSOC, including development of a primary ovarian tumor and metastasis to abdominal viscera. PDX response to standard chemotherapy correlated to that demonstrated in the patient. Pathogenic mutations and HGSOC markers were preserved after multiple mouse passages, indicating retention of underlying molecular mechanisms of carcinogenesis. A BRCA2(MUT) PDX with high p-CHK1 demonstrated a similar delay of tumor growth in response to PARP, CHK1, and ATR inhibitors. A poly (ADP-ribose) polymerase (PARP) inhibitor radiotracer correlated with PARP1 activity and showed response to PARP inhibition in the BRCA2(MUT) PDX model. In summary, the orthotopic HGSOC PDX represents a robust and reliable model to optimize therapeutic strategies for BRCA(MUT) HGSOC.

引用

页数：18

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