Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer.
Cell Reports 16(7):2017 (2016)
Pancreatic ductal adenocarcinoma (PDAC) harbors the worst prognosis of any common solid tumor, and multiple failed clinical trials indicate therapeutic recalcitrance. Here, we use exome sequencing of patient tumors and find multiple conserved genetic alterations. However, the majority of tumors ...
Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer.
Journal of Hepatology 65(2):325 (2016)
Pediatric liver cancer is a rare but serious disease whose incidence is rising, and for which the therapeutic options are limited. Development of more targeted, less toxic therapies is hindered by the lack of an experimental animal model that captures the heterogeneity and metastatic capability ...
Analysis of phosphatases in ER-negative breast cancers identifies DUSP4 as a critical regulator of growth and invasion.
Breast Cancer Research and Treatment 158(3):441 (2016)
Estrogen receptor (ER)-negative cancers have a poor prognosis, and few targeted therapies are available for their treatment. Our previous analyses have identified potential kinase targets critical for the growth of ER-negative, progesterone receptor (PR)-negative and HER2-negative, or "triple-ne...
Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer.
Clinical Cancer Research 22(15):3764 (2016)
BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imb...
BRAF Mutation Testing in Cell-Free DNA from the Plasma of Patients with Advanced Cancers Using a Rapid, Automated Molecular Diagnostics System.
Molecular Cancer Therapeutics 15(6):1397 (2016)
Cell-free (cf) DNA from plasma offers an easily obtainable material for BRAF mutation analysis for diagnostics and response monitoring. In this study, plasma-derived cfDNA samples from patients with progressing advanced cancers or malignant histiocytosis with known BRAF(V600) status from formali...
Direct Upregulation of STAT3 by MicroRNA-551b-3p Deregulates Growth and Metastasis of Ovarian Cancer.
Cell Reports 15(7):1493 (2016)
3q26.2 amplification in high-grade serous ovarian cancer leads to increased expression of mature microRNA miR551b-3p, which is associated with poor clinical outcome. Importantly, miR551b-3p contributes to resistance to apoptosis and increased survival and proliferation of cancer cells in vitro a...
The degree of intratumor mutational heterogeneity varies by primary tumor sub-site.
Oncotarget 7(19):27185 (2016)
In an era where mutational profiles inform treatment options, it is critical to know the extent to which tumor biopsies represent the molecular profile of the primary and metastatic tumor. Head and neck squamous cell carcinoma (HNSCC) arise primarily in the mucosal lining of oral cavity and orop...
Comprehensive Characterization of Molecular Differences in Cancer between Male and Female Patients.
Cancer Cell 29(5):711 (2016)
An individual's sex has been long recognized as a key factor affecting cancer incidence, prognosis, and treatment responses. However, the molecular basis for sex disparities in cancer remains poorly understood. We performed a comprehensive analysis of molecular differences between male and femal...
Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors.
Journal of Clinical Investigation 126(5):1834 (2016)
Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAFV600E melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathway...
Rab11-FIP1C Is a Critical Negative Regulator in ErbB2-Mediated Mammary Tumor Progression.
Cancer Research 76(9):2662 (2016)
Rab coupling protein (FIP1C), an effector of the Rab11 GTPases, including Rab25, is amplified and overexpressed in 10% to 25% of primary breast cancers and correlates with poor clinical outcome. Rab25 is also frequently silenced in triple-negative breast cancer, suggesting its ability to functio...
HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors.
Cancer Research 76(9):2720 (2016)
The stress-inducible chaperone protein HSP70 (HSPA1) is implicated in melanoma development, and HSP70 inhibitors exert tumor-specific cytotoxic activity in cancer. In this study, we documented that a significant proportion of melanoma tumors express high levels of HSP70, particularly at advanced...
Cyclin E Associates with the Lipogenic Enzyme ATP-Citrate Lyase to Enable Malignant Growth of Breast Cancer Cells.
Cancer Research 76(8):2406 (2016)
Cyclin E is altered in nearly a third of invasive breast cancers where it is a powerful independent predictor of survival in women with stage I-III disease. Full-length cyclin E is posttranslationally cleaved into low molecular weight (LMW-E) isoforms, which are tumor-specific and accumulate in ...
Phosphatase PTP4A3 Promotes Triple-Negative Breast Cancer Growth and Predicts Poor Patient Survival.
Cancer Research 76(7):1942 (2016)
Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and women diagnosed with TNBC currently lack targeted treatment options. To identify novel targets for TNBC, we evaluated phosphatase expression in breast tumors and characterized their contributions to in vitro ...
Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies.
Clinical Cancer Research 22(7):1592 (2016)
To test second-line personalized medicine combination therapies, based on genomic and proteomic data, in patient-derived xenograft (PDX) models.
We established 12 PDXs from BRAF inhibitor-progressed melanoma patients. Following expansion, PDXs were analyzed using targeted sequencing and reverse-...
mTOR Inhibitors Suppress Homologous Recombination Repair and Synergize with PARP Inhibitors via Regulating SUV39H1 in BRCA-Proficient Triple-Negative Breast Cancer.
Clinical Cancer Research 22(7):1699 (2016)
Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and has the worst outcome among all subtypes of breast cancers. Although PARP inhibitors represent a promising treatment in TNBC with BRCA1/BRCA2 mutations, there is great interest in identifying drug combinations that can ex...
Inferring causal molecular networks: empirical assessment through a community-based effort.
Nature Methods 13(4):310 (2016)
It remains unclear whether causal, rather than merely correlational, relationships in molecular networks can be inferred in complex biological settings. Here we describe the HPN-DREAM network inference challenge, which focused on learning causal influences in signaling networks. We used phosphop...
Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma.
Cell Reports 14(10):2476 (2016)
On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron...
Reply to M.P. Decatris et al.
Journal of Clinical Oncology 34(8):886 (2016)
Proteomic Characterization of Head and Neck Cancer Patient-Derived Xenografts.
Molecular Cancer Research 14(3):278 (2016)
Despite advances in treatment approaches for head and neck squamous cell carcinoma (HNSCC), survival rates have remained stagnant due to the paucity of preclinical models that accurately reflect the human tumor. Patient-derived xenografts (PDX) are an emerging model system where patient tumors a...
MAPK Activation Predicts Poor Outcome and the MEK Inhibitor, Selumetinib, Reverses Antiestrogen Resistance in ER-Positive High-Grade Serous Ovarian Cancer.
Clinical Cancer Research 22(4):935 (2016)
Although 67% of high-grade serous ovarian cancers (HGSOC) express the estrogen receptor (ER), most fail antiestrogen therapy. Because MAPK activation is frequent in ovarian cancer, we investigated if estrogen regulates MAPK and if MEK inhibition (MEKi) reverses antiestrogen resistance.