Johns Hopkins University

University System of Maryland

Mdxhealth, Sa

Stephen B Baylin

James Gordon Herman

Michele Makos Wales

David Sidransky

Feyruz Rassool

Carine Robert

Jean-Pierre Issa

Manel Esteller

Minoru Toyota

Khadiza Chowdhury

Nidal Muvarak

Drew M Pardoll

Suzanne L Topalian

Geert Trooskens

Wim Van Criekinge

Josef Straub

Leslie Cope

Hiromu Suzuki

Yoshimitsu Akiyama

Nita Ahuja

James Herman

Mi J Yi

Vasudev Bailey

Jeff Wang

Malcolm V Brock

Cynthia Zahnow

Huili Li

Angela Anne Guzzetta

Katherine Chiappinelli

Leander Van Neste

Kornel Schuebel

Joo-Mi Yi

Cancer therapies that combine epigenetic modulating agent(s) with immune modulating agent(s), which were remarkably identified to provide an improved treatment regimen over single agent therapy, are disclosed. In particular embodiments, the invention provides for improved treatment of NSCLC in patients via administration of exemplary immune modulating agents anti-PD-1 antibody or anti-PD-L1 antibody, which were observed to show enhanced activity in combination with the exemplary epigenetic modulating agent 5-deoxyazacytidine. Further, expression markers of responsive neoplastic cells are also disclosed.

Cancer therapy via a combination of epigenetic modulation and immune modulation

The present invention relates to the field of epigenetics. More specifically, the present invention provides methods and compositions useful for predicting response to epigenetic drug therapy. As described herein, we have identified a unique signature termed AZA Immune gene set or AIM that differentiates patients with a low immune and high immune signature and is regulated by epigenetic drugs such as demethylating drugs, histone deacetylase inhibitors. In certain embodiments, patients with a high immune signature may benefit from immunotherapies such as anti PD1 or anti PDL1 antibodies or vaccines. In other embodiments, patients with a low immune signature or low AIM would be patients who would then benefit from treatment with epigenetic drugs and then subsequent immunotherapy.

Predicting response to epigenetic drug therapy

The presently disclosed subject matter provides methods to treat cancer cells using low doses of DNA demethylating agents and poly ADP ribose polymerase (PARP) inhibitors. Methods also are provided for sensitizing a cell to a PARP inhibitor.

Therapy regimen and methods to sensitize cancer cells treated with epigenetic therapy to PARP inhibitors in multiple cancers

The present invention provides methods for identifying metastases by detecting nucleic acid hypermethylation of one or more genes in one or more samples, and in particular in the lymph nodes. The invention further relates to DNA methylation as a predictor of disease recurrence and patient prognosis, specifically in the field of cancer biology.

DNA methylation markers and methods of use

The invention provides compositions and methods for detecting a neoplasia (e.g., pancreatic cancer, lung cancer, colon cancer) in a subject sample (e.g., serum, blood, plasma, tissue). In particular embodiments, the invention provides methods for detecting BNC1 and ADAMTS1 promoter methylation in circulating DNA in serum.

Compositions and methods for detecting a neoplasia

Therapy regimen and methods to sensitize cancer cells treated with epigenetic therapy to PARP inhibitors in lung cancer

Therapy regimen and methods to sensitize cancer cells treated with epigenetic therapy to PARP inhibitors in ovarian cancer

The present invention provides a method for identifying a methylated CpG containing nucleic acid by contacting a nucleic acid with a methylation sensitive restriction endonuclease that cleaves unmethylated PcG sites and contacting the sample with an isoschizomer of the methylation sensitive restriction endonuclease, which cleaves both methylated and unmethylated CpG sites. The method also includes amplification of the CpG-containing nucleic acid using CpG-specific oligonucleotide primers. A method is also provided for detecting an age associated disorder by identification of a methylated CpG containing nucleic acid. A method is further provided for evaluating the responses of a cell to an agent. A kit is useful for detection of a CpG containing nucleic acid is also provided. Nucleic acid sequences encoding novel methylated clones.

Methylated CpG island amplification (MCA)

Methods are provided for identifying the presence of cancer cells in a sample by detecting hypermethylation of the promoter region of a GATA-4 transcription factor gene, a GATA-5 transcription factor gene, or both. Methods for ameliorating a cancer by effecting expression of a hypermethylation silenced GATA-4 and/or GATA-5 transcription also are provided.

Hypermethylation of GATA-4 and GATA-5 transcription factor genes in cancer

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

The present invention provides a method for identifying a methylated CpG containing nucleic acid by contacting a nucleic acid with a methylation sensitive restriction endonuclease that cleaves unmethylated CpG sites and contacting the sample with an isoschizomer of the methylation sensitive restriction endonuclease, which cleaves both methylated and unmethylated CpG sites. The method also includes amplification of the CpG-containing nucleic acid using CpG-specific oligonucleotide primers A method is also provided for detecting an age associated disorder by identification of a methylated CpG containing nucleic acid. A method is further provided for evaluation the response of a cell to an agent A kit useful for detection of a CpG containing nucleic acid is also provided. Nucleic acid sequences encoding novel methylated clones.

The present invention provides methods relating to chemotherapeutic treatment of a cell proliferative disorder. In particular, a method is provided for predicting the clinical response to certain types of chemotherapeutic agents. Alkylating agents, used for the treatment of certain types of tumors including tumors of the nervous system and lymph system, are efficacious agents when the damage they do to tumor cell DNA is not repaired by cellular DNA repair mechanisms. The present invention provides a method for determining the activity of a gene encoding a DNA repair enzyme, thus providing a prediction of the clinical response to alkylating agents.

Method of predicting the clinical response to chemotherapeutic treatment with alkylating agents

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Baltimore, MD, United States of America

Stephen B Baylin