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1.
Nat Med ; 21(11): 1318-25, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26479923

ABSTRACT

Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.


Subject(s)
Antineoplastic Agents/therapeutic use , High-Throughput Screening Assays/methods , Neoplasms/drug therapy , Xenograft Model Antitumor Assays/methods , Animals , Breast Neoplasms/drug therapy , Carcinoma/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Pancreatic Ductal/drug therapy , Colorectal Neoplasms/drug therapy , Disease Models, Animal , Female , Humans , Lung Neoplasms/drug therapy , Melanoma/drug therapy , Mice , Neoplasm Transplantation , Pancreatic Neoplasms/drug therapy , Reproducibility of Results , Skin Neoplasms/drug therapy , Stomach Neoplasms/drug therapy
2.
Nat Genet ; 45(11): 1386-91, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24076604

ABSTRACT

Epigenetic dysregulation is an emerging hallmark of cancers. We developed a high-information-content mass spectrometry approach to profile global histone modifications in human cancers. When applied to 115 lines from the Cancer Cell Line Encyclopedia, this approach identified distinct molecular chromatin signatures. One signature was characterized by increased histone 3 lysine 36 (H3K36) dimethylation, exhibited by several lines harboring translocations in NSD2, which encodes a methyltransferase. A previously unknown NSD2 p.Glu1099Lys (p.E1099K) variant was identified in nontranslocated acute lymphoblastic leukemia (ALL) cell lines sharing this signature. Ectopic expression of the variant induced a chromatin signature characteristic of NSD2 hyperactivation and promoted transformation. NSD2 knockdown selectively inhibited the proliferation of NSD2-mutant lines and impaired the in vivo growth of an NSD2-mutant ALL xenograft. Sequencing analysis of >1,000 pediatric cancer genomes identified the NSD2 p.E1099K alteration in 14% of t(12;21) ETV6-RUNX1-containing ALLs. These findings identify NSD2 as a potential therapeutic target for pediatric ALL and provide a general framework for the functional annotation of cancer epigenomes.


Subject(s)
Chromatin/genetics , Histone-Lysine N-Methyltransferase/genetics , Histones/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Repressor Proteins/genetics , Animals , Base Sequence , Cell Line, Tumor , Child , Female , Genetic Predisposition to Disease , Genetic Variation , Humans , Mice , Mice, SCID , NIH 3T3 Cells , Neoplasm Transplantation , Sequence Analysis, DNA , Xenograft Model Antitumor Assays
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