Identification of Subtypes of Barrett's Esophagus and Esophageal Adenocarcinoma Based on DNA Methylation Profiles and Integration of Transcriptome and Genome Data.

BACKGROUND & AIMS: Esophageal adenocarcinomas (EACs) are heterogeneous and often preceded by Barrett's esophagus (BE). Many genomic changes have been associated with development of BE and EAC, but little is known about epigenetic alterations. We performed epigenetic analyses of BE and EAC tissues and combined these data with transcriptome and genomic data to identify mechanisms that control gene expression and genome integrity. METHODS: In a retrospective cohort study, we collected tissue samples and clinical data from 150 BE and 285 EAC cases from the Oesophageal Cancer Classification and Molecular Stratification consortium in the United Kingdom. We analyzed methylation profiles of all BE and EAC tissues and assigned them to subgroups using non-negative matrix factorization with k-means clustering. Data from whole-genome sequencing and transcriptome studies were then incorporated; we performed integrative methylation and RNA-sequencing analyses to identify genes that were suppressed with increased methylation in promoter regions. Levels of different immune cell types were computed using single-sample gene set enrichment methods. We derived 8 organoids from 8 EAC tissues and tested their sensitivity to different drugs. RESULTS: BE and EAC samples shared genome-wide methylation features, compared with normal tissues (esophageal, gastric, and duodenum; controls) from the same patients and grouped into 4 subtypes. Subtype 1 was characterized by DNA hypermethylation with a high mutation burden and multiple mutations in genes in cell cycle and receptor tyrosine signaling pathways. Subtype 2 was characterized by a gene expression pattern associated with metabolic processes (ATP synthesis and fatty acid oxidation) and lack methylation at specific binding sites for transcription factors; 83% of samples of this subtype were BE and 17% were EAC. The third subtype did not have changes in methylation pattern, compared with control tissue, but had a gene expression pattern that indicated immune cell infiltration; this tumor type was associated with the shortest time of patient survival. The fourth subtype was characterized by DNA hypomethylation associated with structure rearrangements, copy number alterations, with preferential amplification of CCNE1 (cells with this gene amplification have been reported to be sensitive to CDK2 inhibitors). Organoids with reduced levels of MGMT and CHFR expression were sensitive to temozolomide and taxane drugs. CONCLUSIONS: In a comprehensive integrated analysis of methylation, transcriptome, and genome profiles of more than 400 BE and EAC tissues, along with clinical data, we identified 4 subtypes that were associated with patient outcomes and potential responses to therapy.

First-in-Human Phase I Study of MP0250, a First-in-Class DARPin Drug Candidate Targeting VEGF and HGF, in Patients With Advanced Solid Tumors.

PURPOSE: A first-in-human study was performed with MP0250, a DARPin drug candidate. MP0250 specifically inhibits both vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) with the aim of disrupting the tumor microenvironment. PATIENTS AND METHODS: A multicenter, open-label, repeated-dose, phase I study was conducted to assess the safety, tolerability, and pharmacokinetics of MP0250 in 45 patients with advanced solid tumors. In the dose-escalation part, 24 patients received MP0250 as a 3-hour infusion once every 2 weeks at five different dose levels (0.5-12 mg/kg). Once the maximum tolerated dose (MTD) was established, 21 patients were treated with a 1-hour infusion (n = 13, 8 mg/kg, once every 2 weeks and n = 8, 12 mg/kg, once every 3 weeks) of MP0250 in the dose confirmation cohorts. RESULTS: In the dose-escalation cohort, patients treated with 12 mg/kg MP0250 once every 2 weeks experienced dose-limiting toxicities. Therefore, MTD was 8 mg/kg once every 2 weeks or 12 mg/kg once every 3 weeks. The most common adverse events (AEs) were hypertension (69%), proteinuria (51%), and diarrhea and nausea (both 36%); hypoalbuminemia was reported in 24% of patients. Most AEs were consistent with inhibition of the VEGF and HGF pathways. Exposure was dose-proportional and sustained throughout the dosing period for all patients (up to 15 months). The half-life was about 2 weeks. Signs of single-agent antitumor activity were observed: 1 unconfirmed partial response with a time to progression of 23 weeks and 24 patients with stable disease, with the longest duration of 72 weeks and a median duration of 18 weeks. CONCLUSION: MP0250 is a first-in-class DARPin drug candidate with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other anticancer therapies.

POSEIDON Trial Phase 1b Results: Safety, Efficacy and Circulating Tumor DNA Response of the Beta Isoform-Sparing PI3K Inhibitor Taselisib (GDC-0032) Combined with Tamoxifen in Hormone Receptor Positive Metastatic Breast Cancer Patients.

PURPOSE: The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)-positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform-sparing PI3 kinase inhibitor. PATIENTS AND METHODS: 30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a "rolling six" design. RESULTS: Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%), and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically relevant correlates of clinical drug resistance (e.g., mutations in KRAS, ERBB2) in some patients. CONCLUSIONS: Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both PIK3CA mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting.