Johns Hopkins University

Genzyme Corporation

The United States of America, As Represented by the Secretary, Department of Health and Human Services

Esoterix Genetic Laboratories, LLC

Genzyne Corporation

The U.s.a. As Represented by the Secretary of the Hhs

David Sidransky

Jin Jen

Rafael Guerrero-Preston

Stephen L Madden

Stephen B Baylin

James Gordon Herman

Barry Trink

Gary A Beaudry

Mingzhao Michael Xing

Mariana S Nacht

Arthur H Bertlesen

Yoram Cohen

Hiromu Suzuki

Tatiana Dracheva

Edward A Ratovitski

Bert Vogelstein

Kenneth W Kinzler

Mohammad O Hoque

Akira Oki

Rafael Guerrero Preston

Anne Jedlicka

Eugene Izumchenko

Ethan Soudry

Komelia Polyak

Makiko Fliss

Christina Michailidi

Priscilla Brebi-Mieville

Methods for preventing or treating subjects having cancer based on the identification of pharmaceutical agents that target cancer stem cells (CSCs) have been identified. These methods include administering to the subject an effective amount of a COX2 inhibitor and an effective amount of a YAP1 inhibitor. In addition, methods of enhancing chemotherapeutic responses in cancer patients have been discovered and are described herein.

Pharmaceutical agents targeting cancer stem cells

The present invention provides methods for identifying the susceptibility of a cancer cell or population of cells to treatment with Epidermal Growth Factor (EGF) Tyrosine Kinase Inhibitors (TKIs), such as erlotinib. Methods for the in vitro diagnosis of the susceptibility of a tumor in a subject to treatment with TKIs and monitoring tumor susceptibility during treatment are also provided.

TGF(&#x3b2;)-MIR200-MIG6 pathway and its use in the treatment of cancer as an indicator of resistance to EGFR inhibitors

In accordance with one or more embodiments, the inventors have conducted the first comprehensive integrated genomic and epigenomic analysis in HNSCC, focusing on identifying genes that have concurrent promoter methylation, mutation and expression downregulation. The intersection of unbiased genome-wide methylation sequencing and methylation array screens uncovered 316 genes, which undergo promoter methylation in HNSCC. Close to 60% concordance was found between concurrent greater promoter methylation and gene downregulation, with PAX1 and PAX5 exhibiting the greatest expression loss. Methods for analyzing tissue samples from a subject for increased risk of poor survival outcomes from HNSCC are provided. Kits for measuring promoter methylation of the genes are also provided.

Hypermethylation biomarkers associated with poor survival outcomes for head and neck squamous cell cancer

Methods and kits for triaging a human papillomavirus (HPV)-positive woman into colposcopy are disclosed. The methods comprise determining the promoter methylation level of the promoter regions of a group of genes (e.g., viral and host genes) that exhibit increased promoter methylation in women having CIN2+ lesions as compared to women having no intraepithelial lesions or malignancy (NILM).

Method to use viral and host methylation markers for cervical cancer screening and triage in liquid prep, serum/plasma, and urine: PCR and sequencing based process methods

Methods for the quantifying HPV Trans Renal DNA (TrDNA) from a urine sample from a subject using a dual sequence-capture approach are disclosed. The presently disclosed methods can be used to predict cancers including, but not limited to, cervical, anal, penile, and oropharyngeal cancers.

Dual sequence-capture method for quantifying trans renal HPV DNA in urine

Differentially methylated oral squamous cell carcinoma (OSCC) biomarkers, identified in-vitro and validated in well-characterized surgical specimens, have shown poor clinical correlation in cohorts with different risk profiles. To overcome this lack of relevance we used the HumanMethylation27 BeadChip, publicly available methylation and expression array data, and Quantitative Methylation Specific PCR to uncover differential methylation in OSCC clinical samples with heterogeneous risk profiles. A two stage-design consisting of Discovery and Prevalence screens was used to identify differential promoter methylation and deregulated pathways in patients diagnosed with OSCC and head and neck squamous cell carcinoma. This Phase I Biomarker Development Trial identified a panel of differentially methylated genes in normal and OSCC clinical samples from patients with heterogeneous risk profiles. This panel may be useful for early detection and cancer prevention studies.

Hypermethylation biomarkers for detection of head and neck squamous cell cancer

Pap smears and HPV infection tests do not distinguish between lesions that will progress to an invasive carcinoma and those that will not. We aimed to identify epigenetic biomarkers for diagnosis and progression monitoring of premalignant lesions in cervical cancer. Hypermethylated genes were identified as potential biomarkers after validation by MSP, including GGTLA4 and ZNF516. The methylation frequency for these two genes was higher in tumor: GGTLA4 (100%) and ZNF516 (96%); than in normal samples: GGTLA4 (12%) and ZNF516 (16%). The methylation status of GGTLA4 showed a progression in methylation frequency from normal samples to invasive carcinoma. The immunohistochemical expression was lower in tumor for both: GGTLA4 (50.8%) and ZNF516 (66.2%); than in normal samples: GGTLA4 (71.2%) and ZNF516 (88.1%) (p&#x3c;0.05). In conclusion, we identified methylation biomarkers for the molecular screening and characterization of cervical cancer.

Hypermethylation biomarkers for detection of cervical cancer

The present invention provides methods of determination of a global DNA methylation index (GDMI) in a sample from a subject, using a variety of methods which can detect global, genome-wide, and gene-specific DNA methylation to create methylation portraits that can be used for early detection, diagnosis, and clinical management in the personalized medicine space. Further, the invention provides methods of diagnosis of cancer, including gastric cancer and hepatocellular cancer in a subject, by comparing the GDMI in a sample obtained from a subject to the methylation index of standard controls. These methods allow diagnosis of gastric carcinoma and liver cancer in patients who may be asymptomatic or have inconclusive pathology, and allowing earlier treatment of the subject.

Global DNA hypomethylation and biomarkers for clinical indications in cancer

As described in more detail below, the present invention generally features compositions and non-invasive methods useful for the screening, identification, monitoring, or diagnosis of subjects having a neoplasia. The invention further provides highly accurate non-invasive methods for the staging or selection of treatment for a bladder, renal, or prostate cancer in a subject.

Neoplasia screening compositions and methods of use

The present invention provides methods for aiding in the diagnoses of the neoplastic condition of a lung cell and methods of screening for a potential therapeutic agent for the reversal of the neoplastic condition.

Methods for the diagnosis and treatment of lung cancer

The BRAF gene has been found to be activated by mutation in human cancers, predominantly in malignant melanoma. We tested 476 primary tumors, including 214 lung, 126 head and neck, 54 thyroid, 27 bladder, 38 cervical, and 17 prostate cancers, for the BRAF T1796A mutation by polymerase chain reaction (PCR)-restriction enzyme analysis of BRAF exon 15. In 24 (69%) of the 35 papillary thyroid carcinomas examined, we found a missense thymine (T)&#x2192;adenine (A) transversion at nucleotide 1796 in the BRAF gene (T1796A). The T1796A mutation was detected in four lung cancers and in six head and neck cancers but not in bladder, cervical, or prostate cancers. Our data suggested that activating BGRAF mutations may be an important even in the development of papillary thyroid cancer. Moreover, BRAF mutation reliably predicts a poor prognosis for papillary thyroid carcinomas.

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A method of identifying epigenetically silenced genes, e.g., methylation silenced genes, in cancer cells is provided. In addition, methods of identifying a cancer by detecting epigenetic silencing of gene expression are provided, as are methods of treating a subject having such a cancer, for example, a colorectal cancer and/or gastric cancer. Reagents for practicing such methods also are provided.

Genomic screen for epigenetically silenced genes associated with cancer

Methods of genomic screening to identify epigenetically silenced genes, including epigenetically silenced tumor suppressor genes are provided. Also provided are methods of detecting a cancer, for example, an esophageal squamous cell carcinoma or a head and neck squamous cell carcinoma, as are methods of treating a subject having such a cancer.

Genomic screen for epigenetically silenced tumor suppressor genes

We used hierarchical clustering to examine gene expression profiles generated by serial analysis of gene expression (SAGE) in a total of nine normal lung epithelial cells and non-small cell lung cancers (NSCLC). Separation of normal and tumor samples, as well as histopathological subtypes, was evident using the 3,921 most abundant transcript tags. This distinction remained when just 115 highly differentially expressed transcript tags were used. Furthermore, these 115 transcript tags clustered into groups that were suggestive of the unique biological and pathological features of the different tissues examined. Adenocarcinomas were characterized by high-level expression of small airway-associated or immunologically related proteins, while squamous cell carcinomas overexpressed genes involved in cellular detoxification or antioxidation. The messages of two p53-regulated genes, p21and 14-3-3&#x3c3;, were consistently under-expressed in the adenocarcinomas, suggesting that the p53 pathway itself might be compromised in this cancer type. Gene expression observed by SAGE were consistent with the results obtained by quantitative real-time PCR or cDNA array analyses using 43 additional lung tumor and normal samples. Thus, although derived from only a few tissue libraries, molecular signatures of non-small cell lung cancer derived from SAGE most likely represent an unbiased yet distinctive molecular signature for human lung cancer.

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Baltimore, MD, United States of America

David Sidransky