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PATH-27. IDENTIFYING THE GENETIC SIGNATURE OF RESPONSE IN A PHASE II STUDY OF TUMOR TREATING FIELDS IN RECURRENT GLIOBLASTOMA

ABSTRACT: Abstract Prognosis of relapsed glioblastoma (GBM) is dismal and current treatment fails to provide prolonged survival. Small subsets of patients respond well to some novel therapeutics probably due to the genetic variations of tumors and patients. In the Phase 3 EF-11 recurrent GBM trial, a small subset of patients derived significant benefit from TTFields alone. This proof-of-concept trial [NCT01954576] will study adult patients with relapsed GBM treated with TTFields by genetic analysis of primary and recurrent tumors. Post-hoc correlations will be used between clinical response, mutational analyses and quantitative gene expression to define genomic signatures of response. Whole exome and RNA sequencing will be used to identify genomic signature of responders to TTFields. Fifteen patients with bevacizumab-naïve recurrent GBM and 15 patients with bevacizumab-refractory GBM will be treated with TTFields for 6 and 4 months respectively. Patients will undergo standard brain MRI scans without and with gadolinium contrast and perfusion imaging every 8 weeks. Tissue from the primary tumor at recurrence will be genetically analyzed. Genomic DNA (gDNA) will be extracted from patients tumor and blood samples. Purified gDNA fragments will be used for Illumina sequencing library construction. Certain germ-line variants may contribute to gliomagenesis and be associated with somatic mutations within the tumor and subtypes of GBM more or less sensitive to TTFields. Analyses will be conducted on all patients: bevacizumab-naïve and bevacizumab-refractory GBM separately, and patients with objective radiographic response (complete response + partial response (CR + PR) and stable disease (SD) separately. With 50% bevacizumab-refractory GBM patients, response rate will be significantly higher than the baseline rate of 14%. Using an Exact test with type I error of 0.05 and 80% power, the estimated sample sizes will detect a statistical difference on response rate in the TTFields group compared to historical controls. To-date 4 patients have been enrolled.

SUBMITTER: Tran D

PROVIDER: S-EPMC6216658 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Project description:Glioblastoma is the most common yet most lethal of primary brain cancers with a one-year post-diagnosis survival rate of 65% and a five-year survival rate of barely 5%. Recently the U.S. Food and Drug Administration approved a novel fourth approach (in addition to surgery, radiation therapy, and chemotherapy) to treating glioblastoma; namely, tumor treating fields (TTFields). TTFields involves the delivery of alternating electric fields to the tumor but its mechanisms of action are not fully understood. Current theories involve TTFields disrupting mitosis due to interference with proper mitotic spindle assembly. We show that TTFields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics. Increased membrane permeability through the imposition of TTFields was shown by several approaches. For example, increased permeability was indicated through increased bioluminescence with TTFields exposure or with the increased binding and ingress of membrane-associating reagents such as Dextran-FITC or ethidium D or with the demonstration by scanning electron microscopy of augmented number and sizes of holes on the cellular membrane. Further investigations showed that increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24?h after cessation of alternating electric fields thus demonstrating that this phenomenom is reversible. Preliminary investigations showed that TTFields did not induce membrane holes in normal human fibroblasts thus suggesting that the phenomenom was specific to cancer cells. With TTFields, we present evidence showing augmented membrane accessibility by compounds such as 5-aminolevulinic acid, a reagent used intraoperatively to delineate tumor from normal tissue in glioblastoma patients. In addition, this mechanism helps to explain previous reports of additive and synergistic effects between TTFields and other chemotherapies. These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard of care strategies for these diseases.

Dataset Information

PATH-27. IDENTIFYING THE GENETIC SIGNATURE OF RESPONSE IN A PHASE II STUDY OF TUMOR TREATING FIELDS IN RECURRENT GLIOBLASTOMA

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