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DNA repair/modulation

Session: Poster Session

DNAR-05 - Exceptional Responders to Base Excision Repair (BER) Inhibition for Recurrent Glioblastoma Display Enrichment for DNA Damage Response Pathways: RNA Sequencing Analysis from a Multicenter Trial

Friday, November 17, 2023
7:30 PM – 9:30 PM PT
Location: Exhibit Hall A/B
Non-CME

    Author(s)

  • AO

    Ahmad Ozair

    Miami Cancer Institute, Baptist Health South Florida
    Miami, Florida, United States

  • JD

    Jan Drappatz

    University of Pittsburgh Medical Center
    Pittsburgh, Pennsylvania, United States

  • XY

    Xiaobu Ye

    Johns Hopkins university
    Baltimore, Maryland, United States

  • MB

    Michael Berens

    Translational Genomics Research Institute
    Phoenix, Arizona, United States

  • SP

    Sen Peng

    Translational Genomics Research Institute
    Phoenix, Arizona, United States

  • SR

    Sanhita Rath

    Translational Genomics Research Institute
    Phoenix, Arizona, United States

  • HD

    Harshil Dhruv

    Translational Genomics Research Institute
    Phoenix, Arizona, United States

  • Tobias Walbert

    Henry Ford Health
    Detroit, Michigan, United States

  • Matthias Holdhoff

    Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    Baltimore, Maryland, United States

  • Glenn J. Lesser

    Wake Forest University School of Medicine
    Winston-Salem, North Carolina, United States

  • Timothy F. Cloughesy

    University of California Los Angeles
    Los Angeles, California, United States

  • AS

    Andrew E. Sloan

    Piedmont Health
    Atlanta, Georgia, United States

  • MC

    Marta Couce

    University Hospitals Cleveland Medical Center
    Cleveland, Ohio, United States

  • David M. Peereboom

    Cleveland Clinic, Ohio
    Cleveland, Ohio, United States

  • Burt Nabors

    Heersink School of Medicine
    Birmingham, Alabama, United States

  • Patrick Y. Wen

    Dana-Farber Cancer Institute
    Boston, Massachusetts, United States

  • LR

    Lisa Rogers

    Henry Ford Health System
    Detroit, Michigan, United States

  • Stuart A. Grossman

    Department of Oncology, Johns Hopkins University School of Medicine
    Baltimore, Maryland, United States

    • Poster Presenter(s)

  • Manmeet S. Ahluwalia

    Miami Cancer Institute, Baptist Health South Florida
    Miami, Florida, United States


Introduction: Therapies for glioblastoma recurrence after surgery and chemoradiation are warranted. TRC102 (methoxyamine), a small molecule DNA base-excision repair (BER) inhibitor, reverses temozolomide (TMZ) resistance in preclinical glioma models. We had investigated efficacy of TRC102+TMZ for recurrent glioblastoma (rGBM) through a multicenter trial. This work sought to report translational findings from RNA sequencing performed on patients with available tumor tissue.

Method: A two-arm, two-stage, non-randomized, Phase II trial of TRC102+TMZ for adults with rGBM named BERT was conducted. Arm 1 included bevacizumab-naive patients at first recurrence, with primary aim of estimating response rates using RANO criteria. If sufficient activity was identified, arm 2 was planned in bevacizumab-refractory patients. Secondary aims were to determine overall survival (OS), progression-free survival (PFS), 6-month PFS, and toxicity. Exploratory aims were correlating clinical outcomes with MPG expression and MGMT methylation. Differential gene expression profiling was analyzed using DESeq2 GSVA (RRID:SCR_015687) and transformed into enrichment scores for 'hallmark of DNA repair' pathways from Molecular Signatures Database (MSigDB, RRID:SCR_016863) to assign mechanistic signatures of therapeutic vulnerability.

Results: Arm 1 enrolled 19 patients with median of two treatment cycles, but objective responses were not observed. Hence, arm 2 did not open. Median OS was 11.1 months (95%CI 8.2-17.9). Median PFS was 1.9 months (95%CI 1.8-3.7). MGMT promoter was unmethylated in 14/19 patients, and MPG expression was present in 8/14 cases with available tumor tissue. MGMT methylation and MPG non-expression were associated with better OS and PFS. However, two ‘exceptional responders’ had PFS ≥11 months, with MGMT methylated and MPG expressed. RNA sequencing of their tumor tissue demonstrated significant enrichment for DNA damage response (DDR) pathways (MSigDB), chromosomal instability gene signatures (CIN70, CIN25), and proliferative gene signatures (PCNA25).

Conclusion: rGBM patients with elevated levels of MPG and DDR molecular signature may have impaired BER and respond better to TRC102+TMZ.